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1 ICRP ref 4838-2850-7665 2 20 September 2012 3 4 5

6 Annals of the ICRP 7 8 ICRP PUBLICATION XXX 9 10

11 Occupational Intakes of

12 Part 2 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 DRAFT DOCUMENT 37 38 Information in this consultation document is preliminary. The document should not be cited in any published material in 39 advance of final approval for publication by the Commission of ICRP. 40

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41 42 Occupational Intakes of Radionuclides 43 Part 2 44 45 ICRP Publication XXX 46 47 Approved by the Commission in 20XX

48

49 Abstract- The 2007 Recommendations (Publication 103, ICRP, 2007) introduced changes to 50 the radiation and tissue weighting factors used in calculation of effective dose. In addition, 51 Publication 103 clarified the need for separate calculation of equivalent dose to males and 52 females and sex-averaging in the calculation of effective dose (ICRP, 2007) and adopted the 53 use of reference anatomical computational phantoms, in place of the composite mathematical 54 models that have been used previously. 55 These substantial changes implied a revision of the dose coefficients for internal exposure, 56 published previously in the Publication 30 series (ICRP, 1979, 1980, 1981, 1988b). This 57 work was performed by Committee 2 and its Task Groups INDOS and DOCAL. 58 This report is the second in a series of documents replacing the Publication 30 series and 59 Publication 68 (ICRP, 1994b) and providing revised dose coefficients for occupational 60 intakes of radionuclides (OIR) by inhalation and ingestion. It provides data on individual 61 elements and their radioisotopes, including biokinetic data and models, dose coefficients and 62 data for bioassay interpretation. Electronic discs accompanying this series give extensive 63 additional information. 64 This second report in the series provides the above data for the following elements : 65 (H), (C), (P), Sulphur (S), (Ca), (Fe), 66 (Co), (Zn), (Sr), (Y), (Zr), (Nb), 67 (Mo) and (Tc). 68 The current version, posted for public consultation, contains only the biokinetic data and 69 the models. The total set of dose coefficients and data for bioassay interpretation will be 70 included in the final version. 71 © 201X ICRP. Published by Elsevier Ltd. 72 73 Keywords: Occupational exposure, Internal Dose Assessment, Biokinetic and Dosimetric 74 models, Bioassays interpretation. 75

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76 77 CONTENTS

78 PREFACE ...... 7

79 1. INTRODUCTION ...... 9

80 2. HYDROGEN (Z = 1) ...... 12 81 2.1. CHEMICAL FORMS IN THE WORKPLACE ...... 12 82 2.2. ROUTES OF INTAKE ...... 12 83 2.2.1. INHALATION ...... 12 84 2.2.2. INGESTION ...... 18 85 2.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 19 86 2.2.3.1. Summary of the database ...... 19 87 2.2.3.2. Biokinetic models for systemic tritium ...... 22 88 2.3. INDIVIDUAL MONITORING ...... 26

89 3. CARBON (Z = 6) ...... 31 90 3.1. CHEMICAL FORMS IN THE WORKPLACE ...... 31 91 3.2. ROUTES OF INTAKE ...... 31 92 3.2.1. INHALATION ...... 31 93 3.2.2. INGESTION ...... 38 94 3.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 38 95 3.2.3.1. Examples of published biokinetic models for systemic carbon ...... 41 96 3.2.3.2. Biokinetic models for systemic carbon used in this report ...... 45 97 3.3. INDIVIDUAL MONITORING ...... 50

98 4. PHOSPHORUS (Z = 15) ...... 55 99 4.1. CHEMICAL FORMS IN THE WORKPLACE ...... 55 100 4.2. ROUTES OF INTAKE ...... 55 101 4.2.1. INHALATION ...... 55 102 4.2.2. INGESTION ...... 57 103 4.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 57 104 4.2.3.1. Summary of the database ...... 57 105 4.2.3.2. Biokinetic model for systemic phosphorus ...... 59 106 4.3. INDIVIDUAL MONITORING ...... 61

107 5. SULPHUR (Z = 16) ...... 64 108 5.1. CHEMICAL FORMS IN THE WORKPLACE ...... 64 109 5.2. ROUTES OF INTAKE ...... 64 110 5.2.1. INHALATION ...... 64 111 5.2.2. INGESTION ...... 68 112 5.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 68 113 5.2.3.1. Inorganic sulphur ...... 68 114 5.2.3.2. Gaseous inorganic compounds ...... 69 115 5.2.3.3. Generic model for inorganic sulphur ...... 69 116 5.2.3.4. Organic compounds of sulphur ...... 71 117 5.2.3.5. Treatment of radioactive progeny ...... 72 118 5.2.3.6. Gender-related differences in biokinetics ...... 72 119 5.3. INDIVIDUAL MONITORING ...... 73

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120 6. CALCIUM (Z = 20) ...... 75 121 6.1. CHEMICAL FORMS IN THE WORKPLACE ...... 75 122 6.2. ROUTES OF INTAKE ...... 75 123 6.2.1. INHALATION ...... 75 124 6.2.2. INGESTION ...... 76 125 6.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 77 126 6.2.3.1. Summary of the database ...... 77 127 6.2.3.2. Biokinetic model for systemic calcium ...... 77 128 6.2.3.3. Treatment of radioactive progeny ...... 81 129 6.3. INDIVIDUAL MONITORING ...... 83

130 7. IRON (Z = 26) ...... 88 131 7.1. CHEMICAL FORMS IN THE WORKPLACE ...... 88 132 7.2. ROUTES OF INTAKE ...... 88 133 7.2.1. INHALATION ...... 88 134 7.2.2. INGESTION ...... 91 135 7.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 92 136 7.2.3.1. Overview of normal iron metabolism ...... 92 137 7.2.3.2. Biokinetic model for systemic iron ...... 94 138 7.2.3.3. Treatment of radioactive progeny ...... 96 139 7.2.3.4. Differences with gender ...... 98 140 7.3. INDIVIDUAL MONITORING ...... 98

141 8. COBALT (Z = 27) ...... 102 142 8.1. CHEMICAL FORMS IN THE WORKPLACE ...... 102 143 8.2. ROUTES OF INTAKE ...... 102 144 8.2.1. INHALATION ...... 102 145 8.2.2. INGESTION ...... 109 146 8.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 110 147 8.2.3.1. Summary of the database ...... 110 148 8.2.3.2. Biokinetic model for systemic cobalt ...... 113 149 8.2.3.3. Treatment of radioactive progeny ...... 116 150 8.3. INDIVIDUAL MONITORING ...... 116

151 9. ZINC (Z = 30) ...... 121 152 9.1. CHEMICAL FORMS IN THE WORKPLACE ...... 121 153 9.2. ROUTES OF INTAKE ...... 121 154 9.2.1. INHALATION ...... 121 155 9.2.2. INGESTION ...... 123 156 9.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 124 157 9.2.3.1. Overview of zinc biokinetics and balance in adult humans ...... 124 158 9.2.3.2. Biokinetic model for systemic zinc ...... 131 159 9.2.3.3. Treatment of radioactive progeny ...... 134 160 9.3. INDIVIDUAL MONITORING ...... 135

161 10. STRONTIUM (Z = 38) ...... 141 162 10.1. CHEMICAL FORMS IN THE WORKPLACE ...... 141 163 10.2. ROUTES OF INTAKE ...... 141 164 10.2.1. INHALATION ...... 141

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165 10.2.2. INGESTION ...... 144 166 10.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 146 167 10.2.3.1. Summary of the database ...... 146 168 10.2.3.2. Biokinetic model for systemic strontium ...... 146 169 10.2.3.3. Treatment of radioactive progeny ...... 151 170 10.3. INDIVIDUAL MONITORING ...... 152

171 11. YTTRIUM (Z = 39) ...... 158 172 11.1. ROUTES OF INTAKE ...... 158 173 11.1.1. INHALATION ...... 158 174 11.1.2. INGESTION ...... 162 175 11.1.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 163 176 11.1.3.1. Summary of the database ...... 163 177 11.1.3.2. Biokinetic model for systemic yttrium ...... 166 178 11.1.3.3. Treatment of radioactive progeny ...... 167 179 11.2. INDIVIDUAL MONITORING ...... 170

180 12. ZIRCONIUM (Z = 40) ...... 174 181 12.1. CHEMICAL FORMS IN THE WORKPLACE ...... 174 182 12.2. ROUTES OF INTAKE ...... 174 183 12.2.1. INHALATION ...... 174 184 12.2.2. INGESTION ...... 178 185 12.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 179 186 12.2.3.1. Summary of the database ...... 179 187 12.2.3.2. Biokinetic model for systemic zirconium ...... 181 188 12.2.3.3. Treatment of radioactive progeny ...... 184 189 12.3. INDIVIDUAL MONITORING ...... 184

190 13. NIOBIUM (Z = 41) ...... 187 191 13.1. CHEMICAL FORMS IN THE WORKPLACE ...... 187 192 13.2. ROUTES OF INTAKE ...... 187 193 13.2.1. INHALATION ...... 187 194 13.2.2. INGESTION ...... 191 195 13.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 192 196 13.2.3.1. Summary of the database ...... 192 197 13.2.3.2. Biokinetic model for systemic niobium ...... 194 198 13.2.3.3. Treatment of radioactive progeny ...... 197 199 13.3. INDIVIDUAL MONITORING ...... 197

200 14. MOLYBDENUM (Z = 42) ...... 200 201 14.1. CHEMICALS FORMS IN THE WORKPLACE ...... 200 202 14.2. ROUTES OF INTAKE ...... 200 203 14.2.1. INHALATION ...... 200 204 14.2.2. INGESTION ...... 202 205 14.2.3. BIOKINETICS OF SYSTEMIC MOLYBDENUM ...... 203 206 14.2.3.1. Summary of the database ...... 203 207 14.2.3.2. Biokinetic model for systemic molybdenum ...... 205 208 14.2.3.3. Treatment of radioactive progeny ...... 209 209 14.3. INDIVIDUAL MONITORING ...... 210

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210 15. TECHNETIUM (Z = 43) ...... 213 211 15.1. CHEMICAL FORMS IN THE WORKPLACE ...... 213 212 15.2. ROUTES OF INTAKE ...... 213 213 15.2.1. INHALATION ...... 213 214 15.2.2. INGESTION ...... 217 215 15.2.3. SYSTEMIC DISTRIBUTION, RETENTION AND EXCRETION ...... 217 216 15.2.3.1. Summary of the database ...... 217 217 15.2.3.2. Biokinetic model for systemic technetium ...... 223 218 15.2.3.3. Treatment of radioactive progeny ...... 226 219 15.3. INDIVIDUAL MONITORING ...... 227 220 221

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222

223 PREFACE 224 225 The 2007 Recommendations (Publication 103, ICRP, 2007) introduced changes to the 226 radiation weighting factors used in the calculation of equivalent dose to organs and tissues 227 and also changes to the tissue weighting factors used in the calculation of effective dose. In 228 addition, an important development was the adoption of reference anatomical computational 229 phantoms, in place of the composite mathematical models that have been used for all 230 previous calculations of organ doses. Publication 103 also clarified the need for separate 231 calculation of equivalent dose to males and females and sex-averaging in the calculation of 232 effective dose (ICRP, 2007). 233 These changes implied a revision of the dose coefficients initially provided in the 234 Publication 30 series (ICRP, 1979, 1980, 1981, 1988b). This work was performed by 235 Committee 2 and its Task Groups INDOS and DOCAL. 236 This report is the second in a series of documents replacing the Publication 30 series and 237 Publication 68 (ICRP, 1994b) and providing revised dose coefficients for occupational 238 intakes of radionuclides (OIR) by inhalation and ingestion. It provides also - 239 specific information for the design and planning of monitoring programmes and retrospective 240 assessment of occupational internal doses, replacing Publications 54 and 78 (ICRP, 1988a, 241 1997b). 242 The first report of this OIR series included chapters describing the control of occupational 243 exposures, biokinetic and dosimetric models, monitoring methods, monitoring programmes 244 and retrospective dose assessment. 245 The following reports provide data on individual elements and their radioisotopes, 246 including biokinetic data and models, dose coefficients and data for bioassay interpretation. 247 Electronic discs accompanying this series give extensive additional information. 248 This second report in the series provides the above data for the following elements : 249 Hydrogen (H), Carbon (C), Phosphorus (P), Sulphur (S), Calcium (Ca), Iron (Fe), Cobalt 250 (Co), Zinc (Zn), Strontium (Sr), Yttrium (Y), Zirconium (Zr), Niobium (Nb), Molybdenum 251 (Mo) and Technetium (Tc). 252 Subsequent reports will provide data for the other elements. 253 The current version, posted for public consultation, contains only the biokinetic data and 254 the models. The total set of dose coefficients and data for bioassay interpretation will be 255 included in the final version. 256 257 The membership of the Task on Internal Dosimetry (INDOS) at the time of the 258 completion of this report was: 259 260 Members: 261 F Paquet (Chair) G Etherington J L Lipsztein 262 E Ansoborlo A Giussani D Melo 263 M R Bailey R A Guilmette 264 E J A Blanchardon J D Harrison 265 H Doerfel R W Leggett 266 267 Corresponding Members: 268 A Bouville A Luciani D Whillans 269 C-M Castellani D Newton

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270 R Cruz-Suarez D Nosske 271 C Hurtgen D M Taylor 272 273 The membership of the Task Group on Dose Calculations (DOCAL) at the time of the 274 completion of this report was: 275 276 Members: 277 W E Bolch (Chair) A Endo N Ishigure 278 M Zankl V Berkovski T P Fell 279 D Nosske L Bertelli N E Hertel 280 N Petoussi-Henss K F Eckerman J G S Hunt 281 M Pelliccioni 282 283 Corresponding Members: 284 A Birchall H Schlattl 285 G Gualdrini M Stabin 286 D Jokisch R Tanner 287 C Lee X G Xu 288 289 The membership of Committee 2 was: 290 291 (2009-2013) 292 H-G Menzel (Chair) W E Bolch J D Harrison 293 F Paquet M R Bailey R Cox 294 N Ishigure N Petoussi-Henss M Balonov 295 G Dietze R W Leggett A S Pradhan 296 D Bartlett K F Eckerman J L Lipsztein 297 V Berkovski A Endo J Ma 298 299

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300

301 1. INTRODUCTION 302 303 (1) The present report is Part 2 of a report series aimed at providing revised dose 304 coefficients for occupational intakes of radionuclides (OIR) by inhalation and ingestion. It 305 also presents radionuclide-specific information for the design and planning of monitoring 306 programmes and retrospective assessment of occupational internal doses. 307 (2) This report series replaces the Publication 30 series (ICRP, 1979, 1980, 1981, 308 1988b), Publications 54, 68 and 78 (ICRP, 1988a, 1994b, 1997). The revised dose 309 coefficients, dose per unit content values and reference bioassay functions have been 310 calculated using the Publication 100 (ICRP, 2006) Human Alimentary Tract Model (HATM) 311 and a revision of the Publication 66 (ICRP, 1994a) Human Respiratory Tract Model (HRTM) 312 which takes account of more recent data. The revisions made to the HRTM are described in 313 Part 1 of this report series. In addition, information is provided in this report series on 314 absorption to blood following inhalation and ingestion of different chemical forms of 315 elements and their radioisotopes, in those cases for which it is currently judged that the data 316 are sufficient to make specific recommendations. Revisions have been made to many models 317 for the systemic biokinetics of radionuclides, making them more physiologically realistic 318 representations of uptake and retention in organs and tissues and of excretion. 1 319 (3) The dose coefficients and dose per unit content values presented in this report series 3 -1 320 are given for a Reference Worker with an average breathing rate of 1.2 m h during an 8 h 321 working day. These data are provided for a range of physico-chemical forms for each 322 radionuclide and for a range of aerosol particle size distributions. Data for ingestion and 323 injection (i.e. direct entry to the blood) are provided to allow the interpretation of bioassay 324 data for cases of inadvertent ingestion (e.g. of material on contaminated skin) or rapid 325 absorption through intact or damaged skin (injection). 326 (4) Data are presented in a standard format for each element and its radioisotopes. Each 327 element section provides information on chemical forms encountered in the workplace; 328 principal radioisotopes, their physical half-lives and decay modes; reviews of data on 329 inhalation, ingestion and systemic biokinetics; the structure and parameter values for the 330 systemic biokinetic model; and information on the interpretation of individual monitoring 331 data. Each section in the printed documents also includes tables of: 332 333 • Dose coefficients (committed effective dose, Sv, per Bq intake) for inhalation of 5 334 µm AMAD aerosols with the default absorption Types appropriate for the 335 element, for all relevant radioisotopes; 336 • Principal emissions of selected radioisotopes; 337 • Measurement techniques, detection limits typically achieved in a practical 338 monitoring programme, and improved detection limits that could be achieved by 339 suitable choice of measurement parameter values, for selected radioisotopes; 340 • Committed effective dose (Sv) per unit measurement (Bq) for an acute intake by 341 inhalation of a 5 µm AMAD aerosol with the default absorption Types appropriate 342 for the element, for selected radioisotopes;

1 The current version, posted for public consultation, contains only the biokinetic data and the models. The total set of dose coefficients and data for bioassay interpretation will be included in the final version

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343 • Bioassay data (i.e. whole body and/or organ retention, and daily urinary and faecal 344 excretion, Bq per Bq intake), at various times after an acute intake by inhalation of 345 a 5 µm AMAD aerosol with the default absorption Types appropriate for the 346 element; 347 348 (5) Bioassay data are also presented graphically. 349 (6) In cases for which sufficient information is available, lung absorption is specified for 350 different chemical forms and dose coefficients and bioassay data are calculated accordingly. 351 (7) The full data set of this report is provided on electronic disk. This disk contains in 352 addition to the printed document: 353 354 Dose coefficients 355 • Committed equivalent dose coefficients for organs and tissues, for males and 356 females; 357 • Dose coefficients for all chemical forms considered; 358 • Dose coefficients for an inhaled aerosol with particle sizes ranging from an 359 AMTD of 0.001 µm to an AMAD of 20 µm;

360 • Dose coefficients for intake by ingestion, with the default fA values appropriate for 361 the element, for all relevant radioisotopes; 362 • Dose coefficients for radioisotopes not given in the printed reports in this series. 363 364 Bioassay data 365 • Committed effective dose (Sv) per unit measurement (Bq) for an acute intake by 366 inhalation of an aerosol with particle sizes ranging from an AMTD of 0.001 µm to 367 an AMAD of 20 µm; 368 • Committed effective dose (Sv) per unit measurement (Bq) for an acute intake by 369 ingestion, with default fA values appropriate for the element; 370 • Bioassay data (i.e. whole body and/or organ retention, and daily urinary and faecal 371 excretion, Bq per Bq intake), for an acute intake by inhalation of an aerosol with 372 particle sizes ranging from an AMTD of 0.001 µm to an AMAD of 20 µm; 373 • Similar bioassay data for an acute intake by ingestion –1 374 • Figures giving measured activity content per unit dose (Bq Sv ) in selected body 375 tissues, urine (daily excretion) or faeces (daily excretion), at various times after 376 intake by inhalation or ingestion. These data can also be used to facilitate 377 decisions about the design of monitoring programmes and the extent of the 378 assessment required, as described in Chapter 5 of OIR Part 1. 379 380 (8) The list of elements included in this Part 2 is: Hydrogen (H), Carbon ( C), 381 Phosphorus (P), Sulphur (S), Calcium (Ca), Iron (Fe), Cobalt (Co), Zinc (Zn), Strontium (Sr), 382 Yttrium (Y), Zirconium (Zr), Niobium (Nb), Molybdenum (Mo) and Technetium (Tc). 383 384 References 385

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386 ICRP, 1979. Limits for intake of radionuclides by workers. ICRP Publication 30, Part 1. Ann. ICRP 387 2(3/4). 388 ICRP, 1980. Limits for intakes of radionuclides by workers. ICRP Publication 30, Part 2. Ann. ICRP 389 4(3/4). 390 ICRP, 1981. Limits for intakes of radionuclides by workers. ICRP Publication 30, Part 3. Ann. ICRP 391 6 (2/3). 392 ICRP, 1988a. Individual monitoring for intakes of radionuclides by workers: design and 393 interpretation. ICRP Publication 54, Ann. ICRP 19 (1-3). 394 ICRP, 1988b. Limits for intakes of radionuclides by workers: An Addendum. ICRP Publication 30, 395 Part 4. Ann. ICRP 19 (4). 396 ICRP, 1994a. Human respiratory tract model for radiological protection. ICRP Publication 66. Ann. 397 ICRP 24 (1-3). 398 ICRP, 1994b. Dose coefficients for intake of radionuclides by workers. ICRP Publication 68. Ann. 399 ICRP 24 (4). 400 ICRP, 1997. Individual monitoring for internal exposure of workers – Replacement of ICRP 401 Publication 54. ICRP Publication 78. Ann. ICRP 27 (3/4). 402 ICRP, 2006. Human alimentary tract model for radiological protection. ICRP Publication 100. Ann. 403 ICRP 36 (1-2). 404 ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological 405 Protection. ICRP Publication 103. Ann. ICRP 37 (2-4). 406

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407

408 2. HYDROGEN (Z = 1) 409 410 411 2.1. Chemical Forms in the Workplace 412 413 (9) Hydrogen is a non-metallic element which occurs mainly in oxidation states –I and I. 3 414 Hydrogen is able to react chemically with most other elements. Tritium ( H, for convenience 415 the symbol ‘T’ is often used in this section) is a radioactive of hydrogen. It is found in 416 industry in a variety of chemical forms, including hydrogen gas (elemental tritium), tritiated 417 water, methane, metal tritide, luminizing compounds and tritium-contaminated pump oils. It 418 is also present in a wide variety of organic compounds used in research, including DNA 3 419 precursors such as [6- H]-thymidine (Rudran, 1988a; Taylor et al., 1990; Hill and Johnson, 420 1993). Tritium is an important fuel for controlled nuclear fusion in both magnetic and inertial 421 confinement fusion reactor designs. 422 423 Table 2-1. of hydrogen addressed in this report 424 Isotope Physical half-life Decay mode H-3 12.32 y Beta 425 426 2.2. Routes of Intake 427 428 2.2.1. Inhalation 429 430 (10) Extensive information is available from occupational exposures, and from human 431 volunteer studies with inhaled tritium gas and tritiated water. Information is also available 432 from experimental studies of tritiated organic compounds and particulate forms (mainly metal 433 tritides and luminous compounds), in rats and in vitro. 434 435 Classification of gases and vapours, absorption Types and parameter values 436 437 (11) Absorption parameter values and Types, and associated fA values for gas and vapour 438 forms of hydrogen (tritium) are given in Table 2-2 and for particulate forms in Table 2-3. 439 Exposures to gas or vapour forms of tritium are more common than exposures to particulate 440 forms, and it is therefore proposed by the Task group that gas/vapour form should be 441 assumed in the absence of information. 442 443 (a) Gases and vapours 444 445 Tritiated water (HTO) 446 (12) Pinson and Langham (1957) demonstrated that inhaled HTO is translocated to blood 447 almost completely and instantaneously, and then distributes uniformly throughout the body 448 without changing chemical form. For HTO it is therefore assumed here that there is 100% 449 deposition in the respiratory tract, with instantaneous (Type V) absorption. Note that 450 absorption through skin can add significantly to uptake during unprotected exposure to HTO 451 in the air. Uptake through skin is not included in the inhalation dose coefficient, but 452 employers may wish to take account of it for workplace control. Furthermore, urine bioassay

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453 measurements, which are the basis for most tritium dose assessments, represent the body 454 water concentration from all routes of intake, and therefore do take it into account. 455 456 Tritium gas (elemental tritium, HT) 457 (13) Publication 30 (ICRP, 1979) identified tritium in the form of hydrogen gas as one of 37 458 two gases (the other being Ar) and for which exposure is dominated by irradiation of the 459 lung (rather than the skin), because the emissions have insufficient energy to reach the basal 460 layer of the skin. However, as described in Publication 68, Annex A (ICRP 1994), on the 461 assumption that 0.01% of inhaled HT is absorbed and converted to HTO (see below) the 462 effective dose per unit intake from absorbed HT is several times higher than that due to 463 irradiation of the lung from gas within it. That conclusion remains applicable, and therefore 464 dose coefficients are calculated here for tritium in the form of hydrogen gas, based on its 465 absorption. 466 (14) Studies in which human volunteers inhaled tritium gas (composed of 93% HT) 467 showed that ~1% of the inhaled HT dissolved in body fluids and tissues, and that ~1% of the 468 dissolved HT (i.e. ~0.01% of the inhaled HT) was subsequently converted to HTO in the gut 469 and the rest exhaled (Peterman et al., 1985a,b). For further information see Section 1.3.4. 470 These results appear to accord with the data of Pinson and Langham (1957). For HT it is 471 therefore assumed here that there is 0.01% effective deposition in the respiratory tract with 472 instantaneous (Type V) absorption and conversion to HTO. It should be noted that in 473 occupational exposure conditions HT in air is always accompanied by HTO vapour, and the 474 latter dominates with regard to human exposure. 475 476 Tritiated methane, CH4–xTx 477 (15) The dosimetric implications of inhaling methane gas were examined by Phipps et al. 478 (1990). They made the conservative assumption that 1% of the methane was metabolized, 479 based on observations by Dougherty et al. (1967) which indicated that approximately 0.3% of 480 methane infused into sheep was converted to carbon dioxide. Carlisle et al. (2005) 3 14 481 investigated the extent of oxidation and organic fixation of H and C following inhalation of 3 14 482 H-labelled and/or C-labelled methane by rats. A pilot study examined retention of activity 483 in skin, liver, brain and carcass at 1 and 24 hours after a 4-hour exposure. It was estimated 3 484 that uptake was about 0.13% of intake based on retention of H in liver and 0.06% of intake 3 3 485 based on retention of H in the other tissues. About 70% of H retained in liver and 10% of 3 486 H retained in other tissues was organically bound. For tritiated methane it is assumed here 487 that there is 0.1% effective deposition in the respiratory tract with instantaneous (Type V) 488 absorption. It is also assumed here that the absorbed tritium follows the systemic model for 489 HTO. 490 491 Unspecified organic forms 492 (16) Volatile organic compounds have a wide range of solubility in body fluids (see 493 Carbon Section). Therefore, in the absence of specific information, the default option for 494 gases and vapours is taken, which is likely to be conservative. For tritium in unspecified 495 organic forms it is assumed here that there is 100% deposition in the respiratory tract (with 496 default regional distribution, Table 2-2) and Type F absorption. It is also assumed here that 497 the absorbed tritium follows the systemic model for (Organically Bound Tritium) OBT. 498 499 Unspecified tritium gases and vapours 500 (17) Other volatile tritiated compounds have a wide range of solubility in body fluids. 501 Therefore, in the absence of specific information, the default option for gases and vapours is

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502 taken. For tritium in unspecified gas and vapour form it is assumed here that there is 100% 503 deposition in the respiratory tract (with default regional distribution, Table 2-2) and Type F 504 absorption. It is also assumed here that the absorbed tritium follows the systemic model for 505 HTO. 506 507 (b) Particulate materials (liquid and solid) 508 509 (18) Tritium can be released into the work environment in particulate form, and several 510 studies of the dissolution of solid tritiated compounds have been conducted. See the Carbon 511 Section for information on organic compounds, much of which would be applicable to tritium 512 present in such forms. However, dose coefficients and bioassay functions are not given in 513 most cases, because the systemic behaviour of the carbon is specific to the chemical form on 514 intake. 515 (19) Because of the low energy of the tritium beta emissions, self-absorption within 516 particles can significantly reduce doses, even for particles as small as 1 μm diameter. Kropf et 517 al. (1998) calculated that (for tritide, ErT3-x) the fraction of beta energy that escapes 518 was in the range 0.5–0.1 for particle diameters in the range 1–5 μm. 519 (20) Cheng et al. (1997), Inkret et al. (2001) and Zhou and Cheng (2003) demonstrated 520 that tritium is released from metal tritides into simulated lung fluids as HTO. It is assumed 521 here that for inhalation of inorganic particulate material, the biokinetics of tritium absorbed 522 into body fluids follows that of HTO. 523 524 Tritium-contaminated glass 525 (21) Cool and Maillie (1983) followed loss of tritium into simulated lung fluid, from 526 fragments of tritium-filled glass microballoons used in laser fusion research, for 150 days. 527 The fraction of total tritium lost during the first 100 days ranged between 16% and 30% for 528 different glass samples. Dissolution kinetics were reported as the fraction lost per day, which 529 decreased from about 2% initially to about 0.04% at 100 days. Average parameter values –1 –1 530 calculated here were fr ~0.2, sr ~0.1 d and ss ~0.0002 d , consistent with assignment to 531 Type M. Cool and Maillie (1984) followed the tissue distribution and excretion of tritium for 532 80 and 180 days respectively following intratracheal instillation into rats of fragments of 533 tritium-labelled glass microballoons. There is insufficient information given for absorption 534 parameter values to be estimated here. However, the authors reported that results obtained in 535 vivo were in good agreement with the in vitro data obtained from the same type of glass. A 536 large percentage of the tritium present in the glass matrix at the start of the experiments 537 remained with it. The main difference was that generally, a greater proportion of the tritium 538 was associated with the slower phase of tritium dissolution in vivo than in vitro. The uniform 539 distribution of tritium activity found within the various soft tissues of the body was consistent 540 with the hypothesis that tritium lost from the glass matrix is converted to HTO. 541 542 Luminous paint 543 (22) Balonov et al. (1984, 1995) reported that following intratracheal instillation into rats 544 of “Soviet luminous powder (PS-A)” the lung specific activity showed essentially no 545 decrease within 5 months, and hence should be assigned to ICRP Publication 30 Class Y. 546 This indicates that such compounds should be assigned to Type M or S. 547 (23) Results of 5-day in vitro studies of the dissolution in bovine serum of samples of 548 commercial luminous paint powder made from tritium-labelled polystyrene (Rudran, 1988a) 549 were described as on average 12% dissolved on the first day, and about 2% of remaining –1 –1 550 activity on subsequent days, i.e. fr ~0.12, sr >1 d and ss ~0.02 d , consistent with

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551 assignment to Type M. 552 553 tritide 554 (24) Balonov et al. (1984, 1995) reported that, following inhalation by rats, titanium 555 tritide (TiT) showed slow lung clearance, and hence should be assigned to ICRP Publication 556 30 Class Y. This indicates that TiT should be assigned to Type M or S. 557 (25) Measurements were made up to 4 months after intratracheal instillation of TiT (1- 558 μm count median diameter, CMD) into rats, and simulation modelling was applied to obtain a 559 time-dependent absorption function (fractional absorption rate) (Cheng et al., 1999). Fitting –1 560 the HRTM dissolution model to the data gave parameter values: fr = 0.6, sr = 0.71 d and ss = –1 561 0.0002 d with an upper bound on fA of 0.6 (Cheng, 2009) consistent with assignment to 562 Type M. Results of a 30-day in vitro study of the dissolution of the same powder in synthetic 563 serum ultrafiltrate (SUF) (Cheng et al., 1997) were expressed as a two-component –1 –1 564 exponential retention function, giving fr = 0.24, sr = 0.71 d , ss = 0.021 d . This dissolution 565 rate is broadly similar to the absorption rate in vivo, (initially lower, but higher after a few 566 days), and also consistent with assignment to Type M. Dissolution in the same system of a 567 sample of coarse dust (103-μm CMD) was much slower, but still consistent with assignment 568 to Type M. The results indicated that loss of tritium was related to diffusion and hence 569 increases with the specific surface area of the particles. Although specific parameter values 570 for titanium tritide based on in vivo data are available, they are not adopted here, because 571 inhalation exposure to it is unlikely. Instead, titanium tritide is assigned to Type M. 572 573 Zirconium tritide 574 (26) Measurements were made up to 6 months after intratracheal instillation of zirconium 575 tritide (0.3-μm CMD) into rats, and simulation modelling was applied to obtain a fractional 576 absorption rate (Zhou and Cheng, 2004). Fitting the HRTM dissolution model to the data -1 –4 –1 577 gave parameter values: fr = 0.0995, sr = 0.058 d and ss = 3.9x10 d with an upper bound 578 on fA of 0.1 (Zhou et al., 2010), consistent with assignment to Type M. Results of 200-day in 579 vitro studies of the dissolution in SUF of the same powder (Zhou and Cheng, 2004) were –1 580 expressed as a two-component exponential retention function, with fr = 0.048, sr = 0.016 d –3 –1 581 and ss = 1.8x10 d . This dissolution is somewhat faster than the absorption in vivo, but also 582 consistent with assignment to Type M. Although specific parameter values for zirconium 583 tritide based on in vivo data are available, they are not adopted here, because inhalation 584 exposure to it is unlikely. Instead, zirconium tritide is assigned to Type M. 585 586 Carbon tritide 587 (27) The results of a 110-day in vitro study of the dissolution in SUF of carbon tritide (1- 588 μm CMD) samples taken from a test fusion reactor were expressed as a fractional absorption 589 rate (Cheng et al., 2002a). Fitting the HRTM dissolution model to the data gave parameter –1 –4 –1 590 values: fr = 0.035, sr = 0.396 d and ss = 3.72x10 d (Cheng 2009), consistent with 591 assignment to Type S. 592 (28) The results of a 14-day in vitro study of the dissolution in serum simulant of 593 “coarse” and “fine” tritium loaded carbon particles taken from another test fusion reactor 594 were expressed as two-component exponential retention functions (Hodgson et al., 2004). For –1 –3 –1 595 “coarse” particles fr = 0.05, sr = 500 d and ss = 6.3x10 d , giving assignment to Type M. –1 –4 –1 596 For “fine” particles fr = 0.003, sr = 500 d and ss = 3.6x10 d , giving assignment to Type S. 597 Hodgson et al. (2006, 2007) measured dissolution in serum simulant of three samples from 598 two batches of tritium loaded carbon particles from the same reactor for 100 days. Retention 599 of undissolved tritium was expressed as a three-component exponential function. (To take

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600 account of the three components in software that implements the HRTM with only two, dose 601 coefficients were calculated by treating each sample as a mixture of two materials.) For one 602 batch, results for two samples gave assignment to Type M and the third to Type S. For the 603 other batch, results for all three samples gave assignment to Type S. 604 (29) Specific values are not adopted here (Table 2-3), because only in vitro data are 605 available. 606 607 tritide 608 (30) Measurements were made up to 6 months after intratracheal instillation of hafnium 609 tritide (1-μm CMD) into rats, and simulation modelling was applied to obtain a fractional 610 absorption rate (Zhou and Cheng, 2003). Fitting the HRTM dissolution model to the data –4 –1 –5 –1 611 gave parameter values: fr = 3.07x10 , sr = 2.72 d and ss = 1.22x10 d with an upper –4 612 bound on fA of 3.07x10 (Cheng 2009), consistent with assignment to Type S. Results of 613 200-day in vitro studies of the dissolution in SUF of similar powders (Inkret et al., 2001; 614 Cheng et al., 2002b) were expressed as two-component exponential retention functions, with –3 –1 –6 –1 615 fr ~1x10 , sr ~0.015 d and ss ~2.5x10 d . This dissolution is broadly similar to the 616 absorption in vivo, (initially lower, but higher after a few days), and also consistent with 617 assignment to Type S. Although specific parameter values for hafnium tritide based on in 618 vivo data are available, they are not adopted here, because inhalation exposure to it is 619 unlikely. Instead, hafnium tritide is assigned to Type S. 620 621 Rapid dissolution rate for tritium 622 (31) Although no measurements were found for Type F particulate forms, the evidence of 623 rapid uptake of tritiated gases from the lung indicates a rapid rate of absorption of order 100 –1 –1 624 d . A value of 100 d is applied here to all Type F forms of hydrogen. 625 626 Extent of binding of tritium to the respiratory tract 627 (32) The evidence of rapid uptake of tritiated gases from the lung indicates that that there 628 is probably little binding of tritium. It is therefore assumed that for tritium the bound state can 629 be neglected, i.e. fb = 0.0. 630

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631 632 Table 2-2. Deposition and absorption for gas and vapour compounds of hydrogen (tritium)a 633 Percentage depositedb Absorption Systemic c Chemical form/origin Total ET1 ET2 BB bb AI Type fA model Tritiated water (HTO) 100d 0 20 10 20 50 V (f) HTO Tritium gas (HT) 0.01d 0 0.002 0.001 0.002 0.005 V (f) HTO d Tritiated methane (CH4– 0.1 0 0.02 0.01 0.02 0.05 V (f) HTO xTx) Unspecified organic 100e 0 20 10 20 50 F 1.0 OBT forms Unspecifieda 100e 0 20 10 20 50 F 1.0 HTO 634 a For tritium in unspecified gas or vapour form, the default option for gases and vapours is recommended: 635 100% total deposition in the respiratory tract; default distribution between regions (footnote e) and Type F 636 absorption. 637 b Percentage deposited refers to how much of the material in the inhaled air remains behind after exhalation. 638 Almost all inhaled gas molecules contact airway surfaces, but usually return to the air unless they dissolve 639 in, or react with, the surface lining. In the case of tritium gas and methane, a small fraction is absorbed into 640 body fluids and of that, a fraction is metabolised and the rest subsequently exhaled. 641 c HTO = Systemic model for tritiated water, Section 3. OBT = Systemic model for organically bound tritium, 642 which is recommended for prospective use only, and not for interpretation of bioassay data, Section 3. 643 d Since instantaneous absorption to blood is assumed, calculations can be performed assuming direct injection 644 into blood, and the regional deposition does not need to be considered. However, for completeness, the 645 default distribution is assumed (footnote e). e 646 Default distribution between regions (20% ET2, 10% BB, 20% bb and 50% AI). 647 f Not applicable for absorption Type V, because all activity deposited in the respiratory tract is 648 instantaneously absorbed. 649

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650 651 Table 2-3. Absorption parameter values for inhaled particulate forms of tritium and for 652 ingested tritiuma. 653 Absorption parameter Absorption from valuesb the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesc,d Absorption Assigned forms Type F — 1 100 - 1 M Glass fragments; luminous paint; 0.2 3 0.005 0.2 titanium tritide; zirconium tritide; all unspecified compoundse S Carbon tritide; hafnium tritide 0.01 3 1x10-4 0.01

Ingested materials Soluble forms (as assigned to Type F for – – – 1 inhalation) Relatively insoluble forms (Types M and S) – – – 0.1 654 a Following uptake to body fluids, the systemic model for tritiated water is used, Section 3 b 655 It is assumed that for tritium the bound state can be neglected, i.e. fb = 0.0. The value of sr for Type F 656 forms of hydrogen (100 d–1) is element-specific. The values for Types M and S (3 d–1) are the general 657 default values. 658 c Materials (e.g. “Glass fragments”) are listed here where there is sufficient information to assign to a 659 default absorption Type, but not to give specific parameter values (see text). 660 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 661 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 662 absorption Type and the fA value for ingested soluble forms of tritium (1.0). 663 e Default Type M is recommended for use in the absence of specific information, i.e. if the form is 664 unknown, or if the form is known but there is no information available on the absorption of that form 665 from the respiratory tract. 666 667 2.2.2. Ingestion 668 669 Tritiated water (HTO) 670 (33) Investigations in humans have shown that hydrogen in the form of deuterium oxide 671 or tritiated water is rapidly and virtually completely absorbed from the gastrointestinal tract 672 (Pinson and Langham, 1957; Etnier et al., 1984; Travis et al., 1984). 673 674 Organic compounds 3 675 (34) Studies using rodents indicate that about 90% of ingested [ H]-thymidine is 3 676 catabolized into [ H]–thymine in the small intestine and that both compounds pass across the 677 gut by simple diffusion (Lambert and Clifton, 1968). Balonov et al. (1993) showed that 10- 3 3 678 20 % of [ H]-thymidine and 60-100% of [ H]-deoxycytidine are absorbed from the GI tract of 679 rats. For other forms of organic tritium compound, including biochemical substrates 680 absorption of the intact molecule is variable according to the authors; it ranges from about 681 50% for some few specific compounds (Takeda, 1982, 1991; Rochalska and Szot, 1977) to 3 3 3 682 almost 100% for most compounds including [ H]-Cortisol, [ H]-Glucose and [ H]-amino 683 acids (Balonov et al., 1993; Taylor, 2008). 684 (35) Although absorption of organic tritium compounds is likely to vary substantially, it 685 is conservatively assumed here, as in ICRP Publications 30 (1979) and 56 (1989), that

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686 absorption is complete unless specific information is available to indicate otherwise; that is, 687 the default assumption for all organic tritium compounds is that fA= 1. 688 689 Insoluble compounds 690 (36) Insoluble compounds such as metal tritides and luminous compounds are not 691 directly absorbed from the gastro-intestinal tract. In vitro experiments showed that these 692 substances, when in contact with water, gradually release 0.5-5% of the activity which passes 693 into solution in the form of oxide and low molecular organic compounds (Balonov et al., 694 1984). This fraction may then be absorbed and cause a systemic burden. 695 (37) After oral administration of a suspension containing titanium tritide (TiT) particles 696 to rats, the HTO concentration in body water slightly increased during the 1-1.5 days of the 697 residence of TiT in the gastrointestinal tract. Total absorption in these conditions was less 698 than 0.1 (Balonov et al., 1984). 3 699 (38) Following oral administration of [ H]-labeled luminous compounds to rats, less than 700 5 % of the administered activity was absorbed as HTO after dissolution (Balonov et al., 701 1984). Measurements of absorption in cats showed that absorption of tritium from luminous 702 paints depended on the plastic substrate involved, with values of 0.007 for polystyrene, about 703 0.03 for silicone rubber and 0.8 for polyester (Wawerna, 1973; Hill and Johnson, 1993). 704 705 fA values for ingestion 706 (39) For both tritiated water and organic compounds, an fA of 1 is adopted in this report, 707 although it is recognized that absorption may be substantially less than complete in the case 708 of some organic compounds. For metal tritides and luminous paints, the available data -1 709 indicate that an fA value of 1x10 is generally more appropriate. 710 711 2.2.3. Systemic Distribution, Retention and Excretion 712 713 2.2.3.1. Summary of the database 714 715 Tritiated water 716 (40) Tritiated water (HTO) mixes rapidly with total body water after its entry into blood 717 (Pinson and Langham, 1957; Moore, 1962; Balonov et al., 1974). In human subjects the 718 blood tritium concentration stabilized within about an hour after intravenous injection of 719 HTO (Moore, 1962; Balonov et al., 1974). Human studies using deuterium or HTO have 720 confirmed that equilibration of HTO throughout the body water pool is essentially complete 721 within an hour after intake (Balonov et al., 1974; Davies et al., 2001; La Forgia and Withers, 722 2002). 723 (41) A portion of tritium reaching blood as HTO becomes organically bound in the body. 724 Organically bound tritium (OBT) generally has a lower rate of turnover than HTO in body 725 water. The extent of organic binding of tritium reaching blood as HTO and the turnover time 726 of OBT in a given tissue depend on the types of organic molecules that incorporate the 727 tritium atoms (Smith, 1986; Taylor, 1989; Taylor et al., 1990; Konig, 1990). In general, the 728 binding of tritium is greater, but the retention time of bound tritium is shorter, in 729 metabolically active tissues such as liver and intestine than in skin, brain, and other tissues 730 where metabolic activity is less pronounced (Smith, 1986). 731 (42) Measurements on laboratory animals indicate that 1-5% of HTO entering blood 732 becomes incorporated into organic components of tissues (Takeda and Kassida, 1979; 733 Diabaté and Strack, 1993). On the basis of kinetic analysis of urinary excretion data for 734 human subjects following acute intake of HTO (Snyder et al., 1968; Sanders and Reinig,

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735 1968; Lambert et al., 1971; Balonov et al., 1974, 1984; Rudran, 1988b; Trivedi et al., 1997; 736 Trivedi et al., 2000) it is estimated that 0.5-20% of the absorbed tritium may bind to organic 737 components of tissues. Estimates for most subjects fall in the range 0.5-3%. 738 (43) Data from relatively long-term studies of laboratory animals and human subjects 739 exposed to HTO indicate that whole-body retention can be described reasonably well as a 740 sum of three exponential terms (Sanders and Reinig, 1968; NCRP, 1979; Taylor, 2003). 741 These terms presumably represent HTO in body water, tritium incorporated into organic 742 compounds within the tissues, and tritium incorporated into structural tissues. Human data 743 indicate that the removal half-time of HTO in body water ranges from 4-18 days, with an 744 average of about 10 days (Butler and Leroy, 1965). Estimated half-times for the second and 745 third compartments typically are about 30-40 d and a few hundred days, respectively, but 746 depend on the starting and ending times of the observation and subjective distinctions 747 between intermediate and long-term components of retention. Estimated biological half- 748 times of different components of tritium retention data based on studies of human subjects 749 exposed to HTO are summarized in Table 2-4. 750 Table 2-4. Reported biological half-timesa for urinary excretion of tritium by humans exposed to tritiated water, tritium gas, or other inorganic forms of tritium

Number of Reported biological half-time (d) Study subjects Early Intermediate Late Fallot et al., 1957 20 8.5 - - Pinson and Langham, 1957 9 11.3 - - Foy and Schneiden, 1960 10 7.5 - - Richmond et al., 1962 5 9.5 - - Wylie et al., 1963 7 8.5 - - Butler and Leroy, 1965 310 9.5 - - Osborne, 1966 30 10.5 - - Snyder et al., 1968 1 8.7 34 - Sanders and Reinig, 1968 1 6.1 23 344 Minder, 1969 1 ~11 30 139-230 Lambert et al., 1971 1 9.1 36 - Moghissi et al., 1971, 1972 3 - 21-26 280-550 Henry, 1972 1 7.5 63 - Balonov et al., 1974 5 12 39-76 - Rudran, 1988 8 6.0 31-51 87-226 Trivedi et al., 1997 8 8.4 58-104 - a Values listed for groups of subjects are means except where ranges of values are indicated.

751 752 Organic compounds of tritium 753 (44) Tritium taken into the body in organic form may be oxidized and enter the body 754 water as HTO or may be incorporated into the organic constituents of the body without first 755 being converted to HTO. Soluble organic compounds of tritium entering the blood are 756 incorporated into body tissues to an extent that depends on the specific chemical compound 757 and the metabolic activity of the individual tissues. Tritium attached to , sulphur, 758 or phosphorus is in general readily exchangeable with the hydrogen of the body 759 water pool. Tritium bound to carbon normally will be released through enzyme-mediated 760 breakdown of the molecule in which the carbon atom is situated (Smith, 1986). The rate of 761 such breakdown may be rapid for small molecules but slow for carbon-bound tritium 762 incorporated into structural proteins such as collagen, or the phospholipids of some nerve

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763 cells. 764 (45) Animal studies comparing the incorporation of tritium into OBT in body tissues after 765 intakes of HTO and OBT have shown that 3-30 times more OBT is present after intakes of 766 OBT than after intakes of HTO (Rochalska and Szot, 1977; Kirchman et al., 1977; Pietrzak- 767 Flis, 1978; Mewissen et al., 1979; Takeda, 1982, 1991; Takeda et al., 1985; Komatsu et al., 768 1990; Rodgers, 1992). In rats fed HTO, tritiated amino acids, or tritiated DNA/RNA 769 precursors for 22 days, the greatest concentrations of OBT were found after exposure to 770 amino acids with intermediate concentrations found after exposure to DNA/RNA precursors 771 (Takeda, 1991). In rats fed tritiated food or HTO for 5 days, incorporation into OBT was 3 772 times greater for brain and 15–17 times greater for liver and small intestine after ingestion of 773 tritiated food (Rochalska and Szot, 1977). In mice administered HTO or tritium-labeled 774 amino acids in diet for 56 days, the longer-term component of retention, attributable to OBT 775 in tissues, accounted for about 50% of total body activity after administration of amino acids 776 and about 15% after administration of HTO (Rodgers, 1992). 777 (46) There is little information on the biokinetics of many of the tritiated organic 778 compounds that may be encountered in the workplace. Available information indicates that 3 779 tritium retention in the human or animal body after intake of H-labeled substances may vary 780 greatly from one substance to another (Etnier et al., 1984; Rodgers, 1992; Richardson and 781 Dunford, 2003a; Taylor, 2008). Dietary components that provide energy (e.g. fats and 782 carbohydrates) are oxidized to HTO within hours of intake, and their hydrogen atoms follow 783 the clearance of HTO. 784 (47) Hunt et al. (2009) estimated total-body retention half-times of tritium in the range 4- 785 11 d in five volunteers who ate fish taken from waters containing elevated levels of OBT 786 discharged from a facility where tritium was handled. There was no indication of a significant 787 long-term component of retention of tritium. 788 (48) On the basis of a review of the biokinetics of 11 xenobiotic tritiated organic 789 compounds, Taylor (2008) estimated that the clearance half-time was less than 40 d in all 790 cases. Some organic compounds may be incorporated directly into structural components and 791 retained for much longer times. 792 793 Elemental tritium 794 (49) About 1-2% of inhaled tritium gas (HT) is dissolved in the blood and body fluids 795 and the rest is exhaled rapidly (Pinson and Langham, 1957; Peterman et al., 1985b). 796 Experimental studies by Pinson and Langham (1957) showed that rats and man slowly 797 oxidize the retained HT to HTO. The rate of oxidation in the rat was about 50 times faster 798 than in man. Conversion from HT to HTO presumably results from microbial action in the 799 large intestine, since mammalian tissues do not contain the hydrogenase enzyme necessary 800 for the conversion of HT to HTO (Ichimasa et al., 1988). 801 (50) Pinson and Langham (1957) found that equivalent rates of appearance of tritium in 802 body fluids of man following inhalation of HT and HTO occurred when the specific activity 803 of HT in ambient air was about 15,000 times that of HTO. This indicates that about 0.007% 804 of the inhaled HT ultimately was converted in vivo to HTO. Peterman et al. (1985a) repeated 805 the experiments of Pinson and Langham (1957) with a larger group of human subjects and 806 obtained reasonably consistent results. 807

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808 Some other studied forms of tritium 809 (51) Results of in vitro studies by Cheng et al. (1997), Inkret et al. (2001), and Zhou and 810 Cheng (2003) indicate that tritium is released from metal tritides into simulated lung fluids as 811 HTO. 812 (52) Eakins et al. (1975) studied the rate of urinary excretion of tritium in human 813 volunteers whose skin had been exposed by contact with tritium-gas contaminated surfaces. 814 Over the first several days the main form of tritium in urine was OBT, which was excreted in 815 a biphasic pattern with half-times of ~0.2 days (range, 0.1-0.3 d) and 1.7 d (range, 1.1-1.9 d). 816 The concentration of HTO in urine declined with a half-time of ~10 days. At the peak of 817 OBT excretion, which occurred about 24 hours after the exposure, the concentration of OBT 818 was more than 100 times greater than that of HTO. Similar results were observed for 819 exposures to different areas of the skin and from various contaminated metal and glass 820 surfaces. From experimental studies with similarly exposed rats, the distribution of OBT is 821 known to be non-uniform, with the maximum concentration in the skin at the point of contact 822 (Trivedi, 1993). 823 (53) Trivedi (1995) studied the percutaneous absorption and systemic biokinetics of 824 tritium-gas contaminated pump oil in male hairless rats. Skin-contact exposure with the pump 825 oil resulted in uptake of OBT and HTO to blood. The systemic biokinetics indicated that 826 absorbed tritium was mainly in the form of OBT, most of which was transferred from the 827 skin with a half-time of 1.7 d. A second, long-term component of retention of OBT with a 828 half-life of 27.6 d accounted for <3% of the tritium retained in the skin. HTO in the skin also 829 showed two components of retention, with half-times of 3.7 and 18.1 d. A significant level of 830 OBT was excreted shortly after exposure. Elevated levels of tritium were found in the liver 831 and kidneys. Overall, about 60% of the activity applied to skin was excreted in faeces, mostly 832 as OBT, and about.4% was excreted in urine. The remaining ~36% may have been removed 833 gradually from the skin to the environment. The exposed skin was estimated to receive the 834 highest dose of any tissue, primarily due to retention of OBT at the point of contact with the 835 contaminated pump oil. 836 837 2.2.3.2. Biokinetic models for systemic tritium 838 839 (54) A number of biokinetic models for tritium have been published, primarily for tritium 840 as HTO or for generic OBT. The following short summary describes the most recent ICRP 841 models for HTO and OBT and selected models appearing in the open literature in recent 842 years. 843 (55) ICRP Publication 56 (1989) recommended a two-component model for predicting 844 the behavior of tritium that enters the human body as HTO. It is assumed in that model that 845 97% of the tritium is eliminated with a biological half-time of 10 days and 3% becomes 846 organically bound and is eliminated with a biological half time of 40 days. 847 (56) The authors of ICRP Publication 56 (1989) interpreted the available data as 848 indicating that 9-45% of ingested OBT is incorporated into organic constituents of tissues and 849 that on average about 9 times more OBT is present in body tissues after intakes of OBT than 850 after intakes of HTO. ICRP Publication 56 recommended a default model for unknown 851 tritiated organic compounds in the environment in which it is assumed that 50% of the OBT 852 entering the systemic circulation enters into bonds with carbon and is cleared with the same 853 half-time as carbon, assumed in that document to be 40 d. The remaining 50% is assumed to 854 be rapidly metabolized to HTO and removed from the body with a biological half-time of 10 855 days. 856 (57) Taylor (2003) reevaluated data on tritium excretion by human subjects exposed to

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857 HTO in an effort to develop a biokinetic model for HTO that could be used for protection 858 planning and interpretation of bioassay data collected at early, intermediate, or late times 859 after exposure. He proposed a three-component exponential model with half-times of 10 860 days (99%), 40 days (0.98%) and 350 days (0.02%). 861 (58) Richardson and Dunford (2003a, 2003b) designed a generic, physiologically based 862 biokinetic model framework for hydrogen, carbon, nitrogen, and oxygen, with the goal of 863 predicting the biokinetics of each of these elements following ingestion on the basis of the 864 metabolic reactions of the principal nutrients: carbohydrates, fats, and proteins. A relatively 865 simple form of the model consists of compartments representing the principal nutrients. A 866 more complex form includes compartments representing retention of carbohydrates as 867 glycogen, fats as adipose tissue, and proteins in bone and soft tissues. Parameter values for 868 hydrogen were developed, and ingestion dose coefficients were derived for dietary intake of 869 organically bound tritium. 870 (59) Galeriu and coworkers (Galeriu et al., 2009; Galeriu and Melintescu, 2010) proposed 871 a physiologically based biokinetic model for dietary tritium in the mammalian body based on 872 organ specific metabolic rates. The model was first developed for non-human mammals 873 (Galeriu et al., 2009) and tested against experimental data on laboratory and farm animals. 874 Parameter values for a modified model structure were later developed for reference persons 875 living in a temperate climate (Galeriu and Melintescu, 2010). The model for humans included 876 compartments representing blood plasma, red blood cells, body water, brain, viscera, muscle, 877 adipose tissue, residual tissue, stomach content, small intestine content, and large intestine 878 content. Dose coefficients were developed for ingestion of tritiated water or organically 879 bound tritium. 880 881 Model for tritiated water used in this report 882 (60) The model for HTO adopted in the present report is a recycling model that includes 883 compartments representing blood, extravascular body water that exchanges rapidly with 884 blood, and organically bound tritium with intermediate and slow turnover rates. The model 885 structure, which is broadly similar to a number of previously proposed structures for HTO 886 (NCRP, 1979; Saito, 1992; Hill and Johnson, 1993), is shown in Figure 2-1. Parameter 887 values for intake of tritiated water are given in Table 2-5. Excretion is from the blood 888 compartment only. The transfer coefficient from Blood to Excreta is set to yield an initial 889 removal half-time from the body of 10 d. The transfer coefficients from compartments 890 OBT-1 and OBT-2 back to Extravascular HTO correspond to half-times of 40 d and 1 y, 891 respectively; the net retention half-times in these compartments are slightly longer than 40 d 892 and 1 y due to recycling of activity. Specific excretion pathways are not shown in Figure 2-1, 893 but the following division is assumed on the basis of reference data for water balance (ICRP 894 Publication 89, 2002): urine, 55%; faeces, 4%; exhalation, 12%; and loss through skin 895 (sweat plus insensible loss), 29%. 896 897

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898

899 900 Figure 2-1. Structure of the model for tritium entering the systemic circulation as HTO. 901 Transfer from blood to excreta (or excretion pathways) is divided as follows: 55% to urinary 902 bladder contents; 4% to upper colon; 12% exhaled with no retention in lungs; 29% removed 903 through the skin (sweat plus insensible loss) with no retention in skin. 904 905 Table 2-5. Transfer coefficients (d–1) in the systemic model for tritiated water

Path Transfer coefficient From To (d-1) Blood Extravascular HTO 400 Extravascular HTO OBT-1 0.0006 Extravascular HTO OBT-2 0.00008 Blood Excretaa 0.7 Extravascular HTO Blood 44 OBT-1 Extravascular HTO 0.01733 OBT-2 Extravascular HTO 0.0019 a 55% to UB contents, 4% to colon contents, 12% exhaled, and 29% lost through skin. 906 907 (61) Model predictions of the blood content of tritium as a function of time after 908 intravenous injection of HTO are compared in Figure 2-2 with estimates based on data of 909 Moore (1962) and Balonov et al. (1974) for human subjects. The data of Moore (1962) were 910 reported as concentrations of tritium in blood plasma. Derived estimates of tritium in whole 911 blood are based on the assumptions that plasma water represents two-thirds of blood water 912 and red blood cell water equilibrates with plasma water during the first few minutes after 913 injection. The data of Balonov et al. (1974) were reported as relative concentrations over 914 time in whole blood normalized to 1.0 at equilibrium, with equilibrium assumed to be 915 reached within a few hours after injection. These data were converted to percentages of 916 injected tritium by assuming that blood contains 10% of total-body HTO at equilibrium, 917 based on the estimate that blood water represents 10% of total-body water. 918

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919 920 Figure 2-2. Observations and model predictions of blood content of tritium blood following 921 intravenous injection of HTO 922 923 (62) Model predictions of urinary excretion of tritium as a function of time after acute 924 intake of HTO are compared in Figure 2-3 with data for individual human subjects of five 925 different long-term studies. Four of the subjects were accidentally exposed to HTO in the 926 workplace (Snyder et al., 1968; Sanders and Reinig, 1968; Rudran, 1988; Trivedi et al., 927 1997). The fifth subject ingested HTO as part of a controlled biokinetic study (Balonov et al., 928 1974). In two of the cases of accidental exposure, an effort was made to accelerate the 929 removal of tritium from the body at early times after intake, either by administration of an 930 oral diuretic (Sanders and Reinig, 1968, days 3-35) or by increasing fluid intake (Trivedi et 931 al., 1997, days 1-32). The observations and model predictions shown in Figure 2-3 are 932 normalized to a urine concentration of 1.0 on day 1.

933 934 Figure 2-3. Observations and model predictions of urinary excretion of tritium as a function of 935 time after acute intake of HTO by human subjects. Data and model predictions are normalized 936 to a urine concentration of 1.0 on day 1. 937 938

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939 Model for OBT used in this report 3 940 (63) In view of the wide range of H-labelled substances that could be encountered in the 941 workplace and the limited data on their biokinetics, it is not feasible to define specific models 942 for individual organic compounds of tritium. A default model for systemic OBT is adopted 943 in the present report (Figure 2-4). This is a modification of the model for HTO described 944 earlier. It is assumed here that 50% of tritium entering blood as OBT transfers immediately to 945 compartment OBT-1 (the OBT compartment with the shorter half-time) and 50% is converted 946 immediately to HTO within the blood compartment. Tritium entering OBT-1 or Blood 947 follows the HTO model defined in Figure 2-1 and Table 2-5. For application to individual 948 organic tritium compounds the division of absorbed activity between compartment OBT-1 949 and Blood can be modified as allowed by specific information. 950 (64) The default model for OBT predicts that OBT would represent about 65-70% of 951 total-body tritium in a worker who is chronically exposed to OBT. The model for HTO 952 adopted in this report predicts that OBT would represent about 5-6% of total body tritium in a 953 worker who is chronically exposed to HTO. 954 955

956 957 Figure 2-4. The default model for tritium entering the systemic circulation as OBT. Tritium 958 entering OBT-1 or Blood follows the HTO model defined earlier. For application to individual 959 organic tritium compounds the division of absorbed activity between compartment OBT-1 and 960 Blood can be modified as allowed by specific information. 961 962 2.3. Individual monitoring 963 964 (65) Tritium intakes are generally monitored though measurements of the activity 965 excreted in urine. The most common method of analysis is liquid scintillation counting. 966 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 3H Urine Bioassay Liquid Scintillation 100 Bq/L 5-10 Bq/L Counting 967

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968 (66) Currently most laboratories do not perform fecal monitoring of tritium in routine. 969 Fecal monitoring of workers exposed to particulate forms of tritium might be desirable. The 970 AEC (Trivedi et al., 1993) has published a method to measure organically bound tritium in 971 faeces, with an MDA of 5Bq/g. 972 973 References 974 975 Balonov, M.I., Likhtarev, I.A., Moskalev, Yu. I., 1984. The metabolism of tritium compounds and 976 limits for intakes by workers. Health Phys., 47(5), 761–773. 977 Balonov, M.I., Muksinova, K.N., Mushkacheva, G.S., 1993. Tritium radiobiological effects in 978 mammals: Review of experiments in the last decade in Russia. Health Phys. 65, 713-726. 979 Balonov, M.I., Dolgirev, E.I., Likhtarev, I.A., 1974. Exchange kinetics and dosimetry of tritium oxide 980 in man for different routes of administration. Health Phys. 27, 367-375. 981 Balonov, M.I., Likhtarev, I.A., Moskalev, Yu. I., 1984. The metabolism of tritium compounds and 982 limits for intakes by workers. Health Phys. 47, 761–773. 983 Balonov, M., Bruk, G., Zhesko, T., 1995. Dosimetry and standardization of tritium in Russia. Fusion 984 Technol., 28, 809–813. 985 Butler, H.L., Leroy, J.H., 1965. Observation of biological half-life of tritium. Health Phys. 11, 283- 986 285. 987 Carlisle, S.M., Burchart, P.A., McCauley, C., Surette, R.P., 2005. Biokinetics of inhaled radioactive 988 methane in rats: A pilot study. Appl. Radiat. Isot. 62, 847-860. 989 Cheng, Y.S., Zhou, Y. Gentile, C.A., Skinner, C.H., 2002a. Characterisation of carbon tritide particles 990 in a Tokamak fusion reactor. Fusion Sci. Technol. 41, 867–871. 991 Cheng, Y.-S., 2009. Personal communication. 992 Cheng, Y.-S., Dahl, A.R., Jow, H.-N., 1997. Dissolution of metal tritides in a simulated lung fluid. 993 Health Phys. 73(4), 633-638. 994 Cheng, Y.-S., Snipes, M.B., Wang, Y., Jow, H.-N., 1999. Biokinetics and dosimetry of titanium tritide 995 particles in the lung. Health Phys. 76(2), 120-128. 996 Cheng, Y.S., Zhou, Y., Wang, Y.S., Inkret, W.C., Wermer, J.R., 2002b. Dose estimate of inhaled 997 hafnium tritide using the ICRP 66 lung model. Health Phys. 82(6), 817–824. 998 Cool, D.A., Maillie, H.D., 1983. Dissolution of tritiated glass microballoon fragments: Implications 999 for inhalation exposures. Health Phys. 45(3), 791–794. 1000 Cool, D.A., Maillie, H.D., 1984. Tritium distribution and excretion following intratracheal instillation 1001 of glass microballoon fragments in rats. Health Phys. 46(3), 599–606. 1002 Davies, S., Spanel, P., Smith, D., 2001. Rapid measurement of deuterium content of breath following 1003 oral ingestion to determine body water. Physiol. Meas. 22, 651-659. 1004 Diabaté, S., Strack, S., 1993. Organically bound tritium. Health Phys. 65, 698-712. 1005 Dougherty, R.W., O’Toole, J.T., Allison, M.J., 1967. Oxidation of intraarterially administered C-14 1006 labelled methane in sheep. Proc. Soc. Exp. Biol. Med. 124, 1155-1157. 1007 Eakins, J.D., Hutchinson, W.P., Lally, A.E., 1975. The radiological hazard from tritium sorbed on 1008 metal surfaces. Health Phys. 28, 213. 1009 Etnier, E.L., Travis, C.C., Hetrick, D.M., 1984. Metabolism of organically bound tritium in man. Rad 1010 Res., 100, 487-502. 1011 Fallot, P., Aeberhardt, A., Masson, J., 1957. Méthode de dosage de l’eau tritiée et ses applications en 1012 clinique humaine. Int. J. Appl. Radiat. Isot. 1, 237-245. 1013 Foy, J.M., Schneiden, H., 1960. Estimation of total body water (virtual tritium space) in the rat, cat, 1014 rabbit, guinea-pig and man, and of the biological half-life of tritium in man. J. Physiol. 154, 1015 169-176. 1016 Galeriu, D.; Melintescu, A.; Beresford, N. A.; Takeda, H.; Crout, N. M. J., 2009. The dynamic 1017 transfer of 3H and 14C in mammals – A proposed generic model. Radiat. Environ. Biophys. 1018 48, 29-45.

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1019 Galeriu, D.; Melintescu, A., 2009. Retention of tritium in reference persons: A metabolic model. 1020 Derivation of parameters and application of the model to the general public and to workers. J. 1021 Radiol. Prot. 30, 445-468. 1022 Henry, P., 1972. Etude d’une contamination accidentale par l’eau tritiee´. In: Assessment of 1023 Radioactive Contamination in Man (Vienna: International Atomic Energy Agency) pp. 641– 1024 657, STI/PUB/290. 1025 Hill, R.L., Johnson, J.R., 1993. Metabolism and dosimetry of tritium. Health Phys. 65, 628-647. 1026 Hodgson, A., Rance, E.R., Pellow, P.G.D., Stradling, G.N., 2004. In vitro dissolution of tritium 1027 loaded carbon particles from the JET Tokamak. National Radiological Protection Board 1028 NRPB-W55. Available at www.hpa.org.uk. 1029 Hodgson, S.A., Scott, J.E., Hodgson, A., 2006. In vitro Dissolution of Tritium Loaded Particles from 1030 the JET Fusion Machine. RPD-DAR-02-2006. Health Protection Agency, UK, June 2006. 1031 Hodgson, S.A., Scott, J.E., Hodgson, A., 2007. In vitro dissolution of tritium-loaded particles from the 1032 JET Fusion Machine. Radiat. Prot. Dosim. 127, 55-59. 1033 Hunt, J., Bailey, T., Reese, A., 2009. The human body retention time of environmental organically 1034 bound tritium. J. Radiol. Prot. 29, 23-36. 1035 Ichimasa, M., Ichimasa, Y., Hashimoto, N., Oda, M., Akita, Y., 1988. Comparison of oxidation 1036 activity of tritium gas among various animals and man - Analysis of intestinal bacterial flora 1037 for oxidation. In: Proceedings of Third Japan-US Workshop on Tritium Radiobiology and 1038 Health Physics. Japan, Institute of Plasma Physics, Nagoya University; IPPJ-REV-3; pp. 1039 107-111. 1040 ICRP, 1979. Limits on Intakes by Workers, ICRP Publication 30. Ann. ICRP 2(3/4). 1041 ICRP, 1989. Age-dependent doses to Members of the Public from Intake of Radionuclides: Part 1. 1042 ICRP Publication 56, Ann. ICRP 20(2), 15-19. 1043 ICRP, 1994. Dose Coefficients for Intakes of Radionuclides by Workers. ICRP Publication 68. Ann. 1044 ICRP 24(4). 1045 ICRP, 2002. Basic anatomical and physiological data for use in radiological protection: Reference 1046 values. ICRP Publication 89, Ann. ICRP 32(3-4). 1047 Inkret, W.C.T., Schillaci, M.E., Boyce, M.K., Cheng, Y.S., Efurd, D.W., Little, T.T., Miller, G., 1048 Musgrave, J.A., Wermer, J.R., 2001. Internal dosimetry for inhalation of hafnium tritide 1049 aerosols. Radiat. Prot. Dosim. 93(1), 55–60. 1050 Kirchman, R., Charles, P., Van Bruwaene, J., Remy, J., 1977. Distribution of tritium in the different 1051 organs of calves and pigs after ingestion of various tritiated feeds. Curr. Topics Radiat. Res. 1052 Q. 12, 291–312. 1053 Komatsu, K., Okumura, Y., Sakamoto, K., 1990. Radiation dose to mouse liver cells from ingestion of 1054 tritiated food or water. Health Phys. 58, 625–629. 1055 Konig, L.A., 1990. Tritium in the food chain. Radiat. Prot. Dosim. 30, 77–86. 1056 Kropf, R.F., Wang, Y.S., Cheng, Y.S., 1998. Self-absorption of tritium betas in metal tritide particles. 1057 Health Phys. 75(4), 398–404. 1058 La Forgia, J., Withers, R.T., 2002. Measurement of total body water using 2H dilution: impact of 1059 different conditions for determining body fat. Br. J. Nutr. 88, 325-329. 1060 Lambert, B.E., Clifton, R.J., 1968. Radiation doses resulting from the ingestion of tritiated thymidine 1061 by the rat. Health Phys. 15, 3-9. 1062 Lambert, B.E., Sharpe, H.B.A., Dawson, K.B., 1971. An accidental intake of tritiated water. Amer. 1063 Ind. Hygiene Assoc. J. 32, 682-686 1064 Mewissen, D.J., Furedi, M.E., Ugarte, A.S., Rust, J.H., 1979. Tritium distribution and incorporation 1065 from tritiated water or tritiated precursors of DNA, RNA or proteins. In: Behaviour of Tritium 1066 in the Environment, Freeman, S., ed. (Vienna: IAEA) STI/PUB/498, pp. 469-487. 1067 Minder, W., 1969. Interne Kontamination mit Tritium. Strahlentherapie 137, 700-704. 1068 Moghissi, A.A., Carter, M.W., Bretthauer, W., 1972. Further studies on the long-term evaluation of 1069 the biological half-life of tritium. Health. Phys. 23, 805-806. 1070 Moghissi, A.A., Carter, M.W., Lieberman, R., 1971. Long-term evaluation of the biological half-life 1071 of tritium. Health. Phys. 21, 57-60.

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1072 Moore, R., 1962. A comparison of HTO in plasma and expired water vapor. Health Phys. 7, 161-169. 1073 NCRP (1979). Tritium in the environment. NCRP Report 62. National Council on Radiation 1074 Protection and Measurements. Washington, D.C. 1075 Osborne, R.V., 1966. Absorption of tritiated water vapor by people. Health Phys. 12, 1527-1537. 1076 Peterman, B.F., Johnson, J.R., McElroy, R.G.C., 1985a. HT/HTO conversion in mammals. Fusion 1077 Technology 8, 2557-2563. 1078 Peterman, B.F., Johnson, J.R., Dunford, D.W., McElroy, R.G.C., 1985b. Internal dosimetry of 1079 tritiated hydrogen gas. Mississauga, Ontario, Canada: Canadian Fusion Fuel Technology 1080 Project; CFFTP-G-84034/AECL-8651, 1-45. 1081 Phipps, A.W., Kendall, G.M., Fell, T.P., Harrison, J.D., 1990. Doses from radioactive methane. 1082 Radiat. Prot. Dosim. 30, 191-195. 1083 Pietrzak-Flis, Z., Radwan, J., Judeka, L., 1978. Tritium in rabbits after ingestion of freeze-dried 1084 tritiated food and tritiated water. Radiat. Res. 76, 420–428. 1085 Pinson, E.A., Langham W.H., 1957. Physiology and toxicology of tritium in man. J. Appl. Physiol 10, 1086 108-126 (Reprinted Health Phys. 38, 1087-1110, 1980). 1087 Richardson, R.B., Dunford, D.W., 2003a. A biochemical-based model for the dosimetry of dietary 1088 organically bound tritium – Part 1: Physiological criteria. Health Phys. 85, 523-538. 1089 Richardson, R.B., Dunford, D.W., 2003b. A biochemical-based model for the dosimetry of dietary 1090 organically bound tritium – Part 2: Dosimetric evaluation. Health Phys. 85, 539-552. 1091 Richmond, C.R., Langham, W.H., Trujillo, T.T., 1962. Comparative metabolism of tritiated water by 1092 mammals. J. Cell. Comp. Physiol. 59, 45-53. 1093 Rochalska, M., Szot, M., 1977. The incorporation of organically bound tritium in food into some 1094 organs of the rat. Int. J. Radiat. Biol. 31, 391-395. 1095 Rodgers, D.W., 1992. Tritium dynamics in mice exposed to tritiated water and diet. Health Phys. 63, 1096 331-337. 1097 Rudran, K., 1988a. Significance of in vivo organic binding of tritium following intake of tritiated 1098 water. Radiat. Prot. Dosim. 25, 5-13. 1099 Rudran, K., 1988b. Radiation doses to lungs and whole body from use of tritium in luminous paint 1100 industry. Radiat. Prot. Dosim. 25, 117-125. 1101 Saito, M., 1992. A modified three-compartment model for tritium metabolism in man. Rad. Prot. 1102 Dosim. 42, 1017-1024. 1103 Sanders, S.M., Jr., Reinig, W.C., 1968. Assessment of tritium in man. In: H. A. Kornberg and W. D. 1104 Norwood (Eds.), Diagnosis and treatment of deposited radionuclides. Excerpt Medica 1105 Foundation, Amsterdam, pp. 534-542. 1106 Smith, H., 1986. Transformation and conversion of tritium in mammals. Radiat. Prot. Dosim. 16, 1107 135–136. 1108 Snyder, W.S., Fish, B.R., Bernard, S.R., Ford, M.R., Muir, J.R., 1968. Urinary excretion of tritium 1109 following exposure of man to HTO. Phys. Med. Biol. 13, 547-559. 1110 Takeda, H., 1982. Comparative metabolism of tritium in rat after a single ingestion of some tritiated 1111 organic compounds versus tritiated water. J. Radiat. Res. 23, 345–357. 1112 Takeda, H., 1991. Incorporation and distribution of tritium in rats after chronic exposure to various 1113 tritiated compounds. Int. J. Radiat. Biol. 59, 843–853. 1114 Takeda, H., Arai, K., Iwakura, T., 1985. Comparison of tritium metabolism in rat following single or 1115 continuous ingestion of tritium labelled wheat versus tritiated water. J. Radiat. Res. 26, 131– 1116 139. 1117 Takeda, H., Kassida, Y., 1979. Biological behavior of tritium after administration of tritiated water to 1118 the rat. J. Radiat. Res. 20, 174–185. 1119 Taylor, D.M., 1989. An approach to the proposal of an annual limit of intake for the general public 1120 (ALIgp) for organically bound tritium. Radiat. Prot. Dosim. 28, 211–213. 1121 Taylor, D.M., 2003. A biokinetic model for predicting the retention of 3H in the human body after 1122 intakes of tritiated water. Radiat. Prot. Dosim., 105, 225-228. 1123 Taylor, D.M., 2008. Radiation doses from some 3H-labeled organic compounds following ingestion. 1124 Radiat. Prot. Dosim. 128, 299-308.

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1125 Taylor, D.M., Moroni, J.P., Snihs, J.O., Richmond, C.R., 1990. The metabolism of H-3 and C-14 with 1126 special reference to radiation protection. Radiat. Prot. Dosim. 30, 87–93. 1127 Travis, C.C., Etnier, E.L., Hetrick, D.M., 1984. Validation of metabolic model for tritium of 1128 organically bound tritium in man. Rad. Res., 100, 503-509. 1129 Trivedi, A., 1993. Skin-contact exposure to tritium-gas contaminated stainless-steel surfaces. Health 1130 Phys. 65, 514-522. 1131 Trivedi, A., 1995. Percutaneous absorption of tritium-gas contaminated pump oil. Health Phys. 69, 1132 202-209. 1133 Trivedi, A., Duong, T., Leon, J. W., Linauskas, S. H. 1993. Measurement of organically bound tritium 1134 in urine and faeces. Atomic Energy of Canada Limited. AECL-10925. 1135 Trivedi, A., Galeriu, D., Lamothe, E.S., 2000. Dose contribution from metabolized organically bound 1136 tritium after chronic tritiated water intakes in humans. Health Phys. 78, 2-7. 1137 Trivedi, A., Galeriu, D., Richardson, R.B., 1997. Dose contribution from organically bound tritium 1138 after acute tritiated water intake by humans. Health Phys. 73, 579–586. 1139 Wawerna, J.C., 1973. Biological implications of the application of tritium luminous compounds. In: 1140 Moghissi, A.A., Carter, M.W. eds. Tritium. Phoenix, AZ; Messenger Graphics. pp.356-363. 1141 Wylie, K.F., Bigler, W.A., Grove, G.R., 1963. Biological half-life of tritium. Health Phys. 9, 911-914. 1142 Zhou, Y., Cheng, Y.S., 2003. Dose assessment for inhaling hafnium particles based on laboratory rats 1143 study. Health Phys. 84(4), 469–476. 1144 Zhou, Y., Cheng, Y.S., 2004. Dosimetry of metal tritide particles as evaluated by the ICRP 66 model 1145 and a biokinetic model from laboratory rates. Health Phys. 86(2), 155–160 1146 Zhou, Y., Wang, Y.S., Cheng, Y.S., 2010. Dissolution rate and biokinetic model of zirconium tritide 1147 particles in rat lungs. Health Phys. 98, 672–682. 1148 Zhou, Y., Cheng, Y.S., 2003. Dose assessment for inhaling hafnium particles based on laboratory rats 1149 study. Health Phys. 84, 469–476. 1150

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1151 3. CARBON (Z = 6) 1152 1153 3.1. Chemical Forms in the Workplace 1154 1155 (67) Carbon is a non-metal which occurs mainly in oxidation states II and IV. It may be 1156 encountered in industry in a variety of chemical forms, including carbon monoxide, carbon 1157 dioxide and methane, as well as in a wide range of organic carbon compounds and particles 14 1158 containing C. 11 14 1159 (68) Only two are of importance for radiation protection, C and C. 1160 Because of its short half-life, and the penetrating 511 keV annihilation radiation it emits, 11 1161 external irradiation from C may well be a greater hazard than internal exposure.

1162 1163 Table 3-1. Isotopes of carbon addressed in this report 1164 Isotope Physical half-life Decay mode C-11 20.39 min EC, Beta+ C-14a 5700 y Beta- 1165 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 1166 are given on accompanying electronic disk. 1167 1168 3.2. Routes of Intake 1169 1170 (69) It is not feasible to provide biokinetic models, dose coefficients and bioassay 1171 functions for the very large number of compounds with specific biokinetic behaviour. Hence 1172 systemic biokinetic models and dosimetric information are only given for certain forms, 1173 although some information is given on other forms. It is the responsibility of employers to 1174 assess doses to ensure appropriate protection for forms for which dose coefficients are not 1175 provided. 1176 1177 3.2.1. Inhalation 1178 1179 (70) Some information is available on the behaviour of inhaled gases of carbon in man 14 1180 and in experimental animals. Some information is also available on the behaviour of C- 1181 labelled compounds and particles, mainly in rats, and on forms of carbon labelled with other 1182 radionuclides. 1183 (71) Absorption parameter values and Types, and associated fA values for gas and vapour 1184 forms of carbon are given in Table 3-2 and for particulate forms in Table 3-3. 1185 (72) Exposures to both gas/vapour forms and particulate forms of carbon are common, 1186 and it is therefore proposed by the Task group that in the absence of information 50% 1187 particulate; 50% gas/vapour should be assumed (ICRP, 2002a). 1188 1189 (a) Gases and vapours 1190 1191 Carbon monoxide (CO) 1192 (73) Carbon monoxide at high concentration is a potent asphyxiant, and for that reason its 1193 human respiratory physiology has been studied extensively (Lipsett et al., 1994). Carbon 1194 monoxide diffuses readily across the membranes of the gas exchange (alveolar-interstitial, 1195 AI) region (Crapo et al., 1982). Although CO has only a low solubility in biological fluids,

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1196 once absorbed into the pulmonary circulation it binds avidly to haemoglobin molecules 1197 within red blood cells. Peterson and Stewart (1970) estimated the biological half-life of CO in 1198 the blood to be between 150 and 200 minutes, and these values together with the 1199 haemoglobin content of the blood of a reference worker (ICRP, 2002b) can be used to 1200 estimate that 0.4 of the inhaled CO becomes bound to haemoglobin (ICRP, 1981). On that 1201 basis it is assumed that for carbon monoxide there is effective deposition of 40% of the 1202 inhaled activity in the respiratory tract, with instantaneous (Type V) absorption. It is assumed 14 14 1203 that the C-carboxyhaemoglobin formed releases C to the bicarbonate pool with a 1204 biological half-time of 200 minutes, from where it follows the carbon dioxide/bicarbonate 1205 model (Section 3.2.3.). 1206 1207 Carbon dioxide (CO2) 1208 (74) Release to the environment of blood borne carbon dioxide resulting from tissue 1209 carbon metabolism is a central function of the respiratory system, and the transport processes 1210 have been documented in detail (Guyton and Hall, 2000). Because of the very high solubility – 1211 of CO2 and the associated bicarbonate ion (HCO3 ) in tissue fluids, CO2 is transferred 20 1212 times more rapidly than oxygen across the alveolar membrane (Guyton and Hall, 2000). Thus 1213 despite the net flow of CO2 into the alveolar space, inhaled radioactive CO2 rapidly – 1214 equilibrates with blood borne CO2 /HCO3 , and is absorbed quantitatively into the circulation. 1215 On that basis, for carbon dioxide it is assumed here that there is 100% deposition in the 1216 respiratory tract with instantaneous (Type V) absorption. The carbon dioxide/bicarbonate 1217 systemic model (Section 3.2.3.) is applied to the absorbed material. 1218 1219 Methane (CH4) 1220 (75) The dosimetric implications of inhaling methane gas were examined by Phipps et al. 1221 (1990). They made the conservative assumption that 1% of the methane was metabolized, 1222 based on observations by Dougherty et al. (1967) which indicated that approximately 0.3% of 1223 methane infused into sheep was converted to carbon dioxide. Carlisle et al. (2005) 3 14 1224 investigated the extent of oxidation and organic fixation of H and C following inhalation of 3 14 1225 H-labelled and/or C-labelled methane by rats. A pilot study examined retention of activity 1226 in skin, liver, brain and carcass 1 and 24 hours after a 4-hour exposure. It was estimated that 14 1227 uptake was about 0.2% of intake based on retention of C in liver and 0.03% of intake based 14 14 1228 on retention of C in the other tissues. Most (82 – 95%) of retained C was organically 1229 bound. For methane it is therefore assumed here that there is 0.1% deposition in the 1230 respiratory tract with instantaneous (Type V) absorption. It is assumed here that 50% of 1231 carbon in the absorbed methane follows the systemic model for carbon dioxide and 50% 1232 follows the generic systemic model for carbon (Section 3.2.3.). 1233 1234 Benzene (C6H6) 1235 (76) Krins et al. (2003) conducted a study of the distribution, retention and excretion of 14 14 1236 C-labelled benzene [ C] C5H6, based on existing pharmacokinetic models. They reported 1237 that in humans exposed to 55 ppm for 4 hours, about 30% of inhaled benzene is absorbed into 1238 blood (Nomiyama and Nomiyama, 1974a, 1974b). Studies on rats, however, showed that 1239 retention during exposure is highly dependent on the concentration of benzene the inhaled air 1240 (Sabourin et al., 1987). A systemic model for benzene is described in Section 3.2.3. but dose 1241 coefficients are not provided. 1242 (77) As part of a programme to study the disposition of selected industrial organic 1243 chemicals thought to pose an inhalation health risk to humans, biokinetic studies were 1244 conducted on several which might be inhaled in vapour form, including benzene (see above),

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1245 dichloropropene, methyl bromide, butadiene, isoprene, butoxyethanol, and isobutene. Brief 1246 summaries of relevant information follow, but no systemic model, dose coefficients or 1247 bioassay functions are given here for these compounds. Except where noted otherwise, in 1248 these studies retention, metabolism and excretion were followed for about 3 days after a 6- 14 1249 hour inhalation exposure of rats to a vapour of the C-labelled compound. 1250 1251 Dichloropropene (DCP) 1252 (78) It was estimated that 38% of inhaled DCP was absorbed (Bond et al., 1985a, 1253 Dutcher et al., 1985). The results indicated that the absorbed DCP is rapidly metabolised in 1254 tissues and the metabolites excreted. 1255 1256 Methyl bromide 1257 (79) It was estimated that 48% of inhaled methyl bromide was absorbed at the lower 1258 concentrations used, but the fraction decreased to 27% at the highest concentration (Bond et 1259 al., 1985b, Medinsky et al., 1985). The results indicated that the absorbed methyl bromide is 1260 rapidly metabolised in tissues (>90% within an hour) and the metabolites excreted: about 1261 20% of the amount in tissues immediately after exposure was retained at 65 hours. 1262 1263 1,3-Butadiene 1264 (80) Interspecies differences were investigated. About 20% of inhaled butadiene was 1265 absorbed (and retained at the end of exposure) in rats and mice at the lowest concentrations 1266 used, with the fraction decreasing to 2-4% at the highest concentrations (Bond et al., 1986a). 14 1267 Bond et al. (1987) followed the tissue distribution of C for 13 d after 3.4-hour inhalation 14 1268 exposures of rats and mice. In both species, about 90% of C present in the lungs at the end 1269 of exposure cleared with a half-time of several hours, the rest with a half-time of about a 1270 week. In monkeys, the fraction absorbed and excreted within 4 days was lower, at about 3%, 1271 than in rats and mice exposed to the same concentration (Dahl et al., 1991). 1272 1273 Isoprene (2-Methyl-1,3-butadiene). 1274 (81) In rats, about 20% of inhaled isoprene was absorbed (and retained at the end of 1275 exposure) at the lowest concentration used, with the fraction decreasing to about 4% at the 1276 highest concentration. Mice showed similar absorption, but less change with concentration 1277 (Dahl et al., 1987; Bond et al., 1991). 1278 1279 Butoxyethanol 1280 (82) As part of a wider study of the biokinetics and metabolism of glycol ethers 1281 administered by different routes, Sabourin et al. (1992) followed retention and excretion of 14 14 1282 C for 66 hours after 6-hour inhalation exposures of rats to [ C]butoxyethanol. It was 1283 estimated that about 20% of inhaled butoxyethanol was absorbed. 1284 1285 Isobutene (2-Methyl-1-propene) 1286 (83) About 8% of inhaled isobutene was absorbed (and retained at the end of exposure) at 1287 the lowest concentrations used, with the fraction decreasing to about 2% at the highest 1288 concentration (Henderson et al. 1993). 1289 1290 Other organic compounds 1291 (84) The volatility and solubility in body fluids of organic compounds have wide ranges. 1292 Therefore, in the absence of specific information, the default option for gases and vapours is 1293 taken. As for tritium (Section 1.2.1), for carbon (gas or vapour) in unspecified organic forms

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1294 is it is assumed here that there is 100% deposition in the respiratory tract (with default 1295 regional distribution, Table 3-2) and Type F absorption. 1296 1297 (b) Particulate materials (liquid and solid) 1298 14 1299 C-labelled compounds 14 1300 (85) Some information is available for C-labelled compounds administered to rats. For 14 1301 the C-labelled carbon compounds considered in the following sections, the systemic 1302 behaviour is specific to each compound. In these cases no systemic model, dose coefficients 1303 or bioassay functions are given here. 1304 1305 DTPA (diethylenetriaminepentaacetic acid) 1306 (86) Absorption of DTPA from the respiratory tract has been studied in detail mainly 1307 because of the use of DTPA as a decorporation agent for treating intakes of actinides, and 1308 interest in its administration by inhalation. Crawley and Haines (1979b) reported rapid lung 14 14 1309 clearance of C following pulmonary instillation of C-DTPA into rats, with <1% ILD 1310 retained in the lungs at 1 day, and 0.03% ILD retained at 7 days. Dudley et al. (1980a) 111 1311 determined absorption of In-DTPA from the nasopharyngeal (NP), tracheobronchial and 1312 pulmonary regions of beagle dogs, following instillation, to be 16, 48 and 90% respectively. 1313 NP absorption was slightly higher following nasal inhalation (23%) than following nasal 1314 instillation (16%). In rats, Dudley et al., (1980b) found NP absorption to be much higher 1315 (68%) following nasal inhalation than following instillation (19%). In complementary 1316 experiments, Dudley et al. (1980a,b) found absorption from the alimentary tract to be about 14 1317 8% in dogs and 4% in rats. Stather et al. (1983) followed the biokinetics of C for a week 14 1318 after inhalation of C-labelled DTPA by two healthy volunteers. Studies were carried out on 1319 the same subjects following intravenous injection, and in one case by ingestion, (which 1320 indicated that about 3% was absorbed from the alimentary tract). Modelling by the authors –1 1321 gave an estimated rate of absorption from lungs to blood of about 13 d (fr ~1), giving –1 1322 assignment to Type F. A similar absorption rate (~10 d ) has been obtained with technetium- 1323 99m labelled DTPA, which has been extensively used to study pulmonary epithelial 1324 permeability in man (See technetium inhalation section). 1325 1326 cyanide 14 1327 (87) Carbon-14 labelled potassium cyanide (K CN) is an important precursor in the 1328 synthesis of organic compounds. Crawley and Goddard (1977) studied its behaviour 1329 following administration to rats by intravenous injection, pulmonary and gastric intubation, 1330 and skin absorption. Biokinetics following pulmonary intubation were very similar to those 14 1331 following intravenous injection, showing that the K CN was completely and rapidly -1 1332 absorbed from the lungs, with fr ~1.0 and sr >100 d , giving assignment to Type F. 1333 (Absorption following gastric intubation was somewhat slower.) 1334 1335 Methanol 14 14 1336 (88) Crawley (1977) reported that the behaviour of C following administration of C- 14 1337 labelled methanol ( CH3OH) to rats by pulmonary intubation was very similar to that 1338 following intravenous injection. Details were only given for the latter, but indicated that the 14 - 1339 C-methanol was completely and rapidly absorbed from the lungs, with fr ~1.0 and sr >100 d 1 1340 , giving assignment to Type F. 1341 1342 acetate

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14 1343 (89) Crawley and Haines (1978) reported that the behaviour of C following 14 14 1344 administration of C-labelled sodium (2- C) acetate to rats by pulmonary intubation was 1345 very similar to that following intravenous injection, but few details were given. By 1 day 1346 most tissue levels were below 1% of the injected activity, indicating assignment to Type F. 1347 1348 Nitrobenzene 14 1349 (90) Crawley and Haines (1979a) reported that following pulmonary intubation of C- 1350 labelled nitrobenzene into rats, lung clearance was very rapid. Retention could be described 1351 by a three-component exponential function with half-lives of 2.5 minutes (99%), 0.75 d -1 1352 (0.7%) and 5 d (0.3%), giving fr ~0.99 and sr ~400 d , and assignment to Type F. 1353 1354 Other organic compounds 14 1355 (91) Brown and Schanker (1983) measured the absorption rate of a range of C-labelled 1356 drugs for up to an hour after inhalation by rats. For lipid-insoluble compounds the half-time 1357 (range 1.4 – 35 minutes) tended to increase with molecular mass (range 60 – 300 daltons 1358 (Da)). Lipid soluble compounds were more rapidly absorbed (range 0.25 – 6 minutes), with 1359 less clear dependence on molecular mass (range 80 – 700 Da). 1360 (92) Bond et al. (1986a and b) summarised studies of the biokinetics, following 14 3 1361 inhalation by rats, of C- or H-labelled chemicals selected as representative of different 1362 important chemical classes found in atmospheric pollutants: benzo[a]pyrene, 1363 aminoanthracene, nitropyrene, and phenanthridone. The chemicals were inhaled in pure form 1364 and in some cases associated with carbonaceous (diesel exhaust), organic (coal tar) or 1365 inorganic ( oxide) particles. Lung retention and excretion of the labels were followed 1366 for up to 26 days after inhalation. For all four compounds, in pure form, >99% cleared from 1367 the lungs with a half-time <1 day. Association with particles increased lung retention in some 1368 cases but not others. For benzo[a]pyrene associated with coal tar a similar fraction (>99%) 1369 cleared rapidly, with gallium oxide slightly less (98%), and with diesel soot only 50%. For 1370 amino-anthracene associated with coal tar rapid clearance was less (92%). For nitropyrene 1371 associated with gallium oxide >99% cleared rapidly and with diesel soot 92%. Bond et al. 14 1372 (1985c) followed lung retention of C for 4 days after instillation into the lungs of rats of 14 1373 C-labelled anthracene, benz[a]athracene, 1-nitropyrene, 6-nitrobenzo[a]pyrene, and 1374 dibenzo[c,g]carbazole. They found that the retention half-time of the small fraction that was 1375 retained beyond 2 days increased with the lipophilicity (as measured by the octanol: water 1376 partition coefficient) over the range 26 to 63 hours. 1377 (93) Studies were also conducted with azodicarbonamide (ADA). Mewhinney et al. 14 14 1378 (1987) followed the kinetics of C for 102 d after inhalation of C-ADA by rats. In 1379 complementary experiments 30% of administered ADA was absorbed following gavage and 1380 90% following intratracheal instillation. The lungs contained about 0.5% ILD at 3 d after 1381 intratracheal instillation, and there was similar rapid lung clearance after inhalation. Results 1382 suggested that ADA was rapidly converted to biurea, most of which was rapidly eliminated in 1383 urine. 1384 (94) Henderson et al. (1988) reported that a wide range of inhaled organic compounds 1385 with molecular mass less than 300 Da, including those studied by Bond et al. (1985c, 1986a 1386 and b) are cleared rapidly (half-time <12 hours) from the lungs of rats. They determined lung 1387 retention up to 24 hours after instillation into rat lungs of a series of dyes (easily traced 1388 without radiolabels) of varying molecular mass and lipophilicity (which increases with 1389 molecular mass). For organic-soluble compounds the fraction of initial lung deposit (ILD) 1390 retained in the lungs at 24 hours increased from about 3% for molecular mass of 250 Da to 1391 about 90% at 400 Da. However, retention of a compound [1,5-di(2-sulfo-p-toluidino)

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1392 anthraquinone] of higher molecular mass (576 Da), but containing a polar functional group, 1393 was only 21%. The authors concluded that both molecular mass and lipophilicity are 1394 important in determining lung retention. 1395 14 1396 C-labelled particles 14 1397 (95) Some information is also available from experimental studies on C-labelled 1398 particles, for which carbon released in the lungs would reasonably be expected to follow the 1399 generic systemic model for carbon (Section 3.2.3.). 1400 1401 carbonate 14 1402 (96) Crawley and Haines (1979a) followed retention and excretion of C following 14 1403 pulmonary intubation of a suspension of barium C-labelled carbonate into rats. Lung 1404 retention decreased rapidly, from 70% ILD at 6 hours to 0.2% at 8 days, indicating 14 1405 assignment to Type F. Kramer et al. (1996) measured lung retention of C for 550 days after 14 1406 accidental inhalation of barium C-labelled carbonate by a worker. Most of the activity 1407 remaining in the lung at 2 days after the presumed intake (the first in vivo measurement), 1408 cleared rapidly with an effective half-time of 0.77 days, also indicating assignment to Type F. 1409 The carbon dioxide/bicarbonate systemic model (Section 3.2.3.) is applied to the absorbed 1410 carbon. 1411 1412 Elemental carbon 14 1413 (97) Johnson (1989) followed the biokinetics of C for 146 days after administration to 14 1414 rats by intratracheal instillation of C-bearing material obtained from air filters during re- 14 1415 tubing of a CANDU reactor (Greening, 1989). No C above background was detected in 1416 urine or liver, indicating negligible dissolution in the lungs (or alimentary tract). After the 1417 first few days lung clearance was very slow, with more than 70% of the ILD retained at 146 1418 d, giving assignment to Type S. Oberdörster et al. (2002) reported significant translocation of 1419 particles to the liver following inhalation by rats of ultrafine (count median diameter 22 nm) 13 1420 C-carbon particles. However, far less translocation to liver was observed by this group in a 192 1421 similar experiment using Ir-labelled carbon particles (Kreyling et al., 2009). 1422 1423 Diesel exhaust particles 14 14 1424 (98) Lee et al. (1983) followed the biokinetics of C for 365 days after inhalation of C- 1425 labelled diesel exhaust particles by rats and guinea pigs. Lung retention at 180 days was 14 1426 about 15% of the initial lung deposit (ILD) in rats and 80% ILD in guinea pigs, with no C 1427 detected in other tissues after the first day, indicating Type S behaviour. Similar lung 1428 retention in rats was observed in other studies (Chan et al., 1981; Lee et al., 1987). 1429 1430 Carbon particles labelled with isotopes of other elements 1431 (99) Carbon particles may also contain other elements, which may or may not be 1432 chemically bound to the particle matrix. For such particles some information may be 1433 available from studies with particles labelled with a radioisotope of one of the other elements. 1434 For details refer to the Section dealing with the labelling radioelement. 1435 1436 Carbon ‘tritide’ (Tritium-loaded carbon particles) (Section 1.2.1) 1437 (100) The results of in vitro dissolution tests are consistent with assignment to Type S. 1438 1439 Technetium-labelled carbon particles (Section 14.2.1) 1440 (101) The results of human inhalation studies suggest that it is more likely to be Type M or

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1441 S than Type F. 1442 1443 Rapid dissolution rate for carbon –1 1444 (102) Very rapid uptake of carbon (100 d or more) has been observed for several –1 1445 chemical forms. A value of 100 d is applied here to all Type F forms of carbon. 1446 1447 Extent of binding of carbon to the respiratory tract 1448 (103) The evidence of rapid uptake from the lung of carbon gases and several solid and 1449 liquid forms indicates that that there is probably little binding of carbon. It is therefore 1450 assumed that for carbon the bound state can be neglected, i.e. fb = 0.0. 1451 1452 Table 3-2. Deposition and absorption for gas and vapour forms of carbona 1453 Percentage depositedb Absorption Systemic Total ET ET BB bb AI c Chemical form/origin 1 2 Type fA model d Carbon monoxide (CO) 40 0 8 4 8 20 V (f) CO 100d 0 20 10 20 50 Carbon dioxide (CO2) V (f) CO2 0.1d 0 0.02 0.01 0.02 0.05 Methane (CH4) V (f) Methane e Unspecified organic 100 0 20 10 20 50 F 1.0 C compounds 1454 a For carbon in unspecified gas or vapour form, the default option for gases and vapours is recommended: 1455 100% total deposition in the respiratory tract; default distribution between regions (footnote e) and Type F 1456 absorption. 1457 b Percentage deposited refers to how much of the material in the inhaled air remains behind after exhalation. 1458 Almost all inhaled gas molecules contact airway surfaces, but usually return to the air unless they dissolve 1459 in, or react with, the surface lining. In the case of methane, a small fraction is absorbed into body fluids and 1460 of that, a fraction is metabolised and the rest subsequently exhaled. c 1461 CO = Systemic model for carbon monoxide; CO2 = Systemic model for carbon dioxide/bicarbonate; C = 1462 Generic systemic model for other 14C compounds (Section 3)]. 1463 d Since instantaneous absorption to blood is assumed, calculations can be performed assuming direct injection 1464 into blood, and the regional deposition does not need to be considered. However, for completeness, the 1465 default distribution is assumed (footnote e). e 1466 Default distribution between regions (20% ET2, 10% BB, 20% bb and 50% AI). 1467 f Not applicable for absorption Type V, because all activity deposited in the respiratory tract is 1468 instantaneously absorbed. 1469 1470

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1471 1472 Table 3-3. Absorption parameter values for inhaled particulate forms of carbon and for 1473 ingested carbona 1474 Absorption parameter Absorption valuesb from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesc,d Absorption Assigned forms Type F Barium carbonatea 1 100 - 1 M All unspecified formse 0.2 3 0.005 0.2 S Elemental carbon, carbon 0.01 3 1x10-4 0.01 tritide

Ingested materials All chemical forms 1 1475 a Following uptake into body fluids, the generic systemic model for carbon is used (Section 3), with the 1476 exception of barium carbonate, for which the carbon dioxide/bicarbonate systemic model (Section 3) is 1477 applied to the absorbed carbon. b 1478 It is assumed that for carbon the bound state can be neglected i.e. fb = 0. The value of sr for Type F forms 1479 of carbon (100 d–1) is element-specific. The values for Types M and S (3 d–1) are the general default 1480 values. 1481 c Materials (e.g. elemental carbon) are listed here where there is sufficient information to assign to a default 1482 absorption Type, but not to give specific parameter values (see text). 1483 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 1484 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 1485 absorption Type and the fA value for ingested soluble forms of carbon (1.0). 1486 e Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 1487 or if the form is known but there is no information available on the absorption of that form from the 1488 respiratory tract. 1489 1490 3.2.2. Ingestion 1491 1492 (104) The uptake of carbon from the gastrointestinal tract is highly dependent on the form 14 1493 in which it is ingested. Absorption is almost complete for carbon administered as [ C]- 1494 labelled inorganic compounds such as potassium cyanide (Crawley and Goddard, 1977) or 14 1495 [ C]-labelled organic compounds such as methyl methacrylate (Bratt and Hathway, 1977). 1496 Absorption may be much lower for some other organic or inorganic compounds such as 1497 polydiethylstilboesterol, octanoic acid, or hydrolysed polyacrylonitrile grafted cellulose (Lai 1498 et al., 1978). 1499 (105) ICRP Publication 30 (1981) recommended that, in the absence of compound- 1500 specific information, organic compounds labelled with radioactive isotopes of carbon should 1501 be assumed to be completely absorbed from the gastrointestinal tract, and this 1502 recommendation is retained here for all chemical forms (i.e. fA = 1). 1503 1504 3.2.3. Systemic Distribution, Retention and Excretion 1505 1506 (106) The biokinetics of systemic radiocarbon depends on the carbon compound taken into 1507 the body and presumably the location of the radioactive atom within the molecule (Taylor, 14 1508 2004). Internally deposited C-labelled compounds have shown residence times varying

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1509 from a few hours to several months in human volunteers (Stather et al., 1981; Stenström et 1510 al., 1996; Taylor, 2004). The distribution of radiocarbon in the body and the fractions of 1511 ingested or inhaled activity lost by exhalation, urinary excretion, and faecal excretion also 1512 depend on the nature of the carbon compound taken into the body. 1513 (107) Variation in the biokinetics of carbon compounds is illustrated in Table 3-4, which is 1514 based on a review of the literature and a biokinetic and dosimetric analysis of the collected 1515 data (Taylor 2004, 2007). The relative dose estimates represent the effective dose coefficient 1516 derived from the compound-specific information, divided by the effective dose coefficient 1517 based on a generic biokinetic model for carbon introduced in ICRP Publication 30 (1981). 1518 That model assumes that internally deposited carbon is uniformly distributed in the body and 1519 removed with a half-time of 40 d (ICRP, 1981). The 7-d retention values and relative dose 1520 estimates given in Table 3-4 are rough estimates in some cases, and the effective dose 1521 estimates are based on tissue weighting factors that have since been replaced (ICRP, 2008). 1522 Nevertheless, the data demonstrate the large differences in the biokinetics of different carbon 1523 compounds in the body and, as a result, a wide variation in radiation dose per unit intake of 1524 carbon compounds for a given mode of intake. 1525 (108) Compound-specific systemic biokinetic models are applied in the present report only 1526 for radiocarbon that is assumed to reach the systemic circulation as carbon monoxide, carbon 1527 dioxide, bicarbonate, or methane. A common model is applied to carbon dioxide and 1528 bicarbonate. A generic systemic model for carbon is applied in this report to unspecified 1529 forms of carbon. For example, the generic model is used to develop dose coefficients for 1530 inhalation of particulate forms of carbon described as Type F, Type M, or Type S material. 1531 (109) The following section summarizes several published systemic biokinetic models for 1532 internally deposited carbon. A later section describes the models used in the present report. 1533

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1534 Table 3-4. Retention of 14C in the human body at 7 d and relative effective dose estimates for intake of various [14C]-labelled compounds, as estimated by Taylor (2004, 2007) on the basis of a review of biokinetic models and data for carbon

14C-labeled Intake Retention at Relative Reference compound mode 7d (%) effective dosea Testosterone IV <20 0.1 Fukushima et al., 1954 Corticosterone IV ~10 0.05 Migeon et al., 1956 Glycine IV ~35 0.6 Berlin and Tolbert, 1955 Cholesterol IV ~ 55 0.5 Hellman et al., 1955 Cortisol IV < 10 0.02 Hellman et al., 1954 Estrone – Estradiol- IV < 20 0.08 Sandberg and Slaunwhite, 1957 17ß Thymidine IV ~30 1.1 Thierens et al., 1994 Methanolb IV <10 0.09 Crawley, 1977 Acetate IV <10 0.08 Crawley and Haines, 1979 Alanine IV ~18 0.3 Simmons et al., 1982 Inulin IV < 1 0.01 ICRP, 1987; 1998 Glucose IV ~35 0.4 Baker et al. 1954, Fine et al. 1962 Potassium cyanideb Intubation 8 0.2 Crawley and Goddard, 1977 Nitrobenzeneb Intubation <6 0.3 Crawley and Haines, 1979 Barium carbonate Inhalation ~ 80 1.0 Kramer et al., 1996 Carbon monoxide Inhalation < 5 0.004 ICRP, 1981;1996 Methane Inhalation < 1 0.01 ICRP,1998 Benzene Inhalation <1 0.07 Krins et al., 2003 Carbon dioxide Inhalation <10 0.01 Leggett, 2004 Ingestion <10 0.005 Urea Ingestion <10 0.5 ICRP, 1998 Ingestion <10 0.7 Leide-Svegborn et al., 1999 Triolein Ingestion ~10 3.6 ICRP 1998 Ingestion ~10 0.5 Gunnarsson, 2002 Glycocholic acid Ingestion ~35 0.7 Gunnarsson et al., 2003 DTPA Ingestion <1 0.05 Stather et al., 1981 Inhalation 0.4 Delmopinol Ingestion <5 0.05 Eriksson et al., 1998 Dexloxiglumide Ingestion < 7 0.4 Webber et al., 2003 Xylose Ingestion ~15 0.2 Gunnarsson et al., 2003 Colestipol Ingestion <1 0.5 Taylor, 2007 Sevelamer Ingestion <1 0.5 Taylor, 2007 Levitiracetam Ingestion <2 0.02 Taylor, 2007 Ifetroban Ingestion <5 0.3 Taylor, 2007 a Multiple of effective dose based on ICRP’s generic model for carbon introduced in ICRP Publication 30 (1981). b Estimates based on data for rats. 1535 1536

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1537 1538 3.2.3.1. Examples of published biokinetic models for systemic carbon 1539 1540 Generic models for inhaled or ingested carbon 1541 (110) ICRP Publication 30 (1981) recommends a generic biokinetic model for application 14 1542 to C-labelled compounds for which biokinetic data are not available. It is assumed that 14 1543 inhaled or ingested C-labelled compounds are instantly and uniformly distributed 1544 throughout all organs and tissues of the body, where they are retained with a biological half- 1545 time of 40 d. The half-time of 40 d is based on balance considerations, assuming daily carbon 1546 intake of 0.3 kg and a carbon pool of mass 16 kg in Reference Man (ICRP, 1975): 1547 1548 T1/2 = ln 2 x total body carbon / daily carbon intake = 0.693(16/0.3) ~ 40 d. 1549 1550 (111) ICRP Publication 30 (1981) states: “It is considered that this assumption will yield 14 1551 realistic whole body doses for C-labelled metabolites and that it will overestimate whole 14 1552 body doses from most other C-labelled compounds.” This assumption is supported by a 14 1553 review and analysis of the effective doses delivered by a range of C-labelled compounds 1554 (Taylor, 2004), based on tissue weighting factors recommended in ICRP Publication 60 1555 (1991). 1556 (112) This generic model was not applied in Publication 30 to inhaled forms of carbon 1557 expected to show significant retention in the lungs and limited absorption to blood. 1558 (113) The same assumptions applied in the generic model of ICRP Publication 30 (1981) 1559 for inhaled or ingested carbon were used in ICRP Publication 68 (1994b) and Publication 71 1560 (1995) as the basis for a systemic model for radiocarbon. That is, absorbed carbon was 1561 assumed to be uniformly distributed in systemic tissues and removed from the body with a 1562 half-time of 40 d. This generic systemic model was used in conjunction with the Human 1563 Respiratory Tract Model (ICRP, 1994a) to derive dose coefficients for radiocarbon inhaled as 1564 Type F, Type M, or Type S material. 1565 1566 Inhaled carbon monoxide 1567 (114) Inhaled carbon monoxide (CO) diffuses readily across the membranes of the alveolar 1568 interstitial region of the lung and enters the pulmonary blood, where it is bound to 1569 haemoglobin (ICRP, 1987). It is released from haemoglobin and removed from the body in 1570 expired air over a period of hours. In ICRP Publication 30 (1981) it is assumed that 40% of 1571 inhaled CO is instantly absorbed to blood and bound to hemoglobin, and 60% is instantly 1572 exhaled. Carbon monoxide bound to haemoglobin is assumed to be uniformly distributed 1573 throughout all organs and tissues and retained with a biological half-life of 200 min. As 1574 discussed in a later section, essentially the same model is applied in this report to inhaled 1575 carbon monoxide. 1576 1577 Inhaled methane 1578 (115) In ICRP Publication 80 (1998) (in an addendum to ICRP Publication 72, 1996) and 1579 Publication 88 (2001) it is assumed that 1% of radiocarbon inhaled as methane is absorbed to 1580 blood from the lungs and subsequently metabolized. The conservative assumption is made 1581 that one half of the metabolized fraction follows the biokinetics of carbon dioxide and one 1582 half follows the biokinetics of organic carbon as described by models applied in that report to 1583 these forms of carbon. 1584

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1585 Carbon reaching blood as carbon dioxide or bicarbonate 1586 (116) Inhaled carbon dioxide (CO2) is transferred rapidly across the alveolar membrane 1587 into blood (Guyton, 2000). Carbon dioxide is also formed in the body during the metabolism 1588 of organic substances. Because most of the absorbed or internally produced CO2 is converted 1589 to bicarbonate after entering blood (Guyton, 2000), data from metabolic studies involving 14 1590 intravenous injection of [ C]bicarbonate provide information on the systemic biokinetics of 1591 carbon inhaled as CO2. 14 1592 (117) Data for intravenously injected [ C]bicarbonate were used in the development of the 1593 model for inhaled CO2 introduced in ICRP Publications 30 (1981) and applied in several 1594 subsequent ICRP documents on occupational or environmental intake of radionuclides. 1595 According to that model, inhaled CO2 is rapidly and completely absorbed from the lungs and 1596 distributed uniformly throughout the body. Retention, R(t), is described by the sum of three 1597 exponential terms: 1598 1599 R(t) = 0.18 exp(-0.693t/5) + 0.81 exp(-0693t/60) + 0.01 exp(-0.693t/60,000), (Eq. 1) 1600 1601 where t is in minutes. The first two terms are based on a two-exponential curve fit to data of 14 1602 Winchell et al. (1970) on retention of C in 13 normal human subjects over the first 120 min 14 1603 after intravenous injection with [ C]bicarbonate. The third term was added to represent a 1604 small component of relatively long-term retention observed in laboratory animals 14 1605 administered CO2 by inhalation. The coefficient of the third term, 0.01, is based on the 1606 interpretation that the two short-term components of retention identified in the subjects of 1607 Winchell and coworkers accounted for at least 99% of the administered activity. The 1608 removal half-time associated with the third term (~40 d) is the estimated effective half-time 1609 for dietary carbon in a typical adult human, i.e. assuming the body’s carbon behaves as a 1610 single well-mixed pool. 1611 (118) ICRP Publication 80 (1998), which addresses doses from radiopharmaceuticals, 14 1612 describes a recycling model for C as carbon dioxide or bicarbonate formed in the body after 14 1613 administration of C-urea. The model adds bone compartments to a recycling model of 14 1614 Winchell and coworkers (1970) developed from the same [ C]bicarbonate injection data 1615 used by the authors of ICRP Publication 30 to derive the model for inhaled carbon dioxide. 1616 The model of Publication 80 contains a central blood compartment that exchanges carbon 1617 with four tissue compartments: a rapid-turnover soft-tissue compartment, a slow-turnover 1618 soft-tissue compartment (T1/2 ~ 40 d), and two bone compartments representing trabecular 1619 and cortical bone. The bone compartments return carbon to blood at the rate of bone turnover. 1620 Carbon is lost from the body by transfer from blood to the environment in expired air. 1621 (119) Leggett (2004) proposed a more detailed recycling biokinetic model for systemic 1622 radiocarbon taken into the body as carbon dioxide or bicarbonate. Parameter values 1623 describing retention and excretion of activity during the first few weeks after administration 1624 were based on studies of the fate of radiocarbon in human subjects after intake of labeled 1625 bicarbonate or carbon dioxide. Data from laboratory animals given labeled bicarbonate, 1626 carbon dioxide, or carbonate were used to model the tissue distribution and the long-term 1627 retention of carbon. The model includes a central blood compartment that exchanges carbon 1628 with six soft tissue compartments and five bone compartments representing different phases 1629 of retention as indicated by the experimental data. In addition to loss of label through 1630 exhalation of carbon dioxide, the model depicts small losses in urine and faeces and through 1631 skin. The model provides a reasonably close reproduction of reported biokinetic data from 1632 studies of human subjects exposed to labeled bicarbonate or carbon dioxide. The model was 1633 designed to yield higher total-body retention and bone retention of activity than observed in

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1634 laboratory animals exposed to carbon dioxide or bicarbonate in view of the relatively high 1635 metabolic rates and bone turnover rates in the studied animal species. A modified version of 1636 Leggett’s model, described in a later section, is applied in this report to radiocarbon entering 1637 blood as carbon dioxide or bicarbonate. 1638 1639 Inhaled benzene 1640 (120) A biokinetic model for radiocarbon inhaled as benzene was proposed by Krins et al. 1641 (2003). Transfer coefficients depend on the concentration of benzene in air. It is assumed 1642 that inhaled benzene is immediately deposited in a blood pool that exchanges activity with 1643 five compartments: adipose tissue, a muscle group, an organ group, bone marrow, and liver. 1644 The bone marrow and liver compartments feed a metabolite compartment that circulates the 1645 metabolites through the body. The bone marrow and liver compartments are governed by 1646 Michaelis-Menten kinetics such that excretion is nearly equally divided between urine and 1647 breath at high concentrations of benzene in air and is primarily (~90%) in urine at low 1648 concentrations. The water soluble metabolites empty into the urinary bladder after removal 1649 from blood by the kidneys. 1650 1651 Dietary carbon 1652 (121) A number of biokinetic models have been proposed for purposes of estimating 14 1653 radiation doses due to ingestion of C in food and drink. Relatively detailed models with 1654 varying levels of physiological realism have been proposed in recent years by Richardson and 1655 Dunford (2003a,b), Whillans (2003), Galeriu et al. (2009) and Manger (2011). A 1656 physiologically detailed biokinetic model proposed by Richardson and Dunford (2003a,b) 1657 separates dietary carbon into carbohydrates, lipids, and protein. A relatively complex version 1658 of the model further divides carbohydrates into glucose and glycogen, lipids into adipose fat 1659 and fatty acids, and protein into amino acids and soft tissue proteins. The biokinetics of 1660 carbon or other major elements that form the structure of the principal nutrients 1661 carbohydrates, fats, and proteins (hydrogen, nitrogen, oxygen) is assumed to be determined 1662 primarily by the oxidation of glucose, fatty acids, and amino acids and the formation of 1663 water, carbon dioxide, and urea. Carbon-specific transfer coefficients were not presented by 1664 Richardson and Dunford. A simpler biokinetic model for carbon proposed by Whillans 1665 (2003) also separates dietary carbon into carbohydrates, fat, and protein. Transfer coefficients 1666 are based on intakes by Reference Man (ICRP, 1975) and transfer rates suggested by Brown 1667 and Chant (1995). A model proposed by Galeriu et al. (2009) uses anatomical compartments 1668 and transfer coefficients determined from reference physiological constants such as metabolic 1669 rates, body energy densities, and empty body masses. Transfer coefficients were developed 1670 for various farm animals. Organ compositions for farm animals were based on reference 1671 values for man. Organ masses, energy expenditures, and intakes of organic carbon were taken 1672 from the literature on animal metabolism, nutrition, and physiology. 1673 1674 Ingested urea 1675 (122) The urea breath test is a diagnostic method to test for Helicobacter pylori (Hp) 14 1676 infection by oral administration of a cocktail of C-labelled urea to the patient. A biokinetic 14 1677 model for orally administered C-labelled urea is described in ICRP Publication 80 (1998). 14 1678 For the normal case, C-urea is assumed to be completely absorbed by the stomach with a 1679 half-life of 5 minutes. In the Hp positive case, it is assumed that 65% of the intake is 1680 immediately converted into carbon dioxide, and the remaining 35% is absorbed by the 1681 stomach as in the normal case. The urea absorbed by the stomach is rapidly distributed in the 1682 total body water. Eighty percent of the urea in the total body water is excreted by the kidneys

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1683 with a half-time of 6 h, and 20% is rapidly dissociated to ammonia and carbon dioxide and 1684 treated according to the biokinetic model for carbon dioxide used in ICRP Publication 80. 1685 1686 Ingested triolein (glycerol trioleate) 14 1687 (123) Gunnarsson et al. (2000) studied the biokinetics of ingested C-triolein by 1688 performing breath tests on human subjects. The investigators later (Gunnarsson et al., 2003) 14 1689 developed a biokinetic model from the derived data and an ICRP model for C-labelled 14 1690 neutral fat (ICRP, 1993). Ingested C-triolein rapidly passes through the stomach into the 1691 small intestine, where 70% of the ingested material is transported to the liver following 14 1692 hydrolysis. In the liver, 28% of the fat compound is metabolized to CO2 (T1/2 = 1 h) and 1693 transported to the bicarbonate pool. The remaining 42% becomes incorporated into adipose 1694 tissue (85%) (a1=57%, T1/2 = 2 days; a2 = 43%, T1/2 = 137-620 days), muscle (10%) (T1/2 = 2 1695 days), and other organs (5%) (T1/2 = 137-620 days), where the triglycerides are oxidized and 1696 transferred to the bicarbonate pool (Gunnarsson et al., 2003). The kidney-bladder system 1697 receives 25% of the administered activity (T1/2 = 4 h). The remaining 5% of the administered 1698 activity passes through the gastrointestinal tract and is excreted in faeces. 1699 1700 Ingested glycocholic acid 14 1701 (124) [1- C]-Glycocholic acid (GCA) is used to investigate abnormal bacterial 1702 overgrowth or reduced resorption of bile acids in the small intestine. Gunnarsson (2002) 1703 developed a model for the ingestion of labeled GCA consisting of three main physiological 1704 pathways, one involving the conjugated compound, a second involving a liberated glycine 1705 moiety, and a third representing activity converted to carbon dioxide. According to the 1706 model, the ingested conjugated bile acid is absorbed primarily by the terminal ileum during 1707 the enterohepatic cycle and becomes almost exclusively confined to the lumen of the biliary 1708 ducts, gut, and liver. The bile acid undergoes enterohepatic circulation roughly six times per 1709 day. Approximately 18% of the bile acid is deconjugated during each enterohepatic 14 1710 circulation, resulting in a biological half life of 19 h. For the normal case, 46% of the [1- C]- 1711 glycine is transported rapidly through the intestinal tract [T1/2 = 3 h (11%), T1/2 = 14 h 14 1712 (89%)], converted to CO2 by the bacteria in the colon, and transported to the bicarbonate 1713 pool to be exhaled. Roughly the same amount (44%) is transported in the blood from the liver 1714 and incorporated into tissue proteins, where glycine is metabolized to CO2 by tissue enzymes 1715 and transferred to the bicarbonate pool [T1/2 = 6 days (70%) and T1/2 = 77 days (30%)]. The 1716 distribution of glycine within the tissue proteins is divided according to protein contents in 14 1717 various organs (ICRP, 1975). A small fraction (2.5%) of the C is excreted in urine. The rest 1718 (7.5%) is excreted in faeces. 1719 1720 Ingested xylose 1721 (125) Xylose is a monosaccharide used for the diagnosis of abnormal intestinal bacterial 14 1722 flora. Gunnarsson (2002) developed a model for the ingestion of D-[U- C]-xylose. 1723 According to the model, ingested xylose is transported from the stomach to the small 1724 intestines where a major fraction is absorbed and transported to the plasma and extracellular 1725 fluid. It is assumed that 70% of the absorbed xylose is excreted in urine with a half-time of 1726 2.5 h and the remaining 30% is exhaled. Of the exhaled activity, fractions 0.168, 0.232, and 1727 0.6 are removed with half-times 1.1 h, 3 d, and 60 d, respectively. The 3-d half-time is 1728 associated with metabolism of xylose in the liver. The 60-d half-time is associated with 14 1729 incorporation of xylose in adipose tissue and metabolism to CO2. 1730

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1731 3.2.3.2. Biokinetic models for systemic carbon used in this report 1732 1733 Inhaled carbon monoxide 1734 (126) The model for inhaled carbon monoxide used in this report is based on deposition 1735 fractions and retention half-times applied in ICRP Publication 30 (1981) and Publication 1736 71(1995). It is assumed that 40% of inhaled CO is instantly absorbed to blood and bound to 1737 hemoglobin and 60% is instantly exhaled. Carbon monoxide is assumed to be lost from blood 1738 to the environment via the lungs with a biological half-time of 200 min (Glass et al., 1968; 1739 Peterson and Stewart, 1970). 1740 1741 Carbon reaching blood as carbon dioxide or bicarbonate 1742 (127) A variation of the model of Leggett (2004) described earlier is applied in this report 1743 to radiocarbon assumed to reach blood as carbon dioxide or bicarbonate, e.g. as inhaled 1744 carbon dioxide or ingested or intravenously injected bicarbonate. The structure of the 1745 modified model is shown in Figure 3-1. Parameter values are listed in Table 3-5. The 1746 modifications were made to make the model more consistent with the generic modeling 1747 scheme used in this report, simplify implementation of the model by reducing the total 1748 numbers of compartments and pathways, and improve predictions of the long-term urinary 1749 excretion rate by including additional phases of transfer from soft tissues to the urinary 1750 excretion pathway. The modified model adds a blood compartment (Blood 2 in Figure 3-1) 1751 and some paths of movement of carbon but simplifies the original model overall by 1752 eliminating compartments and pathways depicting rapid exchange of activity between blood 1753 and peripheral compartments. The eliminated features of the original model are not of much 1754 practical importance in radiation protection. 1755

1756 1757 Figure 3-1. Structure of the systemic model used in this report for carbon taken into the body 1758 as carbon dioxide or bicarbonate (simplification of a model of Leggett, 2004) 1759 1760 (128) In the model, absorbed carbon is assigned to Blood 1. Activity leaves Blood 1 at the -1 1761 rate 100 d (T1/2 = 10 min), with 60% of the outflow assigned to ST0, 1.8% to ST1, 0.3% to 1762 ST2, 0.44% to ST3, 0.15% to bone surface, 0.01% to bone volume, 36.2% to excreta through 1763 exhalation, 0.3% to excreta via skin, 0.65% to the bladder contents, and 0.15% to the right

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1764 colon contents. Removal half-times from ST0, ST1, ST2, and ST3 are 20 min, 0.5 d, 3 d, and 1765 40 d, respectively. It is assumes that 4% of outflow from ST1, ST2, and ST3 enters Blood 2 1766 and all other outflow from the four soft tissue compartments returns to Blood 1. Activity -1 1767 transfers from Blood 2 to the urinary bladder contents at the rate 1000 d (T1/2 = 1 min). 1768 Based on estimates of the relative masses of trabecular and cortical bone replaced per unit 1769 time in an adult human, 60% of carbon entering bone is assigned to trabecular bone and 40% 1770 is assigned to cortical bone. The trabecular and cortical bone surface compartments are 1771 assumed to lose carbon to Blood 1 with a half-time of 40 d. The bone volume compartments 1772 are assumed to lose carbon to Blood 1 at the rate of bone turnover, which differs for 1773 trabecular and cortical bone. 1774 Table 3-5. Transfer coefficients for the systemic model used in this report for radiocarbon assumed to reach blood as carbon dioxide or bicarbonate

From To Transfer coefficient (d-1) Blood 1 Excreta (exhalation) 36.2 Blood 1 Excreta (via skin) 0.3 Blood 1 Urinary bladder contents 0.65 Blood 1 Right colon contents 0.15 Blood 1 ST0 60 Blood 1 ST1 1.8 Blood 1 ST2 0.3 Blood 1 ST3 0.44 Blood 1 Trabecular bone surface 0.09 Blood 1 Cortical bone surface 0.06 Blood 1 Trabecular bone volume 0.006 Blood 1 Cortical bone volume 0.004 ST0 Blood 1 49.91 ST1 Blood 1 1.331 ST2 Blood 1 0.2218 ST3 Blood 1 0.01664 ST1 Blood 2 0.05545 ST2 Blood 2 0.009242 ST3 Blood 2 0.0006931 Blood 2 Urinary bladder contents 1000 Trabecular bone surface Blood 1 0.01733 Cortical bone surface Blood 1 0.01733 Trabecular bone volume Blood 1 0.000493 Cortical bone volume Blood 1 0.0000821 1775 1776 (129) Total-body retention of carbon following acute input of carbon dioxide or 1777 bicarbonate into blood based on the present model agrees closely with predictions based on 1778 the original model (Leggett, 2004). Also, in agreement with the original model, the present 1779 model predicts that exhalation, urinary excretion, faecal excretion, and loss through skin 1780 accounts for 96.8%, 2%, 0.4%, and 0.8%, respectively, of the total loss of activity from the 1781 body over an extended period. The present model predicts slower accumulation of activity in 1782 bone than the original model, but the two models predict similar levels of activity in bone 1783 beyond a few days after acute input of activity to blood. For example, the present model 1784 predicts that bone contains 0.41% of intake at 1 d, 0.36% at 10 d, and 0.098% at 100 d after 1785 intake, compared with predictions of 0.89% at 1 d, 0.38% at 10 d, and 0.096% at 100 d based

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1786 on the original model. In view of the uncertainty in the early distribution of radiocarbon in 1787 bone, a relatively long residence time of carbon on bone surface (40 d) is assigned in the 1788 original model as a dosimetrically cautious measure. 1789 1790 Inhaled methane 1791 (130) The available data indicate that some radioactive carbon-labelled methane is 1792 oxidised to carbon dioxide (Dougherty et al., 1967), but a large fraction is organically bound 1793 (Carlisle et al., 2005). In ICRP Publication 80 (1998) (in an addendum to ICRP Publication 1794 72, 1996) and in ICRP Publication 88 (2001) the assumption is made that one half of the 1795 metabolised fraction is retained with the half-time of carbon dioxide and one half with that of 1796 organic carbon (ICRP Publication 80, 1998). That assumption is also made here: 50% of 1797 radiocarbon in the absorbed methane enters the blood pool in the carbon dioxide model 1798 (Figure 3-1 and Table 3-5) and follows the kinetics described in that model, and 50% enters 1799 the blood pool in the generic carbon model (described below) and follows the kinetics 1800 described in that model. 1801 1802 Generic model for systemic carbon 1803 (131) For general radiological protection purposes a generic biokinetic is applied in this 1804 report to radiocarbon absorbed to blood following intake in forms other than carbon 1805 monoxide, carbon dioxide, bicarbonate, or methane. The model is less conservative than the 1806 ICRP’s previous generic systemic model for carbon, which assigns a 40-d half-time to 1807 absorbed radiocarbon, but accounts for the possibility that a dosimetrically significant portion 1808 of absorbed radiocarbon may be retained in the body for an extended period. Based on its 1809 design and on comparison of dose estimates with biokinetic models for a number of specific 1810 forms of carbon, the revised generic model seems more likely to overestimate than 14 1811 underestimate dose per unit intake of C in the workplace. 1812 (132) The generic model structure and its connections to the respiratory and alimentary 1813 tract models and urinary bladder are shown in Figure 3-2. Baseline transfer coefficients for 1814 systemic pathways are listed in Table 3-6. 1815 (133) The revised model is based on consideration of retention times and rates of loss 14 1816 along specific excretion pathways identified in published studies of C-labeled carbon 1817 compounds. The model was designed with the goal of providing cautious but not 1818 unnecessarily conservative estimates of dose per unit intake of unknown forms of 1819 radiocarbon, as judged from published biokinetic data for carbon compounds. It was also 1820 considered that the model should be adaptable to case-specific information such as 1821 measurement of the rates of urinary excretion and exhalation of activity following exposure 1822 to a carbon compound in the workplace. 1823 (134) The excretion pathways addressed in the model are urinary and faecal excretion and 1824 exhalation. Three systemic compartments are used to represent blood, relatively short-term 1825 retention in systemic tissues, and relatively long-term retention in systemic tissues. The 1826 short-term compartment represents losses with a half-time of a few days, which typically 1827 accounts for most of the loss of the label from the body as indicated by published studies of 1828 different carbon compounds. The long-term compartment depicts the longer removal half- 1829 times depicted in several models for specific carbon compounds. This long-term retention is 1830 generally associated in these models with adipose tissue. The carbon dioxide / bicarbonate 1831 model defined in Figure 3-1 and Table 3-5 is included as a submodel that describes the fate of 1832 labeled carbon dioxide produced in systemic tissues by metabolism of the initial form of 1833 carbon that reaches blood. Carbon dioxide produced in systemic tissues is assumed to move 1834 instantly to the compartment Blood 1 in the carbon dioxide model (Figure 3-1).

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1835

1836 1837 1838 Figure 3-2. Generic structure for radiocarbon labelled substances. SI is small intestine contents, 1839 and HRTM is the Human Respiratory Tract Model 1840 Table 3-6. Transfer coefficients for the generic model for systemic carbon

Baseline transfer Path coefficients (d-1) Blood to Systemic Tissue (Short-Term) 1.27 Blood to Systemic Tissue (Long-Term) 0.276 Blood to Bladder 1.51 Systemic Tissue (Short-Term) to CO2 Model 0.062 Systemic Tissue (Short-Term) to Blood 0.095 Systemic Tissue (Short-Term) to Colon 0.070 Systemic Tissue (Long-Term) to CO2 Model 0.0099 1841 1842 (135) For the case of ingested radiocarbon, activity moves through the alimentary tract as 1843 described in the Human Alimentary Tract Model and is nearly completely (99%) absorbed to 1844 blood from the small intestine contents (SI). Blood loses activity with a half life of 5 hours, 1845 with 50% of the outflow assigned to the urinary bladder contents; 40% to the short-term 1846 systemic compartment, and 10% to the long-term compartment. The short-term systemic 1847 tissue compartment loses activity with a half-life of 3 days. Outflow from this compartment 1848 is divided as follows: 40% returns to Blood, 30% is secreted into the colon contents and

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1849 subsequently excreted in faeces, and 30% moves to Blood 1 in the carbon dioxide model 1850 (Figure 3-1). Carbon entering the long-term retention compartment is assumed to be 1851 metabolized slowly to carbon dioxide, which moves to Blood 1 in the carbon dioxide model 1852 with a half-time of 70 d. 1853 (136) For the case of inhaled radiocarbon, activity enters the Human Respiratory Tract 1854 Model (HRTM) and is absorbed to blood or transported to the alimentary tract over time. 1855 Activity moving from the HRTM to blood or to the alimentary tract is treated as described 1856 above for the ingestion case. 1857 (137) The baseline transfer coefficients for the systemic pathways (Table 3-6) were 1858 determined by fitting central estimates of excretion rates determined in studies involving 1859 administration of different carbon compounds. Average fractional excretion along the major 1860 excretion pathways was estimated as 0.59 for urine (range, 0.01 – 1.00), 0.24 for exhalation 1861 (range, 0 – 0.95), and 0.17 for faeces (range, 0 – 0.99) (Crawley, 1977; Baker et al., 1954; 1862 Fine et al., 1962; Berlin and Tolbert, 1955; Hellman et al., 1955; Fukushima et al., 1954; 1863 Sandberg and Slaunwhite, 1957; Migeon et al., 1956; Hellman et al., 1954; Thierens et al., 1864 1994; ICRP, 1987; ICRP, 1998; Stather et al., 1981; Crawley and Haines, 1979; Eriksson et 1865 al., 1998; Webber et al., 2003). Up to three phases of urinary excretion were determined in 1866 different studies, depending in part on the length of the observation period (Fukushima et al., 1867 1954; Berlin and Tolbert, 1955; Hellman et al., 1955; Migeon et al., 1956; Sandberg and 1868 Slaunwhite, 1957; Crawley, 1977; ICRP, 1987; Kramer et al., 1996; Eriksson et al., 1998; 1869 Webber et al., 2003). The average half-time was 0.43 d (range 0.07-1.0 d) for the fastest 1870 phase, 3.3 d (range, 0.29-7.0 d) for the intermediate phase, and 70 d (range 33-620 d). The 1871 fast phase typically represented 85% or more and the intermediate component about 5% of 1872 total urinary excretion. In the generic model, the fast phase of loss is represented mainly by 1873 transfer from blood to the urinary bladder contents, and removal half-times and pathways 1874 from the two systemic tissue compartments are used to account for the intermediate and long- 1875 term phases of loss inferred from the published data. 1876 (138) The systemic transfer coefficients shown in Table 3-6 were derived by fitting the 1877 excretion data using computer software. The same type of fitting procedure could be used to 1878 derive case-specific transfer coefficients for the model if reliable bioassay data are available. 14 1879 For example, bioassay data might indicate different fractional excretion of C in urine, 1880 breath, and faeces, or different phases of urinary excretion from those used to derive the 1881 baseline transfer coefficients. 14 1882 (139) Cumulative activity of intravenously injected C in the body based on the generic 1883 model was compared with predictions of models described earlier for benzene, glycocholic 1884 acid, triolein, urea, and xylose, and with the model for inulin described in ICRP Publication 1885 53 (1987). These compounds represent some of the longest and some of the shortest retention 1886 times that have been determined for carbon compounds. Comparison was also made with the 1887 generic systemic model for carbon used in ICRP Publication 71 (1995). Results of the 1888 comparison are shown in Table 3-7. 1889

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Table 3-7. For intravenous injection of 14C, comparison of cumulative activity in the body as predicted by the revised generic model and by existing models for various specific carbon compounds

Modela Nuclear transformations expressed as multiple of value predicted by the revised generic model Revised generic model 1 Benzene 0.05 Glycocholic Acid 1 Inulin (ICRP, 1987) 0.04 Triolein 1 Urea 1 Xylose 2 Generic model in ICRP Publication 71 (1995)b 5 a Models described in this report except for inulin. b Assumes uniform distribution in body and biological half-time of 40 d. 1890 1891 3.3. Individual monitoring 1892 14 1893 (140) C intakes are generally monitored though measurements of the activity excreted in 1894 urine. The most common method of analysis is liquid scintillation counting. Measurements of 14 1895 activity in exhaled breath may be used for C-labeled organic material metabolized to CO2 1896 but there are no information on MDAs or routine use of the technique. 1897 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 14C Urine Bioassay Liquid Scintillation 60 Bq/L 1-5 Bq/L Counting 1898 1899 References 1900 1901 Baker, N., Shreeve, W.W., Shipley, R.A., Incefy, G. E., Miller, M. 1954. C14 studies in carbohydrate 1902 metabolism I. The oxidation of glucose in normal human subjects. J. Biol. Chem. 211, 575- 1903 592. 1904 Berlin, N.I., Tolbert, B.M., 1955. Metabolism of glycine-2-14C in man: V. Further considerations of 1905 pulmonary excretions of C14O2. Proc. Soc. Exp. Biol. Med. 88, 386-389. 1906 Bond, J.A., Bechtold, W. E., Birnbaum, L. S., Dahl, A. R., Medinsky, M. A., Sun, J. D., and 1907 Henderson, R. F. (1991). Disposition of inhaled isoprene in B6C3F1 mice. Toxicol. Appl. 1908 Pharmacol. 107, 494-503. 1909 Bond, J. A., Dahl, A. R., Henderson, R. F., and Birnbaum, L. S. (1987). Species differences in the 1910 distribution of inhaled butadiene in tissues. Am. Ind. Hyg. Assoc. J. 48: 867-872. 1911 Bond, J.A., Dahl, A.R., Henderson, R.F., Dutcher, J.S., Mauderly, J.L., Birnbaum, L.S., 1986a. 1912 Species differences in the disposition of inhaled butadiene. Toxicol. Appl. Pharmacol. 84, 1913 617-627. 1914 Bond, J.A., Dutcher, J.S., Medinsky, M.A., Henderson, R.F., Birnbaum, L.S., 1985b. Disposition of 1915 [14C]methyl bromide in rats after inhalation. Fundam. Appl. Toxicol. 78, 259-267. 1916 Bond, J.A., Medinsky, M.A., Dutcher, J. S., Henderson, R. F., Cheng, Y. S., Mewhinney, J. A., and 1917 Birnbaum, L. S. (1985a). Disposition and metabolism of 2,3-[14C]dichloropropene in rats 1918 after inhalation. Toxicol. Appl. Pharmacol. 78, 47-54.

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1919 Bond, J.A., Baker, S.A., Bechtold, W.E., 1985c. Correlation of the octanol:water partition coefficient 1920 with clearance half-times of intratracheally instilled aromatic hydrocarbons in man. 1921 Toxicology 36, 285-295. 1922 Bond, J.A., Sun, J.D., Mitchell, C.E., Dutcher, J.S., Wolff, R.K., and McClellan, R.O., 1986b. 1923 Biological Fate of Inhaled Organic Compounds Associated With Particulate Matter. In 1924 Aerosols: Research, Risk Assessment and Control Strategies. (Eds. Lee, S.D., Schneider, T., 1925 Grant, L.D. and Verkerk, P.J.), Lewis, Chelsea, Michigan, pp. 579-592. 1926 Bratt, H., Hathway, D.E., 1977. Fate of methyl methacrylate in rats. Br. J. Cancer 36, 114-119. 1927 Brown, Jr., R.A., Schanker, L.S., 1983. Absorption of aerosolized drugs from the rat lung. Drug 1928 Metab. Dispos., 11, 355-360. 1929 Brown, R. M., Chant, L.A., 1995. The dietary intake, excretion and dosimetry of carbon-14. Atomic 1930 Energy Control Board (Canada), INFO-0510. 1931 Carlisle, S.M., Burchart, P.A., McCauley, C., Surette, R.P., 2005 Biokinetics of inhaled radioactive 1932 methane in rats: A pilot study. Appl. Radiat. Isot. 62, 847-860. 1933 Chan, T.L., Lee, P.S., Hering, W.E., 1981. Deposition and clearance of inhaled diesel exhaust 1934 particles in the respiratory tract of Fischer rats. J. Appl. Toxicol. 1, 77-82. 1935 Crapo, R.O., Morris, A.H. and Gardner, R.M., 1982. Reference values for pulmonary tissue volume, 1936 membrane diffusing capacity and pulmonary blood volume. Bull. Eur. Physiopathol. Respir. 1937 18(6), 893-899. 1938 Crawley, F E.H., Haines, J.W., 1979b. The dosimetry of carbon-14 labelled compounds: the 1939 metabolism of diethylenetriamine pentaacetic acid (DTPA) in the rat. Int. J. Nucl. Med. Biol. 1940 6, 9-15 1941 Crawley, F.E.H., 1977. The metabolism and dosimetry of carbon-14 labelled compounds. In Proc 1942 IVth Int. Congr. IRPA, 2. 425-428, Paris, April, 1977. 1943 Crawley, F.E.H., Goddard, E. A., 1977. Internal dose from carbon-14 labelled compounds. The 1944 metabolism of 14C-labelled potassium cyanide in the rat. Health Phys. 32, 135-142. 1945 Crawley, F.E.H., Haines, J.W., 1978. The metabolism and dosimetry of 14C-labelled compounds. 1946 NRPB/ R&D2. National Radiological Protection Board Annual Research and Development 1947 Report 1977, pp. 133-134. 1948 Crawley, F.E.H., Haines, J.W., 1979a. Further studies on the metabolism and dosimetry of 14C- 1949 labelled compounds. NRPB/ R&D3. National Radiological Protection Board Annual 1950 Research and Development Report 1978, pp. 105-106. 1951 Dahl, A.R., Birnbaum, L.S., Bond, J.A., Gervasi, P.G., Henderson, R.F., 1987. The fate of isoprene 1952 inhaled by rats: comparison to butadiene. Toxicol. Appl. Pharmacol. 89, 237-248. 1953 Dahl, A.R., Sun, J.D., Birnbaum, L.S., Bond, J.A., Griffith, W.C., Mauderly, J.L., Muggenburg, B.A., 1954 Sabourin, P.J., Henderson, R.F., 1991. Toxicokinetics of inhaled 1,3-butadiene in monkeys: 1955 comparison to toxicokinetics in rats and mice. Toxicol. Appl. Pharmacol. 110, 9-19. 1956 Dougherty, R.W., O’Toole, J.T., Allison, M.J., 1967. Oxidation of intraarterially administered C-14 1957 labelled methane in sheep. Proc. Soc. Exp. Biol. Med. 124, 1155-1157. 1958 Dudley, R.E., Muggenburg, B.A., Cuddihy, R.G., McClellen, R.O., 1980a. Absorption of 1959 diethylenetria-minepentaacetic acid (DTPA) from the respiratory tracts of beagle dogs. 1960 American Industrial Hygiene Association Journal (AIHAJ) 41, 5–11. 1961 Dudley, R.E., Muggenburg, B.A., Cuddihy, R.G., McClellen, R.O., 1980b. Nasal absorption of DTPA 1962 in rats. Health Phys. 38, 763–768. 1963 Dutcher, J.S., Medinsky, M.A., Bond, J.A., Cheng, Y.S., Snipes, M.B., Henderson, R.F., Birnbaum, 1964 L.S., 1985. Effect of vapor concentration on the disposition of inhaled 2,3-dichloropropene in 1965 Fischer-344 rats. Fundam. Appl. Toxicol. 5, 997-1005. 1966 Eriksson, B., Ottersgard Brorsson, A.–K., Hallstrom, G., Sjodin, T., Gunnarsson, P.O., 1998. 1967 Pharmacokinetics of 14C-delmopinol in the healthy male volunteer. Xenobiotica 28. 1968 Fine, M.G., Michaels, S., Shah, B., Chai, G., Fukuyama, G., Kinsell, L., 1962. The incorporation of 1969 C14 from uniformly labelled glucose in plasma triglycerides in normals and 1970 hyperglyceridemics. Metab. Clin, Exp. 11,, 893-911.

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1971 Fukushima, D.K., Dobriner, K. Gallagher, T.F., 1954. Studies with testosterone-d in normal men. J. 1972 Biol. Chem. 206, 845-861. 1973 Galeriu, D. Melintescu, A. Beresford, N.A., Takeda, H., Crout, N.M.J., 2009. The dynamic transfer of 1974 3H and 14C in mammals: a proposed generic model. Radiat. Environ Biophys 48, 29-45. 1975 Glass, H. I., Brant, A., Clark, J.C., de Garetta, A.C., Day, L.G., 1968. Measurement of blood volume 1976 using red cells labeled with radioactive carbon monoxide. J. Nucl. Med. 9:571-575. 1977 Greening, F.R., 1989. The characterization of carbon-14 rich deposits formed in the nitrogen gas 1978 annulus systems of 500 MWe CANDU reactors, Radiochimica Acta, 47, 209-217. 1979 Gunnarsson, M., 2002. Biokinetics and radiation dosimetry of 14C-labelled triolein, urea, glycocholic 1980 acid and xylose in man. Studies related to nuclear medicine breath tests using accelerator 1981 mass spectrometry. Doctoral Dissertation, University of Lund, Sweden. 1982 Gunnarsson, M., Mattsson, S., Stenström, K., Leide-Svegborn, S., Erlandsson, B., Faarinen, M. 1983 Hellborg, R., Kiisk, M., Neilsson, L-E., Nosslin, B., Persson, P, Skog, G., Aberg, M., 2000. 1984 AMS studies of the long-term turnover of 14C-labelled fat in man. Nucl. Instr. Meth. B., 172, 1985 939-943. 1986 Gunnarsson, M., Stenström, K., Ledie-Svegborn, S., Faarinen, M. Magnusson, C. E., Aberg, M., 1987 Skog, G., Hellborg, R., Mattsson, S., 2003. Biokinetics and radiation dosimetry for patients 1988 undergoing a glycerol tri[14C]oleate fat malabsorption breath test. Appl. Radiat. Isot., 58, 1989 517-526. 1990 Guyton, A.C., Hall, J.E., 2000. Textbook of Medical Physiology, 10th edition (WB Saunders). 1991 Hellman, L., Bradlow, H.L., Adesman, J., Fukushima, D.K., Kulp, J.L., Gallagher, T.F., 1954. The 1992 fate of hydrocortisone-1-C14 in man. J. Clin. Invest. 33, 1106-1115. 1993 Hellman, L., Rosenfeld, R.,S., Eidinoff, M.L., Fukushima, D.K., Gallagher, T.F., Wang, C-I., 1994 Adlersberg, D., 1955. Isotopic studies of plasma cholesterol of endogenous and exogenous 1995 origin. J. Clin. Invest. 34, 48-60. 1996 Henderson, R.F., Bechtold, W.E., Medinsky, M.A., P-Fischer, J., Lee, T.T., 1988. The effect of 1997 molecular weight/lipophilicity on clearance of organic compounds from lungs. Toxicol Appl. 1998 Pharmacol., B95B, 515–521. 1999 Henderson, R.F., Sabourin, P.J., Bechtold, W.E., Steinberg, B., Chang, I.Y., 1993. Disposition of 2000 inhaled isobutene in F344/N rats. Toxicol. Appl. Pharmacol. 123, 50-61. 2001 ICRP, 1975. Report of the Task Group on Reference Man, ICRP Publication 23, Pergamon Press, 2002 Oxford. 2003 ICRP, 1981. International Commission on Radiological Protection. Limits on Intakes of 2004 Radionuclides for Workers. ICRP Publication 30, Pt.3. Pergamon Press, Oxford. Ann. ICRP 2005 6. (2/3). 2006 ICRP, 1987. Doses to Patients from Radiopharmaceuticals. ICRP Publication 53 Ann. ICRP 18(1-4), 2007 43-53. 2008 ICRP, 1991. 1990 Recommendations of the International Commission on Radiological Protection. 2009 ICRP Publication 60, Ann. ICRP, 21(1-3). 2010 ICRP, 1993. Radiological Protection in Biomedical Research. ICRP Publication 62. Ann. ICRP 22 2011 (3). 2012 ICRP, 1994a. Human Respiratory Tract Model for Radiological Protection. ICRP Publication 66, 2013 Ann. ICRP, 24(1-3). 2014 ICRP, 1994b. Dose Coefficients for Intakes of Radionuclides by Workers. Replacement for ICRP 2015 Publication 61. ICRP Publication 68, Ann. ICRP, 24(4). 2016 ICRP, 1995. Age-dependent Doses to Members of the Public from Intakes of Radionuclides: Part 4 2017 Inhalation Dose Coefficients. ICRP Publication 71 Ann. ICRP, 25(3/4). 2018 ICRP, 1996. Age dependent Doses to Members of the Public from Intakes of Radionuclides: Part 5. 2019 Compilation of ingestion and inhalation dose coefficients. ICRP Publication 72. Ann. ICRP 2020 26 (1) 15 and 44. 2021 ICRP, 1998. Radiation doses to patients from radiopharmaceuticals. ICRP Publication 80, Ann. ICRP 2022 28(3). 2023 ICRP, 2001. Biokinetic Data and Models. ICRP Publication 88, Ann ICRP 31(1-3).

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2024 ICRP, 2002a. Guide for the Practical Application of the ICRP Human Respiratory Tract Model. Ann. 2025 ICRP 32(1-2). 2026 ICRP, 2002b. Basic Anatomical and Physiological Data for Use in Radiological Protection: Reference 2027 Values. ICRP Publication 89, Ann. ICRP 32(3-4). 2028 ICRP, 2008. The 2007 Recommendations of the International Commission on Radiological 2029 Protection. ICRP Publication 103. Ann. ICRP 37(2-4). 2030 Johnson, J.R., 1989. Lung retention and clearance classification of a 14C-containing aerosol produced 2031 during re-tubing of a nuclear reactor. Health Phys. 57, 645-647. 2032 Kramer, G.H., Badreddine, A., Tran, T., Meyerhof, D., 1996. Dosimetry of an accident involving 2033 14C. Health Phys. 70, 418-424. 2034 Kreyling, W.G., Semmler-Behnke, M., Seitz, J., Scymczak, W., Wenk, A., Mayer, P., Takenaka, S., 2035 Oberdörster, G., 2009. Size dependence of the translocation of inhaled and carbon 2036 nanoparticle aggregates from the lungs of rats to the blood and secondary target organs. 2037 Inhalation Toxicol., 21 (S1), 55–60. 2038 Krins, A., Karcher, K., Noβke, D., Sahre, P., Schonmuth, T., 2003. Determination of Dose 2039 coefficients and urinary excretion function for inhalation of carbon-14-labelled benzene. Rad 2040 Prot Dosim 104 (2), 139-152. 2041 Lai, C.W., Born, G.S., Kessler, W.V., Christian, J.E., Adams, J.W. Jr., 1978. Synthesis of 14C- 2042 labelled hydrolyzed polyacrylonitrile grafted cellulose and its metabolic fate. Int. J. Appl. 2043 Radiat. Isot. 29, 593-595. 2044 Lee, P.S., Chan, T.L., Hering, W.E., 1983. Long-term clearance of inhaled diesel exhaust particles in 2045 rodents, J. Toxicol. Environ. Health 12, 801-803. 2046 Lee, P.S., Gorski, R.A., Hering, W.E., Chan, T.L., 1987. Lung clearance of inhaled particles after 2047 exposure to carbon black generated from a resuspension system. Environ. Res. 43, 364-373. 2048 Leggett, R.W., 2004. A biokinetic model for carbon dioxide and bicarbonate. Radiat. Prot. Dosim. 2049 108(3), 203-213. 2050 Leide-Svegborn, S., Stenström. K., Olofsson, M., Mattsson, S., Nilsson, L-E., Nosslin, B., Pau, K., 2051 Johansson, L., Erlandsson, B., Hellborg, R. and Skog, G., 1999. Biokinetics and radiation 2052 doses for carbon-14 urea in adults and children undergoing the Helicobacter pylori breath test. 2053 Eur. J. Nucl. Med. 26, 573-580. 2054 Lipsett, M.J., Shusterman, D.J., Beard, R.R., 1994. Inorganic Compounds of Carbon, Nitrogen and 2055 Oxygen, Chapter Forty-four in Patty's Industrial Hygiene and Toxicology, Fourth Edition, 2056 Volume 2, Part F Toxicology, Clayton GD and Clayton FE (Editors) John Wiley and Sons, 2057 Inc. pp. 4523 - 4552. 2058 Manger, R.P., 2011. A generic biokinetic model for Carbon-14. Radiat. Prot. Dosim. 143(1), 42-51. 2059 Medinsky, M.A., Dutcher, J.S., Bond, J.A., Henderson, R.F., Mauderly, J.L., Snipes, M.B., 2060 Mewhinney, J.A., Cheng, Y.S., Birnbaum, L.S., 1985. Uptake and excretion of [14C]methyl 2061 bromide as influenced by exposure concentration. Toxicol. Appl. Pharmacol. 78, 215-225. 2062 Mewhinney, J.A., Ayres, P.H., Bechtold, W.E., Dutcher, J.S., Cheng, Y.S., Bond, J.A., Medinsky, 2063 M.A., Henderson, R.F., Birnbaum, L.S., 1987. The fate of inhaled azodicarbonamide in rats. 2064 Fundam. Appl. Toxicol. 8, 372-381. 2065 Migeon, C.L., Sandberg, A.A., Paul, A.C. Samuels, L.C., 1956. Metabolism of 4-C14-corticosterone 2066 in man. J. Clin. Endocrinol. Metab. 16, 1291-1298. 2067 Nomiyama, K., Nomiyama, H., 1974a. Respiratory retention, uptake and excretion of organic solvents 2068 in man. Benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl 2069 alcohol. Int. Arch. Arbeitsmed. 32, 75-83. 2070 Nomiyama, K., Nomiyama, H., 1974b. Respiratory elimination of organic solvents in man. Benzene, 2071 toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol. Int. Arch. 2072 Arbeitsmed. 32, 85-91. 2073 Oberdörster, G., Sharp, Z., Atudorei, V., Elder, A., Gelein, R., Lunts, A., Kreyling, W., Cox, C., 2002. 2074 Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation 2075 exposure of rats. J. Toxicol. Environ. Health - Part A, 66 (20), 1531–1543

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2076 Peterson, J.E., Stewart, R.D., 1970. Absorption and elimination of carbon monoxide by active young 2077 men. Arch. Environ. Health 21 165-171. 2078 Phipps, A.W. Kendall, G.M. Fell, T.P., Harrison, J.D., 1990. Doses from radioactive methane. Radiat. 2079 Prot. Dosim. 30, 191–195. 2080 Richardson, R.B., Dunford, D.W., 2003a. A biochemical-based model for the dosimetry of dietary 2081 organically bound tritium – Part 1: Physiological criteria. Health Phys. 85(5), 523-538. 2082 Richardson, R.B., Dunford, D.W., 2003b. A biochemical-based model for the dosimetry of dietary 2083 organically bound tritium – Part 2: Dosimetric evaluation. Health Phys. 85(5), 539-552. 2084 Sabourin, P.J., Chen, B.T., Lucier, G., Birnbaum, L.S., Fisher, E., Henderson, R.F., 1987. Effect of 2085 dose on the absorption of [14C] benzene administered orally or by inhalation in rats and mice. 2086 Toxicol. Appl. Pharmacol. 87, 325-336. 2087 Sabourin, P.J., Medinsky, M.A., Birnbaum, L.S., Henderson, R.F., 1992. Effect of exposure 2088 concentration on disposition of inhaled butoxyethanol by F344 rats. Toxicol Appl. 2089 Pharmacol. 114, 232-238. 2090 Sandberg, A.A., Slaunwhite, W.R., 1957. Studies on phenolic steroids in human subjects. II The 2091 metabolic fate and hepato-biliary-enteric circulation of C14-estrone and C14-estradiol in 2092 women. J. Clin. Invest. 36, 1266-1278. 2093 Simmons, P.S., Nissen, S., Haymond, M.W., 1982. Total body absorbed dose from [1-14C]-alanine 2094 for human studies. Health Phys. 43, 561-565. 2095 Stather J.W., Smith, H., Bailey, M.R., Birchall, A., Bulman, R.A., Crawley, F.E.H., 1983. The 2096 retention of 14C-DTPA in human volunteers after inhalation or intravenous injection.. Health 2097 Phys. 44, 45-52. 2098 Stather, J.W., Smith, H., Bailey, M.R., Birchall, A., Bulman, R.A., Crawley, F.E.H., 1981. The 2099 retention of 14C-DTPA in human volunteers after inhalation or intravenous injection. Health 2100 Phys. 44, 45-52. 2101 Stenström, K., Leide-Svegborn, S., Erlandsson, B., Hellborg, R., Mattsson, S., Nilsson, L-E., Nosslin, 2102 B., Skog, G., Wiebert, A., 1996. Application of Accelerator Mass Spectrometry (AMS) for 2103 High-sensitivity Measurements of 14CO2 in Long-term Studies of Fat Metabolism. Appl. 2104 Radiat. Isot., 47, 417-422. 2105 Taylor, D.M., 2004. Biokinetic models for the behaviour of carbon-14 from labelled compounds in 2106 the human body: Can a single generic model be justified? Radiat. Prot. Dosim. 108(3) 187- 2107 202. 2108 Taylor, D.M., 2007. Assessment of contributors to radiation dose following intakes of rapidly- 2109 excreted [14C]-compounds. Radiat. Prot. Dosim. 127, 440-443. 2110 Thierens, H., Van Eijkeren, M., Goethals, P., 1994. Biokinetics and dosimetry for [methyl- 2111 11C]thymidine. Br. J. Radiol. 67, 292-295. 2112 Webber, C., Roth, A., Persiani, S., Peard, A.J., Makovec, F., Kapil, R.P., John, B.A., Holding, J.D., 2113 D’Amato, M., Cybulski, Z.R., Chasseaud, L.F., Rovati, L.C., 2003. Pharmacokinetics and 2114 metabolism of cholecystokinin antagonist Dexloxiglumide in male human subjects. 2115 Xenobiotica 33, 625-641. 2116 Whillans, D., 2003. Structure of a physiologically-based Biokinetic model for use in 14C and OBT 2117 dosimetry. Radiat. Prot. Dosim. 105(1-4), 189-192. 2118 Winchel, H.S., Stahelin, H., Kusubov, N., Slanger, B, Fish, M., Pollycove, M., Lawrence, J.H., 1970. 2119 Kinetics of CO2-HCO3- in normal adult males. J. Nucl. Med. 11, 711-715. 2120 2121

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2122 2123 4. PHOSPHORUS (Z = 15) 2124 2125 4.1. Chemical Forms in the Workplace 2126 2127 (141) Phosphorus is a non-metal which occurs in numerous oxidation states, with V the 2128 most common. It is able to react chemically with many other elements to form organic and 2129 inorganic compounds. The most common phosphorus compounds in solution are phosphates, 2- 3- 2130 which occur in different forms depending on the pH (e.g. HPO4 , PO4 ). Phosphorus may be 2131 encountered in industry in a variety of chemical forms, including the oxide, hydride, halide, 2132 phosphate, phosphide and also organophosphorus and organophosphate. 33 2133 (142) Phosphorus-32 and P are routinely used to produce radiolabelled compounds. 2134 2135 Table 4-1. addressed in this report 2136 Isotope Physical half-life Decay mode P-32a 14.26 d B- P-33 25.34 d B- 2137 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 2138 are given on accompanying electronic disk. 2139 2140 4.2. Routes of Intake 2141 2142 4.2.1. Inhalation 2143 2144 Absorption Types and parameter values 2145 2146 (143) Information is available from a few experimental studies on the behaviour of inhaled 2147 phosphorus. However, most of it relates to phosphates for which the cation, rather than the 2148 phosphorus itself was radiolabelled. 2149 (144) Absorption parameter values and Types, and associated fA values for particulate 2150 forms of phosphorus are given in Table 4-2. 2151 2152 Sodium phosphate 32 2153 (145) Schiessle (1956, 1957) followed retention of P in guinea pigs for 28 days after 32 2154 inhalation of Na3( PO4). Most of the initial lung deposit (ILD) was absorbed over this 2155 period, but not very rapidly: there was little transfer to blood at the end of the 25-minute 2156 exposure, about 40% ILD remained after 1 day and 9% ILD after 28 days. (The author noted 2157 that there was greater uptake to bone compared to liver than after intravenous injection of 32 –1 2158 P.) Specific parameter values were estimated by the task group to be: fr = 0.8, sr = 1 d (t½ –1 2159 ~ 17 hours) and ss = 0.02 d (t½ ~ 3 d), consistent with assignment to Type F. Although 2160 specific parameter values for sodium phosphate based on in vivo data are available, they are 2161 not adopted here, because inhalation exposure to it is so unlikely. Instead, sodium phosphate 2162 is assigned to Type F. However, the data are used as the basis of the default rapid dissolution 2163 rate for phosphorus. 2164 2165 Phosphates labelled with isotopes of other elements 2166 (146) For details relating to zinc and yttrium refer to the sections dealing with the labelling 2167 radioelement. Details are given here for stannic phosphate because inhalation of has not 2168 been covered elsewhere yet.

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2169 2170 Zinc phosphate (Zn3(PO4)2) (See section 9.2.1) 65 2171 (147) The results of a study of inhalation of Zn3(PO4)2 by dogs were consistent with 2172 assignment to Type M. 2173 2174 Yttrium phosphate (YPO4) (See section 11.2.1) 2175 (148) The results of a study of inhalation of 91YPO4 by dogs were consistent with 2176 assignment to Type M. The authors (Newton et al., 1971) noted that following both 91 2177 inhalation and gavage of YPO4, the ratio of deposition in the skeleton to that in the liver 91 2178 was lower than following inhalation of other forms of Y. 2179 2180 Stannic phosphate 113 2181 (149) Morrow et al. (1968) followed lung clearance of Sn for 7 days after inhalation of 113 2182 Sn3(PO4)2 by dogs and rats, but few details are given. Lung retention in dogs was 2183 described by a two-component exponential function with half-times of 2 days (28%: -1 -1 2184 clearance rate 0.35 d ) and 59 days, (clearance rate 0.012 d ), giving predicted lung retention 2185 at 30 d and 180 d to be 50% and 8% of the initial lung deposit (ILD), and indicating Type M 2186 behaviour. 2187 2188 Rapid dissolution rate for phosphorus –1 2189 (150) The value of sr estimated for sodium phosphate above, 1 d , is applied here to all –1 2190 Type F forms of phosphorus. Because it is lower than the general default value of 3 d for 2191 Type M and S materials, it is also applied to Type M and S forms of phosphorus. 2192 2193 Extent of binding of phosphorus to the respiratory tract 2194 (151) Evidence from the sodium phosphate study outlined above suggests that there is 2195 probably little binding of phosphorus. It is therefore assumed that for phosphorus the bound 2196 state can be neglected, i.e. fb = 0.0. 2197 2198 Table 4-2. Absorption parameter values for inhaled and ingested phosphorus 2199 Absorption parameter valuesa Absorption from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorpti Assigned forms on Type F Sodium phosphate 1 1 – 0.8 M Yttrium, stannic and zinc 0.2 1 0.005 0.2 phosphates, all unspecified formsd S — 0.01 1 1x10-4 0.008 Ingested materials All unspecified forms 0.8

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a 2200 It is assumed that for phosphorus the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M 2201 and S forms of phosphorus (1 d–1) are element-specific. 2202 b Materials (e.g. sodium phosphate) are listed here where there is sufficient information to assign to a default 2203 absorption Type, but not to give specific parameter values (see text). 2204 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 2205 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the absorption 2206 Type and the fA value for ingested soluble forms of phosphorus (0.8). 2207 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, or 2208 if the form is known but there is no information available on the absorption of that form from the respiratory 2209 tract. 2210 2211 4.2.2. Ingestion 2212 2213 (152) Phosphorus intake is mainly through the diet in the form of inorganic phosphate and 2214 phosphorus-containing biomolecules such as nucleic acids and phospholipids. According to 32 2215 Eakins et al. (1966), fractional absorption of P from the gastro-intestinal tract is about 0.75 2216 when it is ingested as phosphate under normal dietary conditions, and is above 0.9 while 2217 fasting. The Food and Nutrition Board of the US Institute of Medicine reports absorption 2218 values ranging from 0.55 to 0.70 in adults and from 0.65 to 0.90 in infants and children 2219 (FNB, 1997). 2220 (153) Animal studies have shown that maximal absorption of phosphate occurs in the 2221 ileum for mice and in the duodenum and in the jejunum for rats (Radanovic et al., 2005: 2222 Stauber et al., 2005; Marks et al., 2006). Absorption of phosphorus can be reduced by the 2223 simultaneous administration of unusually high levels of calcium (FNB, 1997). According to 2224 recent findings, the intestinal transport process of inorganic phosphate is known to occur by 2225 both a sodium-independent, non saturable process and via an active process mediated by 2226 sodium-phosphate cotransporters (Katai et al., 1999a). Studies by Katai et al. (1999b) and by 2227 Kirchner et al. (2008) with rats showed that transporter-mediated absorption of inorganic 2228 phosphate is inhibited by nicotinamide and fructose, respectively. Intestinal sodium- 2229 dependent phosphate absorption was significantly reduced (reduction between 35% and 60%) 2230 in mice and rats with simulated inflammable bowel diseases (Chen et al., 2009).

2231 (154) In Publication 30 (ICRP, 1979), the recommended absorption value was 0.8 for all

2232 compounds of the element. This value is used here; that is, fA = 0.8 for all compounds. 2233 2234 4.2.3. Systemic Distribution, Retention and Excretion 2235 2236 4.2.3.1. Summary of the database 2237 2238 (155) Phosphorus represents roughly 1% of the weight of the human body. In adults about 2239 85% of the phosphorus is in bone, 9% is in muscle, and 6% is in remaining tissues and fluids. 2240 Most of the phosphorus in blood is contained in the red blood cells (RBC) (Eakins et al., 2241 1966; ICRP, 1975; Parfitt and Kleerekoper, 1980). 2242 (156) Normal dietary intake of phosphorus is about 1.0-1.5 g/d, in the form of inorganic 2243 phosphates, lipids, and proteins. Roughly three-fourths of phosphorus ingested as phosphate 2244 typically is absorbed to blood. Excretion is primarily in urine as inorganic phosphate (Eakins 2245 et al., 1966). 32 2246 (157) The rate of biological removal of P from the body varied widely in human subjects 32 2247 following intravenous injection of Na2H PO4 (Erf et al., 1941; Hevesy, 1948; Weijer et al., 2248 1962; Eakins et al., 1966). On average, about one-fourth of the administered amount was 2249 excreted in urine and faeces during the first six days, with urinary excretion generally

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2250 representing 90% or more of total excretion. Average daily excretion of activity as measured 2251 in four human injection studies is summarized in Figure 4-1. 2252

2253 2254 Figure 4-1. Average daily urinary excretion of phosphorus following intravenous injection into 2255 human subjects (data summarized by Eakins et al., 1966). The curve shows predictions of the 2256 systemic biokinetic for phosphorus used in this report. 2257 2258 (158) Following intravenous injection, labeled phosphorus is distributed throughout the 2259 extracellular fluids within a few minutes. Kinetic analysis indicates that the rapidly 2260 exchangeable pool is larger than the extracellular pool and thus presumably includes a 2261 portion of the intracellular phosphorus. Labeled phosphate is incorporated quickly into 2262 organic compounds in the body. The tissue turnover rate of phosphate as measured by the 2263 rate of exchange of radio-phosphorus depends on the rate of glycolysis of the tissue and is 2264 relatively high in red blood cells, intermediate in liver and heart, and low in resting muscle 2265 and nerve tissue (Parfitt and Kleerekoper, 1980). 2266 (159) Within a short time after administration of labeled phosphorus to human subjects or 2267 laboratory animals much of the activity accumulates in bone. The behavior of phosphorus in 2268 bone resembles that of calcium. Rapid uptake of both elements occurs on all bone surfaces, 2269 with considerable variability in the uptake rate between different bones and different surfaces 2270 of the same bone. Within a period of hours or days radioisotopes of phosphorus or calcium 2271 diffuse throughout bone volume. Both elements can penetrate into the interior of bone crystal. 2272 The exchangeable and non-exchangeable fractions of the total bone mineral are 2273 approximately the same for phosphorus and calcium (Neuman and Neuman, 1958; Parfitt and 2274 Kleerekoper, 1980). 2275 (160) As is the case for calcium, uptake of phosphorus is considerably greater in forming 2276 or growing bone than in mature bone. Labeled phosphorus and calcium both show high 2277 concentration in forming osteons (Parfitt and Kleerekoper, 1980). In rats injected 32 2278 intraperitoneally with P, skeletal uptake decreased with increasing age at injection, from 2279 about 90% of the injected amount at age 15 d to about 17% of the injected amount at age 170 2280 d (Bonner, 1948). 32 2281 (161) Stather (1974) compared the distribution and retention of P and the alkaline earths

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45 85 133 2282 Ca, Sr, and Ba in the mouse skeleton. At 24 h after intraperitoneal injection into 8-week 2283 old mice the distribution of the four radionuclides was virtually the same throughout the 2284 skeleton, but skeletal content as a percentage of injected activity differed from one 32 45 85 133 2285 radionuclide to another: P, 21.6%; Ca, 61.5%; Sr, 37.3%; and Ba, 48.8%. The 32 2286 skeletal burden represented about 37% of total body P compared with about 90% of total- 85 2287 body Sr. 32 45 2288 (162) Bauer and Carlsson (1955) compared the uptake of P and Ca by bone (tibial 2289 shaft) and incisors in adult rats over the first 5 d after simultaneous subcutaneous injection of 45 2290 these radionuclides. The percentage of the administered Ca found in bone was consistently 32 2291 about 2.3 times the percentage of administered P in the same bone samples at corresponding 45 32 2292 times after administration. The ratio of uptake of Ca and P was about the same for 2293 incisors as for bone. 2294 2295 4.2.3.2. Biokinetic model for systemic phosphorus 2296 2297 (163) Dyson (1966) proposed the compartment model shown in Figure 4-2 as a 2298 sufficiently close description of the biokinetics of phosphorus for radiation protection 2299 purposes. The flow rates are given in terms of the movement of stable phosphorus at 2300 equilibrium. It is assumed that 1 g of phosphorus is absorbed daily from dietary phosphorus. 2301 Presumably, 15% of phosphorus entering plasma is promptly excreted, and the rest is 2302 removed to cell fluids (15%), other soft-tissue components (40%), and bone (30%) with a 2303 half-time of 0.5 days. Phosphorus is returned to plasma from cell fluids and other soft-tissue 2304 components with half-times of 2 d and 19 d, respectively. The removal half-time from bone 2305 to plasma is long compared with the radiological half-lives of radioisotopes of phosphorus. 2306

2307 2308 Figure 4-2. Compartmental model of the biokinetics of systemic phosphorus proposed by Dyson 2309 (1966). The flow rates are given in terms of daily transfers of stable phosphorus at equilibrium. 2310 2311 (164) The biokinetic model for systemic phosphorus used in ICRP Publication 30 (1979) 2312 and ICRP Publication 68 (1994) is based on the model proposed by Dyson (1966). As 2313 implemented in Publication 68 (1994), activity leaves blood with a half-time of 0.5 d and is 2314 distributed as follows: 15% goes to excretion pathways; 30% goes to mineral bone, and 55% 2315 is uniformly distributed in remaining tissues (Other). Other is divided into two

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2316 compartments, one receiving 15% of activity leaving blood and having a removal half-time of 2317 2 d, and the second receiving 40% and having a half-time of 19 d. Activity is permanently 2318 retained in bone. Activity that is promptly excreted or removed from tissues transfers 2319 directly to the urinary bladder contents or right colon contents. A urinary to fecal excretion 2320 ratio of 9:1 is assigned. Phosphorous isotopes with half-life less than 15 d are assumed to be 2321 uniformly distributed on bone surfaces, and all others are distributed in bone volume. 2322 (165) The systemic model for phosphorus used in this report is broadly similar to the 2323 model of Dyson (1966) but describes the movement of phosphorus in more detail. The model 2324 istructure is shown in Figure 4-3. Parameter values are listed in Table 4-3. 2325

2326 2327 Figure 4-3. Structure of the model for systemic phosphorus. Abbreviations: exch = 2328 exchangeable, nonexch = non-exchangeable, RBC = red blood cells. 2329 -1 2330 (166) Phosphorus is assumed to leave blood plasma at the rate 50 d , corresponding to a 2331 removal half-time of 20 min. The outflow from plasma is divided as follows: 3% goes to red 2332 blood cells (RBC), 20% to the urinary bladder contents, 2% to the right colon contents, 20% 2333 to bone surfaces, and 55% to soft tissues. The soft tissues are divided into three 2334 compartments called ST0, ST1, and ST2, representing fast, intermediate, and slow turnover, 2335 respectively. These compartments receive 14.9%, 40%, and 0.1% of outflow from plasma, 2336 respectively, and return activity to plasma with half-times of 2 d, 20 d, and 5 y, respectively. 2337 The biokinetics of phosphorus in the skeleton is assumed to be identical to that of calcium, 2338 including the division of deposited activity between cortical and trabecular bone surfaces. 2339 Fractions 0.445 and 0.555 of the deposited amount (8.9% and 11.1% of the amount reaching 2340 blood) are assigned to cortical and trabecular surfaces, respectively. The transfer coefficients 2341 describing translocation of phosphorus within the skeleton and return from skeletal 2342 compartments to blood plasma are taken from the ICRP’s systemic model for calcium (ICRP, 2343 1995). 2344 2345

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2346

Table 4-3. Transfer coefficients (d–1) in the biokinetic model for systemic phosphorus.

Patha Transfer coefficient From To (d-1) Plasma Urinary bladder contents 10 Plasma Right colon contents 1.0 Plasma Trabecular bone surface 5.55 Plasma Cortical bone surface 4.45 Plasma ST0 7.45 Plasma ST1 20 Plasma ST2 0.05 Plasma RBC 1.5 RBC Plasma 0.13863 STO Plasma 0.34657 ST1 Plasma 0.034657 ST2 Plasma 0.00038 Cortical bone surface Plasma 0.578 Cortical bone surface Exch cortical bone volume 0.116 Trabecular bone surface Plasma 0.578 Trabecular bone surface Exch trabecular bone volume 0.116 Exch cortical bone volume Cortical bone surface 0.002773 Exch cortical bone volume Nonexch cortical bone volume 0.004159 Exch trabecular bone volume Trabecular bone surface 0.002773 Exch trabecular bone volume Nonexch trabecular bone volume 0.004159 Cortical bone volume Plasma 0.0000821 Trabecular bone volume Plasma 0.000493 a ST0, ST1, and ST2 represent soft tissues with fast, intermediate, and slow turnover, respectively; UB = urinary bladder; RBC = red blood cells; Exch = exchangeable; Nonexch = non-exchangeable. 2347 2348 4.3. Individual monitoring 2349 32 2350 (167) P is a pure beta emitter. Monitoring of individuals is done through urine bioassay 2351 techniques, typically liquid scintillation. 2352 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection Limit detection limit 32P Urine Bioassay Liquid 15 Bq/L 0.02Bq/L scintillation counting 2353 2354 References 2355 2356 Bauer, G.C.H., Carlsson, A., 1955. Metabolism of bone salt investigated by simultaneous 2357 administration of 45Ca and 32P to rats. J. Bone Joint Surg. 37B, 658-662. 2358 Bonner, J.F., Jr., 1948. The influence of aage on the uptake of radioactive phosphorus by the skeleton. 2359 PH.D. Thesis, University of Rochester. Also published by U.S. Atomic Energy Commission 2360 (AEC), Oak Ridge, TN, 9-24-48-1000, AECD – 1967. 2361 Chen, H., Xu, H., Dong, J., Li, J. and Ghishan, F. K., 2009. Tumor necrosis factor-alpha impairs 2362 intestinal phosphate absorption in colitis. Am. J. Physiol. Gastrontest. Liver Physiol. 296, 2363 G775-G781. 2364 Dyson, E.D., 1966. A specific activity method for derived working limits of phosphorus-32. Health 2365 Phys. 12, 1521-1526.

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2366 Eakins, J.D., Gomm, P.J., Jackson, S., 1966. The determination of phosphorus-32 in urine and the 2367 evaluation of the findings for the assessment of internal contamination. Health Phys. 12, 593- 2368 603. 2369 Erf, L.A., Tuttle, L.W., Lawrence, J.H., 1941. Clinical studies with the aid of radio-phosphorus. IV. 2370 The retention in blood, the excretion and the therapeutic effect of radio-phosphorus on 2371 patients with leukemia. Ann. Intern. Med. 15, 487-543. 2372 FNB, 1997. Food and Nutrition Board: Dietary reference intakes for calcium, phosphorous, 2373 , vitamin D and fluoride. National Academy Press, Washington DC, pp. 146-189. 2374 Hevesy, G., 1948. Radioactive indicators. New York: Interscience Publishers; pp. 97-128. 2375 ICRP, 1975. International Commission on Radiological Protection, Report of the Task Group on 2376 Reference Man, ICRP Publication 23. Oxford, Pergamon Press. 2377 ICRP, 1979. Limits for intakes of radionuclides by workers. ICRP Publication 30, Part 1. Oxford: 2378 Pergamon Press. 2379 ICRP, 1994. International Commission on Radiological Protection. Dose coefficients for intakes of 2380 radionuclides by workers, ICRP Publication 68. Oxford: Pergamon Press. 2381 ICRP, 1995. International Commission on Radiological Protection. Age-dependent doses to members 2382 of the public from intake of radionuclides, Part 3, ICRP Publication 69. Oxford: Pergamon 2383 Press. 2384 Katai, K., Miyamoto K., Kishida, S., Segawa, H., Nii, T., Tanaka, H., Tani, Y., Arai, H., Tatsumi, S., 2385 Morita, K., Taketani, Y. and Takeda, E., 1999a. Regulation of intestinal Na+-dependent 2386 phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3. Biochem 2387 J. 343, 705-712. 2388 Katai, K., Tanaka, H., Tatsumi, S., Fukunaga, Y., Genjida, K., Morita, K., Kuboyama, N., Suzuki, T., 2389 Akiba, T., Miyamoto, K. and Takeda, E., 1999b. Nicotinamide inhibits sodium-dependent 2390 phosphate cotransport activity in rat small intestine. Nephrol. Dial. Transplant 14, 1195-1201. 2391 Kirchner, S., Muduli, A., Casirola, D., Prum, K., Douard, V. and Ferraris, R. P., 2008. Luminal 2392 fructose inhibits rat intestinalsodium-phosphate cotransporter gene expression and phosphate 2393 uptake. Am. J. Clin. Nutr. 87, 1028-1038. 2394 Marks, J., Srai, S.K., Biber, J., Murer, H., Unwin, R. J. and Debnam, E. S., 2006. Intestinal phosphate 2395 absorption and the effect of vitamin D: a comparison of rats with mice. Exp. Physiol. 91, 531- 2396 537. 2397 Morrow, P.E., Gibb, F.R., Davis, H., Fisher, M., 1968. Dust removal from the lung parenchyma: an 2398 investigation of clearance stimulants. Tox. Applied. Pharm., 12, 372–396. 2399 Neuman, W.F., Neuman, M.W., 1958. The chemical dynamics of bone mineral. Chicago: University 2400 of Chicago Press. 2401 Newton, G.J., Hobbs, C.H., McClellan, R.O., 1971. The intraorgan distribution in the beagle dog of 2402 91Y inhaled as the oxide, phosphate and in fused clay. In: Fission Product Inhalation Program 2403 Annual Report 1970-1971, LF-44, pp. 76-80. Lovelace Foundation for Medical Education and 2404 Research, Albuquerque, New Mexico. Available from National Technical Information 2405 Service, Springfield, Virginia. 2406 Parfitt, A.M., Kleerekoper, M., 1980. The divalent ion homeostatic system – physiology and 2407 metabolism of calcium, phosphorus, magnesium, and bone. In: Maxwell, M. H.; Kleeman, C. 2408 R., eds. Clinical disorders of fluid and electrolyte metabolism, third edition. New York: 2409 McGraw-Hill; pp. 269-398. 2410 Radanovic, T.,Wagner, C. A, Murer, H. and Biber, J., 2005. Regulation of intestinal phosphate 2411 transport. I. Segmental expression and adaptation to low-Pi diet of the type IIb Na+-Pi 2412 cotransporter in mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physio.l 288, 2413 G496–G500. 2414 Schiessle, W., 1956. Die Bedeutung der radioaktiven Isotope (P32, I131) in der medizinischen 2415 Aerosolforschung Ztschr. f. Aerosol-Forsch. 5, 120-122. 2416 Schiessle, W. (1957) Tierexperimentelle Untersuchungen zur Verteilung von radioactivem Phosphor 2417 (P32), Jod (J131) und Zirkonium (Zr95) im Atemtrakt und in lungenfernen Organen nach 2418 Inhalation. Ztschr. f. Aerosol-Forsch. 6, 104-120.

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2419 Stather, J. W., 1974. Distribution of 32P, 45Ca, 85Sr and 133Ba as a function of age in the mouse 2420 skeleton. Health Phys. 26(1), 71-79. 2421 Stauber, A., Radanovic, T., Stange, G., Murer, H., Wagner, C. A. and Biber, J., 2005. Regulation of 2422 intestinal phosphate transport. II. Metabolic acidosis stimulates Na+-dependent phosphate 2423 absorption and expression of the Na+-Pi cotransporter NaPi-IIb in small intestine. Am. J. 2424 Physiol. Gastrointest. Liver Physiol. 288, G501–G506. 2425 Weijer, H.E., Duggan, H.E., Scott, D.B., 1962. Excretion of 32P after therapy for polycythemia rubra 2426 vera. J. Canad. Assoc. Radiol. 13, 81-85. 2427 2428 2429 2430 2431

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2432

2433 5. SULPHUR (Z = 16) 2434 2435 5.1. Chemical forms in the workplace 2436 2437 (168) Sulphur is a non-metal, which occurs mainly in oxidation states –I, -II, II, IV and VI. 2438 It is able to react chemically with many other elements, forming organic and inorganic 2- 2439 compounds. The most common sulphur compound in solution is sulphate (SO4 ). Sulphur-35 2440 is the only isotope of radiological significance that may be encountered in the workplace. It 2441 may occur in industry in a number of different chemical forms, including the gases hydrogen 2442 sulphide (H2S), sulphur dioxide (SO2) and sulphur trioxide (SO3), fluids or their vapours such 2443 as carbon disulphide (CS2), and solid compounds such as barium sulphate (BaSO4). In 2444 research laboratories, it can be present in a wide variety of compounds. 2445 2446 Table 5-1. Isotopes of sulphur addressed in this report 2447 Isotope Physical half-life Decay mode S-35a 87.51 d B- S-38 170.3 m B- 2448 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides are given 2449 on accompanying electronic disk. 2450 2451 5.2. Routes of Intake 2452 2453 5.2.1. Inhalation 2454 2455 (169) Some information is available on the behaviour of inhaled gases of sulphur in man 2456 and in experimental animals. Most of the information available on inhaled particulate forms 2457 of sulphur relates to sulphates. 2458 2459 Classification of gases and vapours, absorption Types and parameter values 2460 (170) Absorption parameter values and Types, and associated fA values for gas and vapour 2461 forms of sulphur are given in Table 5-2 and for particulate forms in Table 5-3. 2462 (171) Exposures to both gas/vapour forms and particulate forms of sulphur are common, 2463 and it is therefore proposed here that in the absence of site-specific information 50% 2464 particulate; 50% gas/vapour should be assumed (ICRP, 2002). 2465 2466 (a) Gases and vapours 2467 2468 Sulphur dioxide (SO2) 2469 (172) In two human studies (Speizer and Frank, 1966; Andersen et al., 1974), about 85% 2470 of the inhaled SO2 was deposited; all in the ET airways. In dogs, more than 95% of the 2471 inhaled gas was deposited in the ET airways during nose breathing and 50 – 90% during 2472 mouth breathing (Frank et al., 1967; 1969). A further study with dogs, in which the trachea 2473 was perfused with SO2, gave 90% deposition in the trachea (Balchum et al., 1960). Studies 2474 exposing rabbits to different SO2 concentrations gave 80% respiratory tract deposition at low 2475 concentrations (0.05 ppm), 98% at high concentrations (700 ppm) (Strandberg, 1964) and 2476 more than 90% upper airway deposition at concentrations between 100 and 300 ppm 2477 (Dalhamn and Strandberg, 1961). Absorption to blood of SO2 deposited in the respiratory

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2478 tract of dogs was consistent with assignment to Type F (Balchum et al., 1960; Frank et al., 2479 1967) For sulphur dioxide it is assumed here that there is 85% deposition in the respiratory 2480 tract (with default regional distribution, Table 5-2) and Type F absorption. 2481 2482 Carbon disulphide (CS2) 2483 (173) Studies have been performed with CS2 in mice, rats, dogs and man (Bergman et al., 2484 1984; McKenna and DiStefano, 1977; McKee et al., 1943; Teisinger and Souček, 1949). In 2485 all cases CS2 was taken up by the respiratory tract and absorbed into the blood. However, 2486 there is no information on the fraction of inhaled vapour deposited, or on the site of 2487 deposition. McKenna and DiStefano (1977) observed that CS2 uptake into blood was 2488 characterised by a single exponential with half-life of 19.3 minutes, consistent with 2489 assignment to Type F. For carbon disulphide it is assumed here by default that there is 100% 2490 deposition in the respiratory tract (with default regional distribution, Table 5-2) and Type F 2491 absorption. 2492 2493 Hydrogen sulphide (H2S) 2494 (174) Patty (1963) reported that H2S is absorbed through the lung and that H2S does not 2495 appear in exhaled breath, indicating that a large fraction is absorbed. In the absence of any 2496 real quantitative data on the fraction of H2S absorbed, the default option for gases and 2497 vapours is taken. For hydrogen sulphide it is assumed here that there is 100% deposition in 2498 the respiratory tract (with default regional distribution, Table 5-2) and Type F absorption. 2499 2500 Carbonyl sulphide (COS) 2501 (175) Little has been published on the uptake of COS. Patty (1963) noted that COS 2502 decomposes in water to H2S and CO2. On this basis it is assumed that the uptake of COS is 2503 the same as that of H2S: in the absence of specific information, the default option for gases 2504 and vapours is taken. For carbonyl sulphide it is assumed here that there is 100% deposition 2505 in the respiratory tract (with default regional distribution, Table 5-2) and Type F absorption. 2506 2507 (b) Particulate materials 2508 2509 (176) No detailed information is available on the rate of absorption of sulphur following 2510 respiratory tract deposition of particulate compounds other than sulphates (see below). 35 2511 However, two cases of accidental exposure of humans to S compounds have been reported. 2512 2513 Elemental sulphur 2514 (177) A worker was contaminated internally and externally following the explosion of a 35 2515 glass vial containing elemental S dissolved in benzene (Maass et al., 1963). Similar 35 2516 amounts of S were excreted in urine and faeces during the first few days, and levels in 2517 plasma and urine fell rapidly, suggesting rapid absorption from the lungs, and hence Type F 2518 behaviour. 2519 2520 Other compounds 35 2521 (178) Two workers were contaminated with S while segregating waste of unknown 2522 chemical composition formed by irradiating KCl targets (Spate et al., 1985). Urine 2523 monitoring indicated that in both subjects about 90% cleared with a half-time of about 6 2524 hours and the rest with a half-time of about 6 days. From this it was inferred that the activity 2525 dissolved rapidly in the lungs, indicating Type F behaviour. 2526

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2527 Sulphates 2528 (179) For details of experiments see the element section for the relevant cation. Those in 2529 OIR documents are listed below. However, in the studies of the biokinetics of inhaled (or 2530 instilled) sulphates only the cation was radiolabelled, and therefore caution must be used in 2531 drawing inferences about the behaviour of the anion. For sulphates that are insoluble in both 2532 aqueous media and in vivo, for example barium sulphate, it is reasonable to assume that the 2533 compound will dissociate slowly, and the behaviour of the sulphate moiety will be broadly 2534 similar to that of the metal. However other sulphates such as those of , and 2535 are very soluble in aqueous media and in vivo would be expected to dissociate into 2536 the respective metal and sulphate ions, each of which will follow its specific biokinetic 2537 pattern. In particular, following deposition in the lungs of thorium sulphate, like other water- 2538 soluble forms of thorium, most of the thorium is retained in particulate form and so is 2539 assigned to Type M. However, it is reasonable to assume that the sulphur would be rapidly 2540 absorbed (Type F). It should also be noted that solubility in water is not a reliable guide to 90 90 2541 solubility in vivo. When SrSO4, which is insoluble in water, was inhaled by mice, the Sr 2542 was rapidly absorbed. 2543 2544 Barium sulphate 2545 (180) Studies of respiratory tract clearance in several species indicate a wide range of 2546 absorption rates and BaSO4 is assigned to Type M. 2547 2548 Caesium sulphate 2549 (181) Measurements following accidental human inhalation indicate Type F behaviour. 2550 2551 sulphate 2552 (182) Measurements following accidental human inhalation were difficult to interpret, and 2553 no assignment was made. 2554 2555 Strontium sulphate 2556 (183) Measurements following inhalation by mice and dogs indicate Type F behaviour. 2557 2558 Thorium sulphate 2559 (184) Measurements following intratracheal instillation into rats indicate Type M 2560 behaviour. 2561 2562 Rapid dissolution rate for sulphur 2563 (185) No reliable estimates have been made of the rapid dissolution rate of sulphur in –1 2564 particulate form. The general default value of 30 d is therefore applied to all Type F forms 2565 of sulphur. 2566 2567 Extent of binding of sulphur to the respiratory tract 2568 (186) The evidence of rapid uptake of sulphur gases from the lung indicates that that there 2569 is probably little binding of sulphur. It is therefore assumed that for sulphur the bound state 2570 can be neglected, i.e. fb = 0.0. 2571

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2572 2573 Table 5-2. Deposition and absorption for gas and vapour forms of sulphura 2574 Percentage depositedb Absorption Total ET ET BB bb AI c Chemical form/origin 1 2 Type fA Systemic model Sulphur dioxide 85d 0 17 8.5 17 42.5 F 1.0 Inorganic Carbon disulphide 100d 0 20 10 20 50 F 1.0 Inorganic Hydrogen sulphide 100d 0 20 10 20 50 F 1.0 Inorganic Carbonyl sulphide 100d 0 20 10 20 50 F 1.0 Inorganic Other organic 100d 0 20 10 20 50 F 1.0 Organic Unspecifieda 100d 0 20 10 20 50 F 1.0 Inorganic 2575 a For sulphur in unspecified gas or vapour form, the default option for gases and vapours is recommended: 2576 100% total deposition in the respiratory tract; default distribution between regions (footnote d) and Type 2577 F absorption. 2578 b Percentage deposited refers to how much of the material in the inhaled air remains behind after 2579 exhalation. Almost all inhaled gas molecules contact airway surfaces, but usually return to the air unless 2580 they dissolve in, or react with, the surface lining. For the forms of sulphur considered here, it is assumed 2581 that most, if not all, of the inhaled sulphur is absorbed into body fluids. 2582 c Systemic model for inorganic sulphur, Section 3.3.1; systemic model for organic sulphur, Section 3.3.2. d 2583 Default distribution between regions (20% ET2, 10% BB, 20% bb and 50% AI). 2584 2585 Table 5-3. Absorption parameter values for inhaled particulate forms of sulphur and for 2586 ingested sulphura. 2587 Absorption parameter valuesb Absorption from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesc,d Absorption Assigned forms Type F Caesium, nickel, 1 30 - 1 strontium, thorium sulphatese M Barium sulphates; 0.2 3 0.005 0.2 all unspecified formsf S — 0.01 3 0.0001 0.01 Ingested materials Unspecified inorganic and organic 1 forms Elemental sulphur and thiosulphate 0.1 2588 a Following uptake into body fluids, the systemic model for inorganic sulphur is used, (see Section 2.3.) b 2589 It is assumed that for sulphur the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M and 2590 S forms of (30, 3 and 3 d–1, respectively) are the general default values. 2591 c Materials (e.g. caesium sulphate) are listed here where there is sufficient information to assign to a default 2592 absorption Type, but not to give specific parameter values (see text). 2593 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 2594 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 2595 absorption Type and the fA value for ingested soluble forms of sulphur (1.0). 2596 e In the case of thorium sulphate the thorium is assigned to Type M and the sulphur to Type F. 2597 f Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 2598 or if the form is known but there is no information available on the absorption of that form from the 2599 respiratory tract. 2600 2601

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2602 2603 5.2.2. Ingestion 2604 35 2605 (187) Bauer (1976) showed that sulphur ingested as radioactive sulphate ( S) by eight 2606 volunteers was completely absorbed in tracer amounts. Volwiler et al. (1955) reported that 2607 the fractional absorption of sulphur given as organic compounds to adult men was greater 2− 2608 than 0.6. Schulz (1984) reported that orally administered thiosulphate (S2O3 ) in humans was − 2609 not absorbed from the gastrointestinal tract, but thiocyanate (CNS ) was completely 2610 absorbed. 35 2611 (188) Results obtained by Dziewiatkowski (1949) for the excretion of S in rats after oral 2612 administration as the sulphate or sulphide indicated that absorption was 0.9 or greater. Minski 35 2613 and Vennart (1971) measured the absorption of [ S]-methionine in rats and obtained a mean 2614 value of about 0.9. Elemental sulphur was found to be less well absorbed with values in rats 2615 of around 0.1 (Dziewiatkowski, 1962). 2616 (189) ICRP Publication 30 (1980) recommended absorption values of 0.8 for inorganic 2617 forms of sulphur and 0.1 for elemental sulphur. In ICRP Publication 67 (ICRP, 1993) a 2618 value of 1 was adopted for dietary intakes. In this report, recommended fA values are 1 for -1 2619 unspecified inorganic and organic compounds, and 1x10 for elemental sulphur and 2620 thiosulphate. 2621 2622 5.2.3. Systemic Distribution, Retention and Excretion 2623 2624 5.2.3.1. Inorganic sulphur 2625 35 2626 (190) Andrews et al. (1960) measured the rate of disappearance of S from blood 2627 following its intravenous administration as sulphate (H2SO4) to an adult male subject with 2628 chondrosarcoma. The measurements indicated two components of biological removal from 2629 blood with half-times of 0.35 d (94%) and 5.6 d (6%). 2630 (191) Schulz (1984) showed that after intravenous injection of thiosulphate into humans 2631 the compound left plasma with a half-time of ~15 min. Most of the thiosulphate was 2632 oxidized to sulphate or incorporated into endogenous sulphur compounds. A small proportion 2633 was excreted through the kidneys. Following oral administration of thiocyanate to human 2634 subjects, sulphur was virtually completely absorbed into the blood and cleared from the ─ 2635 serum with a half-time of ~3 days. The volume of distribution of the CNS ion was ~0.25 2636 L/kg. Elimination was mainly renal (Schulz, 1984). 35 2637 (192) Following intravenous injection of dilute H2 SO4 into 15 normal humans subjects, 2638 an average of 4.5% (range, 1.3-8.8%) of the administered activity was excreted in urine 2639 within 18 min and about half was excreted within 4-9 h (Walser et al., 1953). In a similar 2640 study involving dogs, an average of 3.6% (range, 1-6%) of the administered activity was 2641 excreted within 25-30 min after injection. Following prior water loading by stomach tube in 2642 another group of dogs, mean urinary excretion in the first 25-30 min increased to 5.6% 2643 (range, 3.7-8.2%). 35 2644 (193) In a study involving intravenous administration of S to 21 patients with 2645 chondrosarcoma or chordoma, an estimated 70-90% of administered activity was excreted in 2646 the urine in the first three days (Woodard et al., 1976). Studies of the blood kinetics in six of 2647 these patients indicated a major component with a removal half-time of 0.4-0.7 days. 2648 Measurements of activity in tissues obtained from biopsies or autopsies indicated high initial 2649 uptake in red bone marrow and epiphyseal cartilage. Uptake in other types of cartilage and in

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2650 samples of skin, fibrous tissue, and muscle was relatively low, but subsequent loss from these 2651 tissues was slow. 35 2652 (194) In studies of the behaviour of intravenously injected inorganic S in human subjects 35 2653 and laboratory animals, it was found that a significant portion of the S accumulated in the 2654 cartilage and bone (Denko, 1957; Buck, 1958; Gottschalk, 1959). Activity depositing in these 2655 tissues was removed with a biological half-time of several days. 35 2656 (195) Minski and Vennart studied the biokinetics of S in 76 rats following its intravenous 35 35 2657 administration as the inorganic form Na2 SO4 or the organic form S-L-methionine. 35 2658 Following administration of inorganic S, the cartilage and marrow had the greatest 2659 integrated activity per unit mass, and the soft tissue had the lowest integrated activity. Sulfur- 2660 35 was eliminated from the body at a faster rate when administered as sodium sulphate than 2661 when administered as methionine. The authors determined the retained fraction of 2662 administered activity in several tissues and presented results as tissue-specific retention 2663 functions. 99m 35 2664 (196) Studies in rats showed that after intravenous injection of Tc S-sulphur colloid 99m 35 2665 the rates of clearance of Tc and S from blood and their accumulation in liver and bone 2666 were markedly different. The colloid particles apparently were broken down in vivo with the 2667 release of sulphur (Frier et al., 1981). 2668 2669 5.2.3.2. Gaseous inorganic compounds 2670 2671 Hydrogen sulphide (H2S) 2672 (197) Hydrogen sulphide entering blood is rapidly oxidized to pharmacologically inert 2673 compounds such as thiosulphate and sulphate and excreted in urine (Patty, 1963; Vennart and 2674 Ash, 1976). 2675 2676 Carbon disulphide (CS2) 2677 (198) CS2 is insoluble in water. Results of several studies (Bergman et al., 1984; McKenna 2678 and DiStefano, 1977; McKee et al., 1943; Teisinger and Soucek, 1949) indicate that CS2 is 2679 taken up by fat, reaching equilibrium in humans after 1 to 2 hours under continuous exposure. 2680 Some activity from the fat reserves is then metabolized and ultimately excreted in urine. 2681 McKee et al. (1943) showed that 85-90% of CS2 in the body is metabolized and the 2682 remaining non-metabolized CS2 is eliminated unchanged, mostly in the breath. There is 2683 extensive metabolic incorporation of S released from CS2 during biotransformation. 35 2684 Bergman et al. (1984) showed that, after initial concentration in liver and kidneys, S 2685 labelled metabolites are rapidly eliminated from the body, probably in inorganic form. 2686 2687 Carbonyl sulphide (COS) 35 2688 (199) COS decomposes in water to form H2S and CO2. The S moiety of COS is assumed 2689 to behave like H2S when in the bloodstream. The toxic effects of COS after inhalation appear 35 2690 to result from the toxicity of the H2S produced, supporting the assumption that the S label 2691 can be treated as though it were H2S (Vennart and Ash, 1976). 2692 2693 Sulphur dioxide (SO2) 2694 (200) Sulphur dioxide entering the blood is expected to dissolve and produce sulphite and 2695 sulphate ions. 2696 2697 5.2.3.3. Generic model for inorganic sulphur 2698

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2699 (201) Data for human subjects indicate that following entry of inorganic forms of sulphur 2700 into blood there is a rapid phase of excretion with a half-time of about 0.3 days followed by a 2701 slower phase of elimination with a half-time of at least 7 days and possibly as much as 80 2702 days (ICRP, 1980; 1993). Studies of dietary sulphur suggest that two components of retention 2703 with half-times of this order are insufficient to explain the total-body content of 140 g of 2704 sulphur given for Reference Man, (ICRP, 1975) and that at least one longer-term component 2705 of retention must be present. 2706 (202) The biokinetic model for inorganic sulphur used in ICRP Publication 67 (1993) 2707 assumes a removal half-time from blood of 0.25 days. The fraction 0.8 is assumed to be 2708 promptly excreted, and fractions 0.15 and 0.05 are assumed to be distributed uniformly 2709 throughout the body and removed with biological half-times of 20 and 2000 days, 2710 respectively. 2711 (203) The structure of the systemic model for inorganic sulphur used in the present report 2712 is shown in Figure 5-1. Transfer coefficients are listed in Table 5-4. Sulphur is assumed to -1 2713 be removed from blood at the rate 2.5 d . Deposition fractions in tissue compartments and 2714 excretion pathways are based on data from human studies by Woodard et al. (1976), Andrews 2715 et al. (1960), Gottschalk et al. (1959), Maass et al. (1963), and Denko and Priest (1957) and 2716 rat studies by Dziewiatkowski (1945, 1949, 1953), Denko and Priest (1957), Minski and 2717 Vennart (1971), and Singher and Marinelli (1945). The assumed distribution of activity 2718 leaving blood is as follows: 72% goes to the urinary bladder contents, 10% to the cartilage, 2719 8% to the right colon contents, 7% to other, and 3% to red marrow. The retention half-times 2720 in compartments were set for reasonable consistency with data for human subjects or rats 2721 summarized earlier. 2722

2723 2724 Figure 5-1. Biokinetic model for inorganic sulphur used in this report. 2725 2726

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2727 2728 Table 5-4. Transfer coefficients for inorganic sulphur in adults 2729 Compartments Transfer Coefficient (d-1) Blood to Red Marrow 0.075 Blood to Cartilage 0.25 Blood to Other 0.175 Blood to Urinary Bladder Contents 1.8 Blood to Right Colon Contents 0.2 Red Marrow to Blood 0.3 Cartilage to Blood 0.1 Other to Blood 3.5 2730 2731 5.2.3.4. Organic compounds of sulphur 2732 35 2733 (204) Minski and Vennart (1971) studied the distribution and retention of S in rats 35 2734 following intravenous administration of the organic form S-L-methione and the inorganic 35 2735 form Na2 SO4. Sulfur-35 administered in organic form was removed from blood more 35 2736 slowly and distributed in tissues more uniformly than S administered in inorganic form. 35 2737 Blood disappearance of S administered in organic form was described as a sum of three 2738 exponential terms. The cumulative activity in the total body was an order of magnitude 35 35 2739 higher for S administered as methionine than for S administered as sodium sulphate. The 2740 cartilage and intestines showed the highest cumulative activity per unit mass of tissue 35 2741 following injection of inorganic S but relatively low cumulative activity per unit mass 35 2742 compared with several other tissues following its injection as organic S. The half-time in 2743 blood following administration of the organic form was 40 times larger than that following 2744 administration of the inorganic form. 2745 (205) Taking account of these data and dietary intake and the total body content of sulphur 2746 in adult humans (ICRP, 1975), Vennart and Ash (1976) proposed that organic sulphur 2747 ingested in food should be assumed to be completely absorbed from the gastrointestinal tract, 2748 uniformly distributed throughout the body tissues and eliminated with a single biological 2749 half-time of 140 days. These assumptions form the basis for the systemic model for organic 2750 sulphur adopted in ICRP Publication 30 (1980) and carried over to ICRP Publication 67 2751 (1993). In Publication 67 a urinary to faecal excretion ratio of 9:1 was assigned. 2752 (206) The structure of the systemic model for organic sulphur used in this report is 2753 presented in Figure 5-2. Transfer coefficients are listed in Table 5-5. The distribution of 2754 activity in the body and the removal half-times from tissues to blood are based on data for 2755 rats (Minski and Vennart, 1971). Minski and Vennart described sulphur retention in the blood 2756 by a three component exponential – 34% with a half time of 0.16 days, 14% with a half time 2757 of 4.1 days and 52% with a half time of 60.5 days. The initial transfer from Blood 1 to the 2758 Urinary Bladder occurs with a half time of approximately 0.16 days. Since there is no 2759 selective uptake of organic radiosulphur, it was determined that sulphur is deposited in a Soft 2760 Tissue compartment and removed with a biological half time of 160 days. Organic sulphur is 2761 excreted via three primary pathways: urine, faeces, and hair. 2762

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2763 2764 Figure 5-2. Biokinetic model for organic sulphur used in this report. 2765 2766 5.2.3.5. Treatment of radioactive progeny 2767 38 2768 (207) The only radioactive progeny of a sulphur isotope addressed in this report is Cl 38 38 2769 (T1/2 = 37.24 m), produced by decay of S. It is assumed for dosimetric purposes that Cl 2770 decays at its site of production in the body. 2771 2772 Table 5-5. Transfer coefficients for organic sulphur in adult humans 2773 Compartments Transfer Coefficient (d-1) Blood 1 to Blood 2 8.3 Blood 1 to Urinary Bladder Contents 4. Blood 2 to Urinary Bladder Contents 0.0011 Blood 2 to Excreta (Hair) 0.0009 Blood 2 to SI Contents 0.0002 Blood 2 to Soft Tissue 0.0170 Soft Tissue to Blood 2 0.0042 2774 2775 (208) Model predictions of the clearance of intravenously injected organic sulphur from 2776 blood are consistent with the clearance pattern determined for rats following intravenous 35 2777 administration of S-L-methione (Minski and Vennart, 1971). 2778 35 2779 Applicability of the S-L-methionine model 35 2780 (209) For general radiological protection purposes, this modified biokinetic model for S- 2781 L-methionine could be applied with caution to other organic forms of sulphur in the absence 2782 of other compound-specific data. However, this model should not be used for the 2783 interpretation of bioassay data. 2784

2785 2786 5.2.3.6. Gender-related differences in biokinetics 2787 2788 (210) There are insufficient data either from human or animal studies to define any 35 2789 systematic gender related differences in organ retention functions or excretion for S 35 2790 compounds. However, some gender-related differences in the biokinetics of S might be

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2791 expected following entry of certain types of labelled organic compound. 2792 2793 5.3. Individual monitoring 2794 35 2795 (211) S intakes are generally monitored though measurements of the activity excreted in 2796 urine. The most common method of analysis is liquid scintillation counting. 2797 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 35S Urine Bioassay Liquid Scintillation 15 Bq/L 1-5 Bq/L Counting 2798 2799 References 2800 2801 Andersen, I., Lundqvist, G.R., Jensen, P.L., Proctor, D.F., 1974. Human response to controlled levels 2802 of sulphur dioxide. Arch. Environ. Health, 28, 31–39. 2803 Andrews, J.R., Swarm, R.L., Schlachter, L. Brace, K. C., Rubin, P., Bergenstal, D.M., Gump, H., 2804 Siegel, S., Swain, R.W., 1960. The effects of one curie of sulphur 35 administered 2805 intravenously as sulphate to a man with advanced chondrosarcoma. Am. J. Roentgenol., 2806 Radium therapy Nuclear med. 83 (1), 123-134. 2807 Balchum, O.J., Dybicki, J., Meneely, G.R., 1960. The dynamics of sulphur dioxide inhalation. 2808 Absorption, distribution and retention. A. M. A. Arch. Ind. Health, 21, 564–569. 2809 Bauer, J.H., 1976. Oral administration of radioactive sulphate to measure extracelluler fluid space in 2810 man. J. Appl. Physiol. 40, 648-652. 2811 Bergman, K., Danielsson, B.R.G., d'Argy, R., 1984. Tissue disposition of carbon disulfide: I. 2812 Whole-body autoradiography of 35S- and 14C-labelled carbon disulfide in adult male mice. 2813 ActaPharmacol.etToxicol., 54, 141–150. 2814 Buck, R.C., Heagy, F.C., 1958. Uptake of radioactive sulphur by various tissues of normal and 2815 cholesterol-fed rabbits. Can. J. Biochem. Physiol., 36, 63-69. 2816 Dalhamn, T., Strandberg, L., 1961. Acute effect of sulphur dioxide on the rate of ciliary beat in the 2817 trachea of rabbit, in vivo and in vitro, with studies on the absorptional capacity of the nasal 2818 cavity. Int. J. Air and Water Poll., 4, 154–167. 2819 Denko, C.W., Priest, R.E., 1957. distribution of radiosulfur, S35 I.In the Human Adult II.In the Young 2820 and Adult Rat. J. Lab. and Clin. Med., 50 (1), 107-112. 2821 Dziewiatkowski, D.D., 1962. Sulfur. In : Mineral Metabolism, Ch 28, Vol II, Part B (C.L. Comar and 2822 F. Bronner, Eds,). Academic press, New York. 2823 Dziewiatkowski, D.D., 1945. Fate of ingested sulphide sulphur labelled with radioactive sulphur in 2824 the rat. J. Biol. Chem., 161, 723-9. 2825 Dziewiatkowski, D.D., 1949. Rate of excretion of radioactive sulfur and its concentration in some 2826 tissues of the rat after intraperitoneal administration of labelled sodium sulphate. J. Biol. 2827 Chem., 178, 197-202. 2828 Dziewiatkowski, D.D., 1953. Sulfate-sulfur metabolism in the rat fetus as indicated by sulphur-35. J. 2829 Exp. Med. 98 (2), 119-128. 35 2830 Frank, N.R., Yoder, R.E., Brain, J.D., Yokoyama, Eiji., 1969. SO2( S labeled) absorption by the nose 2831 and mouth under conditions of varying concentration and flow. Arch. Environ. Health, 18, 2832 315–322. 35 2833 Frank, N.R., Yoder, R.E., Yokoyama, E., Speizer, F.E., 1967. The diffusion of SO2 from tissue 35 2834 fluids into the lungs following exposure of dogs to SO2. Health Phys., 13, 31–38. 2835 Frier, M., Griffiths, P., Ramsey, A., 1981. The biological fate of sulphur colloid. Eur. J. Nucl. Med. 6, 2836 371-374.

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2837 Gottschalk, R.G., Louis, K.A., Miller, P.O., 1959. The use of large amounts of radioactive sulphur in 2838 patients with advanced chondrosarcomas II. Distribution and tissue irradiation. Cancer Res., 2839 19 (10), 1078-85. 2840 ICRP, 1975. Report of the Task Group on Reference Man. ICRP Publication 23. Pergamon Press, 2841 Oxford. 2842 ICRP, 1980. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Pt.2. Ann. ICRP 4 2843 (3/4). 2844 ICRP, 1993. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 2, 2845 Ingestion dose coeffcients .ICRP Publication 67. Ann. ICRP 23. (3/4). 2846 ICRP, 2002. Guide for the Practical Application of the ICRP Human Respiratory Tract Model.ICRP 2847 Supporting Guidance 3 Annals of the ICRP 32(1-2). 2848 Maass, A.R., Flanagan, T.L., Blackburn, D., Smyth, M., 1963. Accidental personnel exposure to 2849 elemental S35. Health Phys., 9, 731–740. 2850 McKee, R.W., Kiper, C., Fountain, J.H., Riskin, A.M., Drinker, P., 1943. A solvent vapor, carbon 2851 disulphide. Absorption, elimination, metabolism and mode of action. J.A.M.A., 122, 217– 2852 222. 2853 McKenna, M.J., DiStefano, V., 1977. Carbondisulphide I. The metabolism of inhaled carbon 2854 disulphide in the rat.Journal of Pharmacol.and Experimental Therapeutics, 202, 245–252. 2855 Minski, M., Vennart, J., 1971. Maximum permissible intakes of 35S-l-methionine and 35S-sodium 2856 sulphate deduced from experiments in rats. Health Phys. 20, 1-9. 2857 Patty, F.A., 1963. Industrial hygiene and toxicology.Interscience Publishers, a division of John Wiley 2858 and Sons, New York/London. 2859 Schulz, V., 1984. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate. 2860 Clin. Pharmacokinet. 9, 239-251. 2861 Singher, H.O., Marinelli, L., 1945. Distribution of radioactive sulphur in the rat. Science, 101 (2625) 2862 414-415. 2863 Spate, V.L., Langhorst, S.M., DuChemin, A.M., 1985. Excretion of 35S from two contaminated 2864 workers. Health Phys., 49, 84–87. 2865 Speizer, F.E., Frank, N.R., 1966. The uptake and release of SO2 by the human nose. Arch. Environ. 2866 Health, 12, 725–728. 2867 Strandberg, L.G., 1964. SO2 absorption in the respiratory tract.Studies on the absorption in rabbit, its 2868 dependence on concentration and breathing phase. Arch. Environ. Health, 9, 160–166. 2869 Teisinger, J., Souček, B., 1949. Absorption and elimination of carbon disulphide in man. J. Ind. Hyg. 2870 Toxicol., 31, 67–73. 2871 Vennart, J., Ash, P.J.N.D., 1976. Derived limits for S-35 in food and air. Health Phys., 30, 291-294. 2872 Volwiler, W., Goldworthy, P.D., MacMartin, M.P., Wood, P.A., Mackay, I.R., Fremont-Smith, K., 2873 1955. Biosynthetic determination with radioactive sulphur of turnover rates of various plasma 2874 proteins in normal and cirrhotic men. J. Clin. Invest. 34, 1126-1146. 2875 Walser, M., Seldin, D.W., Grollman, A., 1953. An Evaluation of Radiosulphate for the Determination 2876 of the Volume of Extracellular Fluid in Man and Dogs. J. Clin. Invest., 32, 299-311. 2877 Woodard, H.Q., Pentelow, K.S., Mayer, K., Laughlin, J.S., Marcove, R.C., 1976. Distribution and 2878 Retention of 35S-Sodium Sulphate in Man. J. Nucl. Med. 17, 285-289. 2879 2880

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2881 6. CALCIUM (Z = 20) 2882 2883 6.1. Chemical Forms in the Workplace 2884 2885 (212) Calcium is an alkaline earth element, which mainly occurs in oxidation state II. It is 2886 an essential element for life. Chemical forms encountered in industry include oxides, 45 47 2887 phosphates, nitrates, sulphides, chlorides, carbonates and fluorides. Ca and Ca are 2888 occasionally used in research and in medicine. 2889 2890 Table 6-1. addressed in this report 2891 Isotope Physical half-life Decay mode Ca-41 1.02E+5 y EC Ca-45 162.67 d B- Ca-47 4.536 d B- 2892 2893 6.2. Routes of Intake 2894 2895 6.2.1. Inhalation 2896 2897 Absorption Types and parameter values 2898 2899 (213) No information was found on the behaviour of inhaled calcium in man. Information 2900 is available from experimental studies of calcium chloride. 2901 (214) Absorption parameter values and Types, and associated fA values for particulate 2902 forms of calcium are given in Table 6-2. 2903 2904 Calcium chloride 45 2905 (215) Schiessle et al. (1964) followed the retention of Ca in the lungs of guinea pigs for 2906 28 days after inhalation of CaCl2. Most of the initial lung deposit was very rapidly absorbed: 2907 at 1 day less than 1% of the initial lung deposit remained, consistent with assignment to Type –1 2908 F. Specific parameter values were estimated by the task group to be: fr = 0.996, sr = 70 d (t½ –1 2909 ~ 14 minutes) and ss = 0.07 d (t½ ~ 10 d), consistent with assignment to Type F. Although 2910 specific parameter values for calcium chloride based on in vivo data are available, they are 2911 not adopted here, because inhalation exposure to it is so unlikely. Instead, calcium chloride is 2912 assigned to Type F. However, the data are used as the basis for the default rapid dissolution 2913 rate for calcium. Hence specific parameter values for calcium chloride would be the same as 2914 default Type F calcium parameter values. 2915 2916 Rapid dissolution rate for calcium –1 2917 (216) The value of sr estimated for CaCl2 above, 70 d , is applied here to all Type F forms 2918 of calcium. 2919

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2920 2921 Table 6-2. Absorption parameter values for inhaled and ingested calcium 2922 Absorption parameter valuesa Absorption from the –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) alimentary tract, fA Default parameter valuesb,c Absorptio Assigned forms n Type F Calcium chloride 1 70 – 0.4 M All unspecified formsd 0.2 3 0.005 0.08 S — 0.01 3 1x10-4 0.004 Ingested materials All unspecified forms 0.4 a 2923 It is assumed that for calcium the bound state can be neglected i.e. fb = 0. The value of sr for Type F forms 2924 of calcium (70 d–1) is element-specific. The values for Types M and S (3 d–1) are the general default 2925 values. 2926 b Materials (e.g. calcium chloride) are generally listed here where there is sufficient information to assign 2927 to a default absorption Type, but not to give specific parameter values (see text). 2928 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 2929 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the -1 2930 absorption Type and the fA value for ingested soluble forms of calcium (4x10 ). 2931 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is 2932 unknown, or if the form is known but there is no information available on the absorption of that form 2933 from the respiratory tract. 2934 2935 Extent of binding of calcium to the respiratory tract 2936 (217) Evidence from the calcium chloride study outlined above suggests that there is 2937 probably little binding of calcium. It is therefore assumed that for calcium the bound state can 2938 be neglected, i.e. fb = 0.0. 2939 2940 6.2.2. Ingestion 2941 2942 (218) Calcium is the first member of the series and it may exist under 2943 physiological conditions partly as a divalent cation and partly as complexes with proteins and 2944 other ligands. However, unlike strontium, barium and radium, the other alkaline earth 2945 elements, calcium is an essential element and physiological mechanisms facilitate its 2946 intestinal absorption. 2947 (219) Calcium absorption has been measured in numerous volunteer studies and in most 2948 cases the reported mean absorption values were in the range 0.2 to 0.5 (Samachson, 1963; 2949 DeGrazia and Rich, 1964; Lutwak, 1969; Mautalen et al., 1969; Jovanovic, 1978; Cochet et 2950 al., 1983; Marchandise et al., 1986; Spencer et al., 1987; Harvey et al., 1988; Heaney et al., 2951 1989, 1999). Greater mean values of 0.6 (Sambrook et al., 1985) and 0.7 (Rumenapf and 2952 Schwille, 1987) have also been reported for normal volunteers. These differences may 2953 probably be explained by the large inter-individual differences in calcium absorption 2954 observed in healthy subjects, with individual values ranging from 0.3 to 0.6 (Barger-Lux and 2955 Heaney, 1995) or even from 0.4 to 0.9 (Isaksson et al., 2000). Indeed calcium absorption 2956 depends first on the intraluminal concentration of ionized calcium (Schachter et al., 1960) 2957 which can be locally reduced by the presence of calcium binding agents such as EDTA or 2958 citrate ions (Rumenapf and Schwille, 1987). Additional variability may be associated with

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2959 morphological factors since Ca absorption is positively correlated to body size (Davies et al., 2960 2000, Barger-Lux and Heaney, 2005) and to many nutritional factors. It is known that 2961 fractional calcium absorption is increased by high intakes of vitamin D, and by a high protein 2962 or carbohydrate diet, by calcium deficiency or low calcium intake and by pregnancy or 2963 lactation (Allen, 1982; Spencer et al., 1987; Heaney et al., 1989, Cashman and Flynn, 1996; 2964 Griffin et al., 2002; Kerstetter et al., 2005, Holloway et al., 2007). On the other hand, caffeine 2965 intake or oral supplementation with magnesium decreased calcium absorption in humans 2966 (Barger-Lux and Heaney, 1995; De Swart et al., 1998, Heaney 2002). 2967 (220) Calcium absorption is known to occur mainly from the small intestine (ICRP 2006). 2968 However, a few percent of calcium may also be absorbed from other sites, such as the colon, 2969 which, at 26 hours after ingestion, can absorb as much as 4% of calcium provided to healthy 2970 peri-menopausal women (Barger-Lux et al., 1989). 2971 (221) In ICRP Publication 30 (1980) and ICRP Publication 71 (1995), an absorption value 2972 of 0.3 was recommended. Since absorption appears to be generally greater than 0.3 in normal 2973 subjects, an fA value of 0.4 for all chemical forms is adopted here. 2974 2975 6.2.3. Systemic Distribution, Retention and Excretion 2976 2977 6.2.3.1. Summary of the database 2978 2979 (222) The biokinetics of calcium in the human body has been investigated extensively in 2980 physiological and clinical studies and in radiobiological studies comparing the behavior of 2981 isotopes of the alkaline earth elements. Reviews and bibliographies can be found in ICRP 2982 Publication 20 (1973), ICRP Publication 71 (1995), and an article by Leggett (1992). The 2983 primary datasets underlying specific parameter values in the model for systemic calcium used 2984 in this report are summarized below. 2985 2986 6.2.3.2. Biokinetic model for systemic calcium 2987 2988 (223) The structure of the model for systemic calcium is shown in Figure 6-1. This is a 2989 simplified version of the generic model for bone-volume seekers. All soft tissues including 2990 the liver and kidneys are included in the three "Other tissue" compartments, ST0, ST1, and 2991 ST2 corresponding to rapid, intermediate, and slow exchange of activity with plasma, 2992 respectively. These soft tissue compartments are defined on a kinetic basis rather than an 2993 anatomical or physiological basis, but ST0 may correspond roughly to interstitial fluids plus 2994 some rapidly exchangeable cellular calcium (Heaney 1964, Harrison et al., 1967, Hart and 2995 Spencer 1976); ST1 may be a composite of several pools with slower exchange rates, 2996 including mitochondrial calcium, cartilage calcium, and exchangeable dystrophic calcium 2997 (e.g. arterial plaque and calcified nodes) (Heaney 1964, Borle 1981); and ST2 may be 2998 associated with relatively nonexchangeable dystrophic calcium that gradually accumulates in 2999 the human body (Heaney 1964). 3000 (224) Blood is treated as a uniformly mixed pool that exchanges calcium with soft tissues 3001 and bone surfaces. Calcium is assumed to be lost from the body only by urinary or faecal 3002 excretion. Activity going to urine is first transferred from plasma to the urinary bladder 3003 contents, and activity going to faeces is first transferred from plasma to the contents of the 3004 right colon contents. 3005

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3006 3007 Figure 6-1. Structure of the model for systemic calcium. 3008 Abbreviations: exch = exchangeable, nonexch = non-exchangeable. 3009 3010 Parameter values 3011 (225) The parameter values applied to systemic calcium in the present report are the same 3012 as those applied in ICRP Publication 71 (1995). These values are listed in Table 6-3. The 3013 selection of each parameter value is described briefly in the following and explained in more 3014 detail by Leggett (1992). 3015 (226) In the following, the "removal half-time" from a compartment refers to the 3016 biological half-time that would be observed if there were no recycling to that compartment. 3017 This will generally differ from the apparent (or net, or externally viewed) half-time that may 3018 be estimated at any given time in the presence of recycling. The "deposition fraction" for a 3019 compartment fed by plasma is the fraction of instantaneous outflow from plasma that is 3020 transferred to that compartment. For example, the deposition fraction for ST1 is 0.1. This 3021 means that ST1 receives 10% of activity leaving plasma over a period of a few seconds. 3022 (227) Kinetic analysis of plasma disappearance curves for normal subjects intravenously 3023 injected with radioisotopes of the alkaline earth elements indicates that these elements 3024 initially leave plasma at a rate of several hundred plasma volumes per day and equilibrate 3025 rapidly with an extravascular pool (presumably consisting largely of interstitial fluids) 3026 roughly three times the size of the plasma pool (Heaney, 1964; Harrison et al., 1967; Hart and 3027 Spencer, 1976). The present model does not depict the rapid exchange of calcium between 3028 plasma and this extravascular pool within the first few minutes after introduction of calcium 3029 into blood. However, the model includes a soft-tissue compartment (ST0) that receives more 3030 than half of activity leaving plasma, returns activity to plasma with a half-time of a few 3031 hours, and contains three times as much activity as plasma at times more than a few hours 3032 after introduction of calcium to blood. This compartment is used to account for relatively 3033 high concentrations of calcium tracers observed in soft tissues during the first few hours after 3034 injection and to help maintain the proper amount of material in plasma. A total transfer rate -1 3035 from plasma of 15 d (i.e. a removal half-time of ln(2)/15 d = 0.04621 d) yields reasonable

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3036 fits to plasma disappearance curves for calcium or strontium tracers at times beyond 1-2 h 3037 after injection into human subjects (Barnes et al., 1961; Heaney ,1964; Heaney et al., 1964; 3038 Harrison et al., 1967; Neer et al., 1967; ICRP, 1973; Newton et al., 1990). 3039 (228) It is assumed that 58% of calcium leaving plasma moves to the rapid-turnover 3040 soft-tissue compartment ST0; this is the balance after deposition percentages in other 3041 compartments are assigned. The corresponding transfer rate from plasma to ST0 is 0.58 × 15 -1 -1 3042 d = 8.7 d . Based on the assumed relative amounts of calcium in ST0 and plasma, the 3043 transfer rate from ST0 to plasma is set at one-third the transfer rate from plasma to ST0, or -1 3044 2.9 d . 3045 (229) Readily exchangeable calcium in soft tissues, meaning calcium that is turned over to 3046 a substantial extent in a period of hours or days, is represented in this model as the sum of 3047 calcium in compartments ST0 and ST1. The amount of readily exchangeable calcium in soft 3048 tissues is approximately 0.35% of total-body calcium in a middle-aged adult human (Heaney, 3049 1964; Borle, 1981). Since plasma contains about 0.03% of total-body calcium in the adult 3050 (ICRP, 1975), the threefold larger compartment ST0 is estimated to contain 0.09% and ST1 is 3051 estimated to contain about 0.35% - 0.09% = 0.26% of total-body calcium during chronic 3052 intake. Parameter values for ST1 are set to reproduce these steady-state conditions while 3053 approximating soft-tissue retention data for terminally ill human subjects intravenously 45 3054 injected with Ca at times up to 124 d before death (Schulert et al., 1959). This is 3055 accomplished by assigning to ST1 a deposition fraction of 0.1 and a removal half-time to -1 -1 3056 plasma of 4 d. The derived transfer rate from plasma to ST1 is 0.1 × 15 d = 1.5 d and from -1 3057 ST1 to plasma is ln(2) / 4 d = 0.1733 d . 3058 (230) Parameter values for Compartment ST2 are set for consistency with estimates of the 3059 accumulation of relatively nonexchangeable calcium in adult humans (Heaney, 1964), an 3060 estimate of the fraction of total-body calcium in soft tissues under conditions of chronic 45 3061 exposure (Schlenker et al., 1982), and the observed retention of Ca in human soft tissues at 3062 3 mo after injection (Schulert et al., 1959). Reasonable agreement with these three values is 3063 achieved by assuming that ST2 receives 0.005% of outflow from plasma and that the removal 3064 half-time from ST2 to plasma is 5 y. The resulting transfer rate from plasma to ST2 is -1 -1 3065 0.00005 × 15 d = 0.00075 d , and the transfer rate from ST1 to plasma is ln(2) / (5 × 365 d) -1 3066 = 0.00038 d . 3067 (231) Data for laboratory animals indicate that fractional deposition on bone surfaces is 3068 similar for calcium, strontium, barium, and radium. This is inferred from the similar skeletal 3069 contents of these elements in the first few hours after injection (Bligh and Taylor, 1963; 3070 Kshirsagar et al., 1966; Domanski et al., 1969, 1980). Use of a common bone-surface 3071 deposition fraction for all four elements is consistent with autoradiographic measurements of 3072 surface activity in bone samples taken at autopsy from subjects injected with radiocalcium at 3073 0.6 d or longer before death (Riggs et al., 1971, ICRP, 1973); measurements of radiocalcium 3074 and radiostrontium in bone samples from subjects injected 3 h or longer before death 3075 (Schulert et al., 1959); and external measurements of the buildup of radiocalcium (Anderson 3076 et al., 1970; Heard and Chamberlain, 1984) and radiobarium (Korsunskii et al., 1981) after 3077 intravenous injection. Based on these data, 25% of calcium, strontium, barium, or radium 3078 leaving plasma is assigned to bone surfaces. The transfer rate from plasma to cortical and -1 -1 3079 trabecular surfaces combined is 0.25 × 15 d = 3.75 d . 3080 (232) The initial distribution between different bones of the skeleton and between the two 3081 bone types (cortical and trabecular) appears to be similar for calcium, strontium, barium, and 3082 radium (Ellsasser et al., 1969; Wood et al., 1970; Liniecki, 1971; Stather, 1974; Lloyd et al., 3083 1976). Relative deposition of alkaline earth elements on cortical and trabecular bone surfaces 3084 is based on the estimated calcium turnover rate of each bone type. This approach agrees with

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3085 measurements on laboratory animals (Kshirsagar et al., 1966; Norrdin and Arnold, 1980). As 3086 an average over adult ages, deposition on trabecular bone is estimated to be 1.25 times that on 3087 cortical bone (Leggett et al., 1982). The transfer rate from plasma to trabecular bone surface -1 -1 3088 is (1.25/2.25) × 3.75 d = 2.08 d and from plasma to cortical bone surface is (3.75 - 2.08) -1 -1 3089 d = 1.67 d . 3090 (233) The removal half-time of calcium from bone surfaces to all destinations (plasma and 3091 exchangeable bone volume) is estimated as 1 d. This is based on autoradiographic 3092 measurements of surface activity in human and canine bone samples taken at times ranging 45 3093 from few hours to a few days after intravenous injection of Ca (Riggs et al., 1971, Groer et 3094 al., 1972, Groer and Marshall, 1973, ICRP, 1973). 3095 (234) Parameter values for exchangeable bone volume are estimated from whole-body 3096 measurements using data for times after bone surfaces and soft tissues have largely cleared of 3097 activity but before loss from bone resorption becomes an important consideration. Based on 3098 whole-body retention curves for human subjects injected with radioisotopes of calcium, 3099 strontium, barium, or radium (Spencer et al., 1960; Bishop et al., 1960; Heaney et al., 1964; 3100 Harrison et al., 1967; Maletskos et al., 1969; Phang et al., 1969; Carr et al., 1973; Likhtarev 3101 et al., 1975; Malluche et al., 1978; Henrichs et al., 1984; Newton et al., 1990, 1991), the 3102 fraction of activity that moves from bone surfaces back to plasma is assumed to be the same 3103 for all four elements. Specifically, five-sixths of activity leaving bone surfaces is assumed to 3104 return to plasma and one-sixth is assumed to transfer to exchangeable bone volume. The 3105 transfer rate from trabecular or cortical bone surface to the corresponding exchangeable bone -1 3106 volume compartment is (1/6) × ln(2)/1 d = 0.116 d , and the transfer rate from trabecular or -1 3107 cortical bone surface to plasma is (5/6) × ln(2)/1 d = 0.578 d . 3108 (235) Element-specific removal half-times from the exchangeable bone volume 3109 compartments are based in part on fits to the intermediate-term retention data indicated 3110 above. However, it is also considered that the assigned half-times should increase roughly in 3111 proportion to the likelihood of entering nonexchangeable sites in bone mineral, as suggested 3112 by data from in vitro experiments with hydroxyapatite crystals and whole-body retention 3113 patterns for alkaline earth elements in human subjects. A removal half-time of 100 d is 3114 assigned to calcium, compared with values of 80 d for strontium, 50 d for barium, and 30 d 3115 for radium (Leggett, 1992). Because the data do not allow the derivation of removal half- 3116 times as a function of bone type, the same half-time is applied to cortical and trabecular 3117 exchangeable bone volume compartments. 3118 (236) Discrimination between alkaline earth elements by bone is accounted for by 3119 fractional transfer of activity from exchangeable to nonexchangeable bone volume. It is 3120 assumed, in effect, that calcium, strontium, barium, and radium are all equally likely to 3121 become temporarily incorporated in bone mineral after injection into plasma but that the 3122 likelihood of reaching a non-exchangeable site in bone crystal decreases in the order calcium 3123 > strontium > barium > radium. Fractional transfers of calcium, strontium, barium, and 3124 radium from exchangeable to nonexchangeable bone volume are set at 0.6, 0.5, 0.3, and 0.2, 3125 respectively, for consistency with whole-body and skeletal retention data on these elements 3126 (Spencer et al., 1960; Bishop et al., 1960; Heaney et al., 1964; Harrison et al., 1967; Phang et 3127 al., 1969; Maletskos et al., 1969; Carr et al., 1973; Likhtarev et al., 1975; Malluche et al., 3128 1978; Henrichs et al., 1984; Newton et al., 1990, 1991) as well as results of in vitro 3129 measurements on hydroxyapatite crystals (Neuman, 1964; Stark, 1968). The derived transfer 3130 rate from exchangeable trabecular or cortical bone volume to the corresponding -1 3131 nonexchangeable bone volume compartment is 0.6 × ln(2)/100 d = 0.004159 d and to the -1 3132 corresponding bone surface compartment is 0.4 × ln(2)/100 d = 0.002773 d . 3133 (237) Biological removal from the nonexchangeable bone volume compartments of

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3134 cortical and trabecular bone is assumed to result from bone turnover. The average bone -1 -1 3135 turnover rates during adulthood are estimated as 3% y and 18% y for cortical and 3136 trabecular bone, respectively (ICRP, 2002). The corresponding transfer rates from the 3137 nonexchangeable bone volume compartments of cortical and trabecular bone to plasma are -1 -1 3138 0.00008219 d and 0.0004932 d , respectively. Age-specific rates of bone turnover, 3139 including changes with age during adulthood, are provided in the paper by Leggett (1992) for 3140 application of the model to specific cases. 3141 (238) Clearance of calcium from plasma to urine and faeces has been studied in human 3142 subjects, many of them healthy (Bishop et al., 1960; Spencer et al., 1960; Barnes et al., 1961; 3143 Cohn et al., 1963 Heaney et al., 1964; Samachson, 1966; Phang et al., 1969; Carr et al., 1973; 3144 Newton et al., 1990). Based on results of these studies, it is assumed that 4% of calcium 3145 leaving plasma is transferred to the contents of the urinary bladder contents and subsequently 3146 to urine and 3% is transferred to the contents of the right colon and subsequently to faeces. -1 3147 Therefore, the transfer rate from plasma to the urinary bladder contents is 0.04 × 15 d = 0.6 -1 -1 -1 3148 d and from plasma to the contents of the right colon is 0.03 × 15 d = 0.45 d . 3149 Table 6-3. Transfer coefficients for systemic calcium

Froma Toa Transfer coefficient (d-1) Blood Urinary bladder contents 0.60 Blood Right colon contents 0.45 Blood Trabecular bone surface 2.08 Blood Cortical bone surface 1.67 Blood ST0 8.70 Blood ST1 1.50 Blood ST2 0.00075 Trabecular bone surface Blood 0.578 Trabecular bone surface Exch trabecular bone volume 0.116 Cortical bone surface Blood 0.578 Cortical bone surface Exch cortical bone volume 0.116 ST0 Blood 2.9 ST1 Blood 0.1733 ST2 Blood 0.00038 Exch trabecular bone volume Trabecular bone surface 0.002773 Exch trabecular bone volume Nonexch trabecular bone volume 0.00416 Exch cortical bone volume Cortical bone surface 0.002773 Exch cortical bone volume Nonexch cortical bone volume 0.00416 Nonexch cortical bone volume Blood 0.0000821 Nonexch trabecular bone volume Blood 0.000493 a Exch = exchangeable; Nonexch = non-exchangeable; ST0, ST1, and ST2 are compartments within Other soft tissues with fast, intermediate, and slow turnover, respectively. 3150 3151 6.2.3.3. Treatment of radioactive progeny 3152 3153 Experimental data 3154 (239) The only calcium isotope addressed in this report that decays to another radionuclide 47 47 47 3155 is Ca (T1/2 = 4.54 d), which decays to Sc (T1/2 = 3.35 d). The biological behavior of Sc 47 3156 produced in vivo by decay of Ca has been investigated in rats (Taylor, 1966) and mice 3157 (Freed et al., 1975).

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47 47 47 3158 (240) After intravenous administration of a mixture of Ca and Sc to rats, the Sc 3159 introduced as a parent radionuclide accumulated primarily in liver, spleen, kidneys, and bone 47 3160 (Taylor, 1966). There was evidence that Sc also translocated to the liver and spleen after its 47 47 3161 production by decay of Ca at other sites in the body. Most of the Sc produced in vivo by 47 47 3162 decay of Ca arose in bone due to the high uptake and retention of Ca by bone. Nearly all 47 3163 of the Sc produced in bone was retained in bone at times greater than a few days after 47 3164 intake, presumably after Ca was contained almost entirely in bone volume. 47 3165 (241) In mice, redistribution of Sc produced in the body following intravenous 47 47 3166 administration of Ca accounted for a large part of Sc found in soft tissues and blood 47 3167 (Freed et al., 1975). At times greater than 2 d after injection Sc was contained largely in 47 3168 bone. It appeared that Sc escaped to some extent from its site of production in bone during 47 47 3169 the early hours after administration of Ca, but no preferential loss of Sc from bone was 47 3170 observed thereafter. At 1-11 d after injection, loss of Sc from bone was slower than that of 47 47 3171 Ca. After 11 d the rate of loss of Sc from bone approached that of the parent, suggesting 3172 removal of both radionuclides by the process of bone resorption. 3173 3174 General assumptions 47 47 3175 (242) It is assumed in this report that Sc produced by decay of Ca in soft tissues and 3176 bone surface is removed to blood with a biological half-time of 3 d and then follows the 3177 characteristic model for , i.e. behaves as if injected into blood as a parent 3178 radionuclide. The removal half-time of 3 d is the shortest removal half-time of scandium 3179 from tissues in the characteristic model for scandium used here. Scandium-47 produced in a 3180 bone volume compartment of the calcium model is assumed to be removed to blood at the 3181 rate of bone turnover and then to follow the characteristic model for scandium. 3182 3183 Characteristic model for systemic scandium 3184 (243) The structure of the characteristic model for scandium is a modification of the 3185 generic model structure for bone-surface-seeking radionuclides. Scandium is treated as a 3186 bone-surface seeker based on analogy with its chemical analogue yttrium. The spleen is 3187 added to the generic model structure because human and animal data indicate that it is an 3188 important repository for scandium. The generic structure is also modified with regard to 3189 routes of transfer to and from the marrow compartments, based on indications from animal 3190 studies of relatively high transfer from plasma to marrow (Rosoff et al., 1963, 1965; Hara and 3191 Freed, 1973; Byrd et al., 1975; Lachine et al., 1976). 3192 (244) Transfer coefficients in the characteristic model for scandium are set for consistency 3193 with the following observations of the behavior of scandium isotopes in human subjects and 3194 laboratory animals: (1) in human subjects with various illnesses, blood clearance over 3 d, 3195 urinary and faecal excretion rates over 15 d, whole body retention over 1.5 y, and activity 3196 concentrations in autopsy tissues of subjects dying 5-7 mo after injection (Rosoff et al., 3197 1965); (2) measurements of the time-dependent systemic distribution of activity in rats, mice, 3198 and rabbits (Durbin, 1960; Rosoff et al., 1963; Basse-Cathalinat et al., 1968; Hara and Freed, 3199 1973; Byrd et al., 1975; Lachine et al., 1976). 3200 (245) Blood is divided into compartments Blood 1 and Blood 2 representing two 46 3201 components of retention as indicated by data for intravenously injected Sc NTA in human 3202 subjects (Rosoff et al., 1965). Blood 1 is a central compartment that exchanges activity with 3203 Blood 2 and several tissue compartments. Scandium-47 migrating to blood from sites of 3204 production is assigned to Blood 1. Blood 2 represents scandium that is firmly bound to 3205 plasma proteins. -1 3206 (246) The total outflow rate from Blood 1 is 3 d . Blood 2 receives 15% of outflow from

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3207 Blood 1 and loses scandium back to Blood 1 with a half-time of 1.5 d. This half-time is taken 3208 from the model for the chemically similar element yttrium. 3209 (247) The liver is divided into two compartments called Liver 1 and Liver 2. Liver 1 3210 receives 20% of outflow from Blood 1. Activity is removed from Liver 1 with a half-time of 3211 3 days, with 50% moving to Blood 1, 25% to Liver 2, and 25% to the SI contents 3212 (representing biliary secretion). Faecal excretion of scandium is assumed to arise solely from 3213 transfer of scandium from Liver 1 to the SI content based on data of Rosoff et al. (1965) for a 3214 human subject. Almost all of the scandium secreted into the small intestine is lost in faeces 3215 because of the low rate of absorption of scandium from the small intestine to blood. Activity 3216 transfers from Liver 2 to Blood 1 with a half-time of 100 d. 3217 (248) The kidneys are represented as a single compartment that exchanges activity with 3218 Blood 1. This compartment receives 3% of outflow from Blood 1 and loses scandium to 3219 Blood 1 with a half-time of 20 d. Urinary excretion of scandium is represented as a direct 3220 transfer from Blood 1 to Urinary bladder content, without intermediate retention in the 3221 kidneys. Urinary bladder content receives 1.8% of outflow from Blood 1. 3222 (249) Trabecular and cortical marrow each receives 5% of outflow from Blood 1. Activity 3223 is removed from the marrow compartments to Blood 1 with a half-time of 100 d. 3224 (250) The spleen receives 2% of outflow from Blood 1. The removal half-time from spleen 3225 to Blood 1 is 1 y. 3226 (251) Other soft tissues are divided into two compartments representing relatively fast 3227 (T1/2 = 3 d) and relatively slow (T1/2 = 100 d) return of scandium to Blood 1. These 3228 compartments receive 20% and 18.2% of outflow from Blood 1, respectively. The deposition 3229 fraction in the latter compartment is the balance of outflow from Blood 1 after all other 3230 deposition fractions in the model were assigned. 3231 (252) Bone surface receives 10% of outflow from Blood 1. The deposition on bone surface 3232 is equally divided between trabecular and cortical surface. The fate of scandium deposited on 3233 bone surfaces is described by the generic model for bone-surface-seekers, except that 3234 scandium biologically removed from bone is assumed to return to blood rather than to be 3235 channeled through bone marrow. Thus, scandium is removed from cortical or trabecular bone 3236 surfaces at a rate proportional to (1.5 times) the turnover rate of that bone type. The assumed -1 -1 3237 bone turnover rates are 3% y for cortical bone and 18% y for trabecular bone. One-third of 3238 activity removed from bone surfaces is buried in bone volume and two-thirds transfers to 3239 Blood 1. Activity is removed from cortical or trabecular bone volume to Blood 1 at the rate of 3240 turnover of that bone type. 3241 3242 6.3. Individual Monitoring 3243 45 45 3244 (253) Ca is a beta emitter. Ca intakes are generally monitored though measurements of 3245 the activity excreted in urine. The most common method of analysis is liquid scintillation 3246 counting. 3247 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 45Ca Urine Bioassay Liquid Scintillation 15 Bq/L 1-5 Bq/L Counting 3248 3249 3250 References

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3251 3252 Allen, L., 1982. Calcium bioavailability and absorption a review. Am. J. Clin. Nutr. 35, 783-808. 3253 Anderson, J., Tomlinson, R.W.S., Ramsay, I.D., Clarke, M.B., Osborn, S.B., 1970. Radiocalcium 3254 uptake in the bones of the foot. Br. J. Radiol. 43, 168-172. 3255 Barger-Lux, M.J., Heaney, R.P., 1995. Caffeine and the calcium economy revisited. Osteoporos Int. 3256 5(2), 97-102. 3257 Barger-Lux, M.J., Heaney, R.P., 2005. Calcium absorptive efficiency is positively related to body 3258 size. J Clin. Endocrinol. Metab. 90, 5118-5120. 3259 Barger-Lux, M.J., Heaney, R.P., Recker, R.R., 1989. Time course of calcium absorption in humans: 3260 evidence for a colonic component. Calcif. Tissue Int., 44(5), 308-311 3261 Barnes, O.W., Bishop, M., Harrison, G.E., Sutton, A., 1961. Comparison of the plasma concentration 3262 and urinary excretion of strontium and calcium in man. Int. J. Radiat. Biol. 3, 637-646. 3263 Basse-Cathalinat, B., Blanquet, P., Collignon, G., Mirande-Iriberry, J., 1968. Bone scintigraphy with 3264 47Sc and the scintillation camera. J. Nucl. Med. 9:436-438. 3265 Bishop, M., Harrison, G.E., Raymond, W.H.A., Sutton, A., Rundo, J., 1960. Excretion and retention 3266 of radioactive strontium in normal man following a single intravenous injection. Int. J. Radiat. 3267 Biol. 2, 125-142. 3268 Bligh, P.H., Taylor, D.M., 1963. Comparative studies of the metabolism of strontium and barium in 3269 the rat. Biochem. J. 87, 612-618. 3270 Borle, A.B., 1981. Control, modulation, and regulation of cell calcium. Rev. Physiol. Biochem. 3271 Pharmacol. 9, 13-153. 3272 Byrd, B. L., Watson, E.E., Cloutier, R.J., Hayes, R.L., 1975. Effect of stable scandium on the long- 3273 term whole body retention of intravenously administered 46Sc citrate in the rat. Health Phys. 3274 29, 375-379. 3275 Carr, T.E.F., Harrison, G.E., Nolan, J., 1973. The long-term excretion and retention of an intravenous 3276 dose of Ca-45 in two healthy men. Calcif. Tissue Res. 12, 217-226. 3277 Cashman, K.D., Flynn, A., 1996. Effect of dietary calcium intake and meal calcium content on 3278 calcium absorption in the rat. Br. J. Nutr. 76, 463-470. 3279 Cochet, B., Jung, A., Griessen, M., Bartholdi, P., Schaller, P., Donath, A., 1983. Effects of lactose on 3280 intestinal calcium absorption in normal and lactase-deficient subjects. Gastroenterology. 84, 3281 935-940. 3282 Cohn, S.H., Lippincott, S.W., Gusmano, E.A., Robertson, J.S., 1963. Comparative kinetics of 47Ca 3283 and 85Sr in man. Radiat. Res. 19, 104-119. 3284 Davies, K.M., Heaney, R.P., Recker, R.R., Lappe, J.M., Barger-Lux, M.J., Rafferty, K., Hinders, S., 3285 2000. Calcium intake and body weight. J. Clin. Endocrinol. Metab., 85(12), 4635-4638. 3286 De Swart, P.M., Buseman Sokole E., Wilmink J.M., 1998. The interrelationship of calcium and 3287 magnesium absorption in idiopathic hypercalciura and renal calcium stone disease. J. Urol. 3288 159 (3), 669-672. 3289 DeGrazia, J., Rich, C., 1964. Studies of intestinal absorption of calcium-45 in man. Metabolism. 13. 3290 650-660. 3291 Domanski, T., Liniecki, J., Witkowska, D., 1969. Kinetics of calcium, strontium, barium, and radium 3292 in rats. In: Delayed Effects of Bone-Seeking Radionuclides; ed. C. W. Mays, Univ. Utah 3293 Press, Salt Lake City pp. 79-94. 3294 Domanski, T., Witkowska, D., Garlicka, I., 1980. Influence of age on the discrimination of barium in 3295 comparison with strontium during their incorporation into compact bone. Acta. Physiol. Pol., 3296 31, 289-296. 3297 Durbin, P.W., 1960. Metabolic characteristics within a chemical family. Health Phys. 2:225-238. 3298 Ellsasser, J.C., Farnham, J.E., Marshall, J.H., 1969. Comparative kinetics and autoradiography of 3299 Ca-45 and Ba-133 in ten-year-old beagle dogs. J. Bone Jt. Surg. 51A, 1397-1412. 3300 Freed, B. R., Woodard, H.Q., Laughlin, J.S., 1975. Kinetics of 47Sc generated by decay of 47Ca in 3301 vivo. Abstract from proceedings of the twentieth meeting of the Health Physics Society. 3302 Health Phys. 29, 900.

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3303 Griffin, I.J., Davila, P.M., Abrams, S.A., 2002. Non-digestible oligosaccharides and calcium 3304 absorption in girls with adequate calcium intakes. Br. J. Nutr. 87 Suppl 2, S187-191. 3305 Groer, P.G., Marshall, J.H., 1973. Mechanism of calcium exchange at bone surfaces. Calc. Tiss. Res. 3306 12, 175-192. 3307 Groer, P.G., Marshall, J.H., Farnham, J.E., Rabinowitz, S.A., 1972. Comparative autoradiography of 3308 Ca-45 and Ba-133 in beagles. In: Radiological and Environmental Research Division annual 3309 report, Center for human radiobiology July 1971 through June 1972; Argonne, IL: Argonne 3310 National Laboratory; ANL-7960, Part II, Biology and Medicine, 41-47. 3311 Hara, T., Freed, B.R., 1973. Preparation of carrier-free 47Sc by chemical separation from 47Ca and its 3312 distribution in tumor bearing mice. Int. J. Appl. Radiat. Isotop. 24, 373-376. 3313 Harrison, G.E., Carr, T.E.F., Sutton, A., 1967. Distribution of radioactive calcium, strontium, barium 3314 and radium following intravenous injection into a healthy man. Int. J. Radiat. Biol. 13, 3315 235-247. 3316 Hart, H.E., Spencer, H., 1976 Vascular and extravascular calcium interchange in man determined with 3317 radioactive calcium. Radiat. Res. 67, 149-161. 3318 Harvey, J.A., Zobitz, M.M., Pak, C.Y.C., 1988. Dose dependency of calcium absorption: a 3319 comparison of calcium carbonate and calcium citrat. J. Bone Min. Res. 3, 253-258. 3320 Heaney, R., Recker, R., Stegman, M., Moy, A., 1989. Calcium absorption in woman: relationships to 3321 calcium intake, estrogen status and age. J. Bone Min. Res., 4, 469-475. 3322 Heaney, R.P., 1964. Evaluation and interpretation of calcium-kinetic data in man. Clin. Orthop. Rel. 3323 Res. 31, 153-183. 3324 Heaney, R.P., 2002. Effects of caffeine on bone and the calcium economy. Food Chem. Toxicol., 3325 40(9), 1263-1270. 3326 Heaney, R.P., Bauer, G.C.H., Bronner, F., Dymling, J.-F., Lafferty, F.W., Nordin, B.E.C., Rich, C., 3327 1964. A normal reference standard for radiocalcium turnover and excretion in humans. J. Lab. 3328 Clin. Med., 64, 21-28. 3329 Heaney, R.P., Dowell, M.S., Barger-Lux, M.J., 1999. Absorption of calcium as the carbonate and 3330 citrate salts, with some observations on method. Osteoporos Int., 9(1), 19-23 3331 Heard, M.J., Chamberlain, A.C., 1984. Uptake of Pb by human skeleton and comparative metabolism 3332 of Pb and alkaline earth elements. Health Phys. 47, 857-865. 3333 Henrichs, K., Werner, E., Schmitt, A., 1984. Re-evaluation of radiation exposure due to 3334 administration of radioactive calcium-47. In: A. Kaul (ed.) IRPA, 6th Congress, Berlin, May 3335 7-12, 1984 Radiation-risk-protection, Fachverband für Strahlenschutz eV., Jülich, pp. 3336 458-461. 3337 Holloway, L., Moynihan, S., Abrams, S.A., Kent, K., Hsu, A.R., Friedlander, A.L., 2007. Effects of 3338 oligofructose-enriched inulin on intestinal absorption of calcium and magnesium and bone 3339 turnover markers in postmenopausal women. Br. J. Nutr. 97, 365-372. 3340 ICRP, 1973. Alkaline earth metabolism in adult man, Publication 20. Pergamon Press, Oxford. 3341 ICRP, 1975. Report of the task group on reference man, Publication 23. Pergamon Press, Oxford. 3342 ICRP, 1980. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Pt.2, Ann. ICRP 3343 4, (3/4). 3344 ICRP, 1995. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 4, 3345 Inhalation dose coefficients. ICRP Publication 71, Ann. ICRP 25, (3/4). 3346 ICRP, 2002. Basic anatomical and physiological data for use in radiological protection: Reference 3347 values. ICRP Publication 89, Ann. ICRP, 32(3/4). 3348 ICRP, 2006. Human Alimentary Tract Model for Radiological Protection. ICRP publication 100. Ann. 3349 ICRP 36, (1-2) 3350 Isaksson, M., Fredlund, K., Sandberg, A.S., Almgren, A., Rossander-Hulthen, L., 2000. 3351 Determination of the retention of 47Ca by whole-body counting. Appl. Radiat. Isot., 52, 3352 1441-1450. 3353 Jovanovic, V., 1978. Determination of intestinal radiocalcium absorption by double tracer methods 3354 with scandium-85. Eur. J. Nucl. Med. 3. 115-120.

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3355 Kerstetter, J.E., O'Brien, K.O., Caseria, D.M., Wall, D.E., Insogna, K.L., 2005. The impact of dietary 3356 protein on calcium absorption and kinetic measures of bone turnover in women. J. Clin. 3357 Endocrinol. Metab. 90, 26-31. 3358 Korsunskii, V.N., Tarasov, N.F., Naumenko, A.Z., 1981. Clinical evaluation of Ba-133m as an 3359 osteotropic agent. ORNL/TR-86/30 (7 pgs); Translated from the Russian UDC 3360 616.71-006-073.916, Meditsinskaya Radiologiya No. 10, pp. 45-48. 3361 Kshirsagar, S.G., Lloyd, E., Vaughan, J., 1966. Discrimination between strontium and calcium in 3362 bone and the transfer from blood to bone in the rabbit. Br. J. Radiol. 39, 131-140. 3363 Lachine, E. E.; Noujaim, A. A.; Ediss, C.; Wiebe, L. I. (1976). Toxicity, tissue distribution and 3364 excretion of 46ScCl3, and 46Sc-EDTA in mice. Int. J. Appl. Radiat. Isotop. 27:373-377. 3365 Leggett, R.W., 1992. A generic age-specific biokinetic model for calcium-like elements. Radiat. Prot. 3366 Dosim. 41, 183-198. 3367 Leggett, R.W., Eckerman, K.F., Williams, L.R., 1982. Strontium-90 in bone: a case study in 3368 age-dependent dosimetric modeling, Health Phys., 43, 307-322. 3369 Likhtarev, I.A., Dobroskok, I.A., Ilyin, L.A., Krasnoschekova, G.P., Likhtareva, T.M., Smirnov, B.I., 3370 Sobolev, E.P., Shamov, V.P., Shapiro, E.L., 1975. A study of certain characteristics of 3371 strontium metabolism in a homogeneous group of human subjects. Health Phys., 28, 49-60. 3372 Liniecki, J., 1971. Kinetics of calcium, strontium, barium and radium in rabbits. Health Phys. 21, 3373 367-376. 3374 Lloyd, R.D., Mays, C.W., 1976. Atherton, D. R. Distribution of injected Ra-226 and Sr-90 in the 3375 beagle skeleton. Health Phys. 30, 183-189. 3376 Lutwak, L., 1969. Tracer studies of intestinal calcium absorption in man. Amer. J. Clin. Nutr., 22. 3377 771- 785. 3378 Maletskos, C.J., Keane, A.T., Telles, N.C., Evans, R.D., 1969. Retention and absorption of Ra-224 3379 and Th-234 and some dosimetric considerations of Ra-224 in human beings. In: Mays, C.W., 3380 Jee, W.S.S., Lloyd, R.D., Stover, B.J., Dougherty, J.H., Taylor, G.N. (Eds.), Delayed effects 3381 of bone-seeking radionuclides. Salt Lake City, UT: University of Utah Press, 29-49. 3382 Malluche, H.H., Werner, E., Ritz, E., 1978. Intestinal absorption of calcium and whole-body calcium 3383 retention in incipient and advanced renal failure. Miner. Electrolyte Metab., 1, 263-270. 3384 Marchandise, X., Pagniez, D., Gilquin, B., Ythier,H., Duquesnoy, B., Wemeau, J., 1986. Influence of 3385 accompanying anion on intestinal radiocalcium absorption. Calcif. Tissue Int. 40, 8-11. 3386 Mautalen, C., Cabrejas, M., Soto, R., 1969. Isotopic determination of intestinal calcium absorption in 3387 normal subjects. Metabolism. 18, 395-405. 3388 Neer, R., Berman, M., Fisher, L., Rosenberg, L.E., 1967. Compartmental analysis of calcium kinetics 3389 in normal adult males. J. Clin. Invest., 46, 1364-1379. 3390 Neuman, W.F., 1964. Blood-bone exchange. In: Frost, H.M. (Eds.), Bone biodynamics. Boston: 3391 Little, Brown, and Co, 393-408. 3392 Newton, D., Harrison, G.E., Kang, C., Warner, A.J., 1991. Metabolism of injected barium in six 3393 healthy men. Health Phys., 61, 191-201. 3394 Newton, D., Harrison, G.E., Rundo, J., Kang, C., Warner, A.J., 1990. Metabolism of Ca and Sr in late 3395 adult life. Health Phys., 59, 433-442. 3396 Norrdin, R.W., Arnold J.S., 1980. Comparison of 47Ca accumulation in samples of trabecular and 3397 cortical bone and its retention in ribs, humerus, and femur. In: Jee, W.S.S., Parfitt, A.M. 3398 (Eds.), Bone Histomorphometry, pp. 499-500 (abstract). 3399 Phang, J.M., Berman, M., Finerman, G.A., Neer, R.M., Rosenberg, L.E., Hahn, T.J., 1969. Dietary 3400 Perturbation of calcium metabolism in normal man: compartmental analysis. J. Clin. Invest., 3401 48, 67-77. 3402 Riggs, B.L., Marshall, J.H., Jowsey, J., Heaney, R.P., Bassingthwaighte, J.B., 1971. Quantitative 3403 Ca-45 autoradiography of human bone. J. Lab. Clin. Med., 78, 585-598. 3404 Rosoff, B., Siegel, E., Williams, G.L., Spencer, H., 1963. Distribution and excretion of radioactive 3405 rare-earth compounds in mice. Int. J. Appl. Radiat. Isotop. 14, 129-135. 3406 Rosoff, B., Spencer, H., Cohn, S.H., Gusmano, E.A., 1965. Metabolism of scandium-46 in man. Int. J. 3407 Appl. Radiat. Isotop. 16, 479-485.

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3408 Rumenapf, G., Schwille, P., 1987. The influence of oral alkali citrate on intestinal calcium absorption 3409 in healthy man. Clinical Science, 73, 117-121. 3410 Samachson, J., 1963. Plasma values after oral calcium-45 and strontium-85 as an index of absorption. 3411 Clinical Science, 25, 17-26. 3412 Samachson, J., 1966. The gastrointestinal clearance of strontium-85 and calcium-45 in man. Radiat. 3413 Res., 27, 64-74. 3414 Sambrook, P., Abeyasekera, G., Ansell, B. et al., 1985. Calcium absorption In rheumatoid arthritis. 3415 Ann. Rheumatic Diseases, 44, 585-588. 3416 Schachter, D., Dowdle, E.B., Schenker, H., 1960. Active transport of calcium by the small intestine of 3417 the rat. Am. J. Physiol., 198, 263-268, 3418 Schiessle, W., Schmidtke, I., Philipp, K., Schroff, E., 1964. Inhalationsuntersuchungen mit 3419 radioactivem Calcium (Ca45) beim Meerschweinchen. Z. Aerosolforsch. 11, 373–396. 3420 Schlenker, R.A., Keane, A.T., Holtzman, R.B., 1982. The retention of Ra-226 in human soft tissue 3421 and bone; implications for the ICRP 20 alkaline earth model. Health Phys., 42, 671-693. 3422 Schulert, A.R., Peets, E.A., Laszlo, D., Spencer, H., Charles, M., Samachson, J., 1959. Comparative 3423 metabolism of strontium and calcium in man. Int. J. Appl. Radiat. Isotop., 4, 144-153. 3424 Spencer, H, Rubio, N, Kramer, L, Norris, C, Osis, D., 1987. Effect of zinc supplements on the 3425 intestinal absorption of calcium. J. Amer. College of Nutrition, 6, 47-51. 3426 Spencer, H., Li, M., Samachson, J., laszlo, D., 1960. Metabolism of Strontium-85 and Calcium-45 in 3427 Man. Metabolism, 9, 916-925. 3428 Stark, G., 1968, Studies on synthetic hydroxyapatite crystals with regard to metabolism of calcium, 3429 strontium, barium and radium in bone. I. The discrimination against calcium. Biophysik 5, 3430 42-54. 3431 Stather, J.W., 1974. Distribution of P-32, Ca-45, Sr-85 and Ba-133 as a function of age in the mouse 3432 skeleton. Health Phys., 26, 71-79. 3433 Taylor, D.M., 1966. The metabolism of scandium-47 produced by the decay of calcium-47 in vivo. 3434 Br. J. Radiol. 39, 620-622. 3435 Wood, S.K., Farnham, J.E., Marshall, J.H., 1970. Ca-45, Ba-133, and Ra-226 in 6-to 10-year-old 3436 beagle dogs: A 100-day study. In: Radiological Physics Division annual report, Center for 3437 Human Radiobiology, July 1969 through June 1970; Argonne, IL: Argonne National 3438 Laboratory; ANL-7760, Part II, Biology and Medicine; 110-132. 3439

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3440 7. IRON (Z = 26) 3441 3442 7.1. Chemical Forms in the Workplace 3443 3444 (254) Iron is a transition metal, occurring mainly in oxidation states II and III. Iron is a 3445 vital constituent of plant and animal life, and is the key component of haemoglobin. Iron is 3446 used in industry in a variety of chemical forms, including oxides (FeO, Fe2O3, Fe3O4), 3447 chlorides, fluorides and bromides. 59 3448 (255) The main radioactive isotope is Fe, which is used as ferrous citrate, chloride or 59 3449 sulphate for diagnostic applications in hospitals. In the nuclear industry, Fe is an important 3450 neutron activated corrosion product. It is likely to be present as oxides in different parts of the 3451 primary circuits of water cooled reactors (Collier et al., 1994). 3452 3453 Table 7-1. addressed in this report 3454 Isotope Physical half-life Decay mode Fe-52 8.275 h EC, B+ Fe-55 2.737 y EC Fe-59a 44.495 d B- Fe-60 1.5E+6 y B- 3455 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 3456 are given on accompanying electronic disk. 3457 3458 7.2. Routes of Intake 3459 3460 7.2.1. Inhalation 3461 3462 Absorption Types and parameter values 3463 (256) Extensive information was found on the behaviour of iron inhaled in oxide form in 3464 both animals and in man, because it has been used as a test material to study lung clearance. 3465 Some information was also found on other forms, such as the chloride. 3466 (257) Absorption parameter values and Types, and associated fA values for particulate 3467 forms of iron are given in Table 7-2. 3468 3469 Iron chloride (FeCl3) 59 3470 (258) Morrow et al. (1968) followed lung retention of Fe for 7 days after inhalation of 59 3471 FeCl3 by dogs and rats, but few details are given. Lung retention in dogs was represented by 3472 a two-component exponential function with half-times of 1.9 days (17%: clearance rate 0.36 -1 -1 3473 d ) and 85 days (clearance rate 0.0081 d ), giving predicted lung retention at 30 d and 180 d 3474 to be 65% and 19% of the initial lung deposit (ILD), and indicating Type M behaviour. 3475 3476 Iron oxide (Fe2O3) 3477 (259) Radiolabelled ferric oxide, Fe2O3 has been used as a test material in many studies of 3478 the respiratory tract deposition and clearance of inhaled particles, including several human 3479 studies of lung retention of duration 2–8 months (See review in ICRP Publication 66, Annexe 3480 E, Table E.19) (ICRP, 1994). Over this period, retention could be adequately represented by 3481 a single exponential function, with a half-time between about 60 and 600 d, but in most cases 3482 less than 200 d, indicating Type M behaviour. The results are difficult to interpret as the 51 3483 retention followed was that of the label, which varied, in some cases being Cr (Albert et al.,

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3484 1967; Morrow et al., 1967a,b; Waite and Ramsden, 1971a, Ramsden and Waite, 1972) and in 237 3485 one case Pu (Waite and Ramsden, 1971b, Ramsden and Waite, 1972). As observed in 3486 ICRP Publication 30 (ICRP, 1980) this raises questions about the contributions to retention 3487 made by the iron oxide particle matrix itself, and by the chemical form of the label. 3488 However, Ramsden and Waite (1972) after careful correction for leaching of the label, 3489 estimated a retention half-time for the iron oxide matrix of about 270 d. 59 3490 (260) Some studies used material labelled with Fe itself. Results following inhalation of 59 3491 Fe2O3 by rats and dogs showed that lung retention could be fit by a single exponential with -1 3492 a rate of 0.01 d (half-time ~70 d) (Gibb and Morrow, 1962; Morrow et al., 1964; Morrow et 3493 al., 1968). Calculations by the task group indicate that lung retention at 30 d and 180 d would 3494 be 71% and ~13% ILD. Similar experiments performed on rats showed similar results with a -1 59 3495 clearance rate of 0.011 to 0.013 d (Muhle and Bellman, 1986). Other studies where Fe- 3496 labelled iron oxide particles were periodically inhaled by rats showed that lung retention -1 3497 followed a single exponential function with a rate from 0.008 to 0.011 d , depending on the 3498 age of the animals (Bellmann et al., 1991). 3499 (261) Studies on the retention of instilled iron oxide particles in human alveolar 3500 macrophages (AM) indicated that particles were cleared from the lungs with a rapid-phase -1 -1 3501 clearance rate of 1.4 d and long term clearance rate of about 0.006 d (Lay et al., 1998). All 3502 these results indicate Type M behaviour. 3503 3504 Magnetite (Fe3O4) 3505 (262) Ferromagnetic iron oxide particles, Fe3O4, have also been used as a test material in 3506 studies of the lung retention of inhaled particles, measured using magneto-pneumography 3507 (MPG), i.e. measurement of the remanent magnetic field from particles within the chest, after 3508 application of a strong magnetic field to it. The results of measurements made in groups of 3509 volunteers for up to about a year after inhalation (Cohen et al., 1979; Freedman et al., 1988; 3510 Möller, 1991; Stahlhofen and Möller, 1991; Möller et al., 2001; 2004; 2006) are consistent 3511 with assignment to Type M. In particular, Möller et al. (2001) measured long-term retention 3512 of ferromagnetic iron oxide particles in healthy and diseased subjects. In healthy non- 3513 smokers, on average less than 10% ILD cleared from the lungs rapidly (within 2 d). This 3514 fraction was somewhat greater (10-20%) in smokers and patients with sarcoidosis, and 3515 considerably greater in patients with idiopathic pulmonary fibrosis (IPF) (~30% ILD) and 3516 chronic obstructive bronchitis (COB) (~50% ILD). The half-time of the slow phase of lung 3517 clearance varied between groups as follows: young (20-39 years) healthy non-smokers 124 ± 3518 66 d; young cigarette smokers 220 ± 74 d; older (40-65 years) healthy non-smokers 162 ± 3519 120 d; older smokers 459 ± 334 d; sarcoidosis patients 275 ± 109 d; IPF patients 756 ± 345 d; 3520 COB patients (mostly ex-smokers) 240 ± 74 d. Since lung clearance in healthy subjects was 3521 faster than measured in healthy human volunteers with inert particles like Teflon (Philipson 3522 et al., 1996), it was concluded that lung clearance was determined by particle dissolution in 3523 alveolar macrophages, which was impaired by cigarette smoking and the diseases 3524 investigated. 3525 3526 Contaminated dusts (‘residues’) formed at nuclear power plant (NPP) 59 3527 (263) The biokinetics of Fe were followed for 84 days after intratracheal instillation into 59 3528 rats of a suspension of corrosion 'crud' particles (oxide bearing debris, 5% Fe activity) from 3529 the primary containment of a water cooled reactor (Collier et al., 1994). Few details are 59 3530 given, but it was assessed here that the results indicate Type S behaviour of the Fe present. 3531 3532 Welding fumes

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3533 (264) Kalliomäki et al. (1978, 1983a, 1985) used MPG to measure the lung contents of 3534 magnetic dusts in groups of welders with similar exposures. A single exponential model was 3535 applied to lung retention. Repeated measurements over a 6-year period on welders who -1 3536 worked with mild steel gave a clearance constant of 0.2 y (t½ ~3.5 y). Results of a cross- 3537 sectional study on stainless steel welders gave a t½ of 8.5 y. Both indicate Type S behaviour 3538 for at least some of the material. 3539 (265) To simulate occupational exposure, rats inhaled fumes from manual metal arc 3540 (MMA) or metal inert gas (MIG) welding of stainless steel for 1 hour per working day for 4 3541 weeks (Kalliomäki et al., 1983b,c). Lung contents of iron, , and nickel 3542 were measured by neutron activation analysis (NAA) for 106 d after the end of exposure. 3543 Retention of exogenous iron (i.e. that derived from the welding fume) was also followed by 3544 MPG. For the MMA welding fume, results indicate Type M behaviour for all elements 3545 measured except iron measured by NAA (Type S). Clearance was slower following 3546 inhalation of MIG welding fumes, indicating Type S for all elements studied except iron 3547 measured by MPG (Type M). 59 51 58 3548 (266) Kalliomäki et al. (1986a,b, 1987) followed lung retention of Fe, Cr and Co (as 3549 indicators of iron, chromium and nickel respectively) in rats for 106 d after intratracheal 3550 instillation of neutron-activated fumes from manual metal arc (MMA) or metal inert gas 59 3551 (MIG) welding of stainless steel (SS), or mild steel (MS) ( Fe only). Results indicate Type S 59 3552 behaviour for the Fe present in all fumes studied except MMA (MS) (Type M); Type S 3553 behaviour for the chromium and nickel present in MIG (SS) fumes and Type M for these 3554 elements in MMA (SS) fumes. 3555 3556 Other compounds 3557 (267) Measurements following inhalation of neutron-activated fly ash by hamsters indicate 59 3558 Type M behaviour for the Fe present (Wehner and Wilkerson, 1981). Measurements 3559 following inhalation of neutron-activated volcanic ash by rats indicate Type M or S 59 3560 behaviour for the Fe present (Wehner et al., 1984). 3561 3562 Rapid dissolution rate for iron 3563 (268) Little experimental information is available except for iron oxide, which is relatively 3564 insoluble. Although there is some experimental information for ferric chloride, which is 3565 probably absorbed more rapidly, it is insufficient to estimate the rapid dissolution rate. There 3566 is therefore no justification for choosing a rate different from the general default value of 30 –1 3567 d , which is applied here to all Type F forms of iron. 3568 3569 Extent of binding of iron to the respiratory tract 3570 (269) The only experimental information for iron administered in solution relates to ferric 3571 chloride. This indicates Type M behaviour, suggesting that there could be significant binding 3572 of iron. However, there is insufficient information to estimate the extent of any bound state. 3573 Although it is not clear that the bound state for iron is negligible, it is assumed by default that 3574 fb = 0. 3575

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3576 3577 Table 7-2. Absorption parameter values for inhaled and ingested iron 3578 Absorption parameter valuesa Absorption from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorption Assigned forms Type F — 1 100 – 0.1 M Ferric chloride; ferric 0.2 3 0.005 0.02 oxide; all unspecified formsd S Corrosion products 0.01 3 1x10-4 0.001 Ingested materials All unspecified forms 0.1 a –1 3579 It is assumed that for cobalt a bound fraction fb = 0.03 with an uptake rate sb = 0.002 d is applied to 3580 material deposited in the AI region only. It is assumed that fb = 0.0 for material deposited in other regions. –1 3581 The values of sr for Type F, M and S forms of cobalt (1 d ,) are element-specific. 3582 b Materials (e.g. cobalt nitrate) are listed here where there is sufficient information to assign to a default 3583 absorption Type, but not to give specific parameter values (see text). 3584 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 3585 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 3586 absorption Type and the fA value for ingested soluble forms of iron (0.1). 3587 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 3588 or if the form is known but there is no information available on the absorption of that form from the 3589 respiratory tract. 3590 3591 7.2.2. Ingestion 3592 3593 (270) The gastrointestinal absorption of iron has been extensively studied because of its 3594 important role in nutrition. 3595 (271) Freiman et al. (1963) reported a mean absorption value of 0.7 for a group of 16 3596 volunteers aged between 27 and 60. Brozovic (1975) reviewed data from radioactive iron 3597 uptake studies involving a total of 990 normal human volunteers, and concluded that 3598 absorption values of 0.05 - 0.1 are usual. However, individual studies produced mean figures 3599 as great as 0.4 for men and 0.6 for women. Some of the variation may be caused by 3600 differences in the techniques used to measure absorption, but much of it is caused by dietary 3601 and physiological factors as reviewed by Brozovic (1975), Underwood (1977), Morris 3602 (1983), Lynch (1984), Cook et al. (1991), Whiting, (1995); Teucher et al. (2004). Human 3603 milk and organic acids (ascorbic, lactic, citric…) are enhancers of iron absorption, while 3604 dietary fibres (pectins, cellulose…), tannates in tea, polyphenols in coffee and even calcium 3605 supplements in diet are potent inhibitors. Similarly, lowered iron status of the individual 3606 results in increased iron uptake, as shown by menstruating women and sufferers from 3607 anaemia. Uptake is also increased during pregnancy. These latter points, associated to 3608 hormonal differences, result in higher iron absorption in females compared to males 3609 (Brozovic 1975, Woodhead et al., 1991, Fletcher et al., 1994). 3610 (272) Iron is known to be, in some circumstances, retained in the wall of the small 59 3611 intestine. Study of whole body retention of Fe in human volunteers after oral administration

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59 3612 provided evidence of temporary retention of approximately 20% of the ingested Fe (Werner 3613 et al., 1987, ICRP, 2006). It was suggested that this part of iron was incorporated by 3614 macrophages lying under the epithelial layer and then transferred to goblet cells before 3615 excreted back in the lumen of the intestine. All these data are consistent with a half-time of 3616 intestinal retention of about 3 days (ICRP, 2006). 3617 (273) This iron retention in the intestine wall seems to be dependant of the iron status and 3618 to form part of the mechanism operating to regulate iron absorption (Werner et al., 1987). 3619 (274) In Publication 30 (ICRP, 1980) and Publication 69 (ICRP, 1995) an absorption

3620 value of 0.1 for both males and females was recommended.

3621 (275) In this report it is recommended an fA value of 0.1 for all chemical forms. 3622 3623 7.2.3. Systemic Distribution, Retention and Excretion 3624 3625 7.2.3.1. Overview of normal iron metabolism 3626 3627 (276) The biokinetics of iron has been investigated extensively in healthy human subjects 3628 as well as patients with iron deficiency or overload. The following overview of the 3629 physiological functions and normal biokinetics of iron in the human body is based mainly on 3630 the authoritative treatise by Bothwell et al., 1979. See also Saito et al., 1964; Green et al., 3631 1968; Munro and Linder, 1978; Trubowitz and Davis, 1982; Barton and Edwards, 2000. 3632 (277) The mass of iron in the human body typically is about 3.5-4.0 g in adult males and 3633 2.0-2.5 g in adult females. The small mass of iron in the body does not reflect its important 3634 role in many physiological functions. This small mass usually is sufficient to maintain the 3635 normal physiological functions of iron because systemic iron has low rates of entry into the 3636 urinary bladder, gastrointestinal contents, and other excretion pathways and is reused 3637 repeatedly by the body. 3638 (278) The body’s iron content may be divided into two categories: essential (functional) 3639 iron and storage iron. 3640 (279) Essential iron is the portion of the body’s iron representing integral components of 3641 molecules that fulfill well defined physiological functions. For example, iron is an essential 3642 component of the oxygen carrying proteins haemoglobin and myoglobin and of numerous 3643 haem and non-haem enzymes involved in metabolic processes. The adult human body 3644 typically contains 30-40 mg of essential iron per kg of body mass. About 80-85% of this is 3645 found in haemoglobin within the red blood cells (RBC), and about 10-12% is found in 3646 myoglobin within muscle and other tissues. The remainder is distributed throughout the body 3647 tissues as haem enzymes (2-3% of body iron) and non-haem enzymes (3-4% of body iron). 3648 Essential iron typically represents about two-thirds of total body iron in adult males and four- 3649 fifths or more of total body iron in pre-menopausal adult females. 3650 (280) Storage iron is an iron reserve in the body that assures an adequate supply of iron for 3651 normal physiological processes during periods of unusually low intake or rapid loss. It is 3652 stored as ferritin and haemosiderin, which hold iron in a relatively non-reactive form. 3653 Storage iron is located mainly in two tissues, the reticuloendothelial (RE) system and hepatic 3654 parenchyma. In most situations where body iron is increased, storage iron accumulates in 3655 both parenchymal and RE cells. The only condition in which selective parenchymal overload 3656 occurs is idiopathic hemochromatosis, in which there appears to be an associated defect in the 3657 way in which RE cells handle iron, with the result that RE stores are disproportionately small. 3658 (281) Typical iron requirements in males (i.e. uptake to blood from diet) are about 1.2 mg -1 3659 d , or 6% of a typical daily intake of 20 mg by an adult male. Iron balance is favorable in the 3660 adult male, as reflected by the rarity of nutritional iron deficiency in males. By age 30 y there

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3661 is usually a reserve store of iron on the order of 1 g in males. 3662 (282) Iron balance is less favorable in the adult pre-menopausal female due to loss of 3663 circulating iron via menstruation. The amount of dietary iron required to replace this loss 3664 varies greatly, but the median value is probably about 0.4-0.5 mg/d. The total daily 3665 requirement in the female typically is about 1.4 mg, but variation is great. Total-body iron in 3666 the adult female typically is about 38 (34- 42) mg/kg. This corresponds to about 2300 mg of 3667 total-body iron in a 60-kg female. Essential iron in the adult female is roughly 33 mg/kg. 3668 This concentration is 10-20% lower than that in the male, reflecting differences in red cell 3669 mass and a larger amount of myoglobin in muscle in the male. The mean hepatic non-haem 3670 iron concentration is estimated as 0.1 mg/g liver in women, compared with about 0.27 mg/g 3671 liver in men. The average marrow storage iron has been estimated as about 300 mg in adult 3672 males and 100 mg in adult females. 3673 (283) Iron is distributed within the body by blood plasma. Nearly all plasma iron is bound 3674 to the transport protein transferrin. The removal half-time of transferrin iron from plasma to 3675 tissues is about 90 minutes. Most of the transferrin-bound iron leaving plasma enters a circuit 3676 starting in the erythroid marrow. A portion enters the extravascular spaces and returns to 3677 plasma mainly via the lymphatics. The rest is delivered to the parenchymal tissues, mainly 3678 the liver. 3679 (284) The erythroid marrow takes up transferrin iron from plasma for incorporation into 3680 haemoglobin. Most of this iron appears in circulating RBC in the next few days and remains 3681 there for the life of the cells. The life span of RBC typically is about four months. The 3682 portion that does not appear in circulating RBC consists of defective cells or extruded 3683 components of developing cells. This portion, called the wastage iron of erythropoiesis, 3684 typically represents 20-30% of iron that enters the erythroid marrow. This portion is collected 3685 by the body’s reticuloendothelial (RE) system, degraded, and returned to plasma. 3686 3687

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3688 7.2.3.2. Biokinetic model for systemic iron 3689 3690 (285) The structure of the systemic model for iron used in this report is shown in Figure 3691 7-1. Baseline transfer coefficients are listed in Table 7-3. The model structure and parameter 3692 values have been modified slightly from a model developed to compare the normal 3693 biokinetics of iron with its biokinetics in persons with hemochromatosis (Leggett et al., 3694 2000). The parameter values were based on data for adult males. 3695

3696 3697 3698 Figure 7-1. Structure of the biokinetic model for systemic iron used in this report. 3699 3700

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3701 Table 7-3. Transfer coefficients for systemic iron

From To Transfer coefficient (d-1) Other plasma Plasma transferrin 7.00E+01 Other plasma Urinary bladder content 1.00E-02 Other plasma Right colon content 1.00E-01 Plasma transferrin Marrow synthesis 9.43E+00 Plasma transferrin Liver parenchyma 5.55E-01 Plasma transferrin Extravascular transferrin 1.11E+00 RBC Other plasma 8.33E-04 RBC Marrow transit 7.29E-03 RBC Right colon content 2.00E-04 RBC Urinary bladder content 1.50E-05 Marrow synthesis RBC 2.43E-01 Marrow synthesis Marrow transit 1.04E-01 Marrow transit Other plasma 1.39E+00 Marrow transit Marrow storage 6.35E-02 Marrow transit Liver RE 1.06E-02 Marrow transit Spleen 1.70E-02 Marrow transit Other RE 6.35E-02 Marrow storage Marrow transit 3.80E-03 Liver RE Marrow transit 3.80E-03 Spleen Marrow transit 3.80E-03 Other RE Marrow transit 3.80E-03 Liver parenchyma Plasma transferrin 3.64E-03 Liver parenchyma Small intestine content 3.70E-04 Extravascular transferrin Plasma transferrin 8.88E-01 Extravascular transferrin Other parenchyma 2.22E-01 Other parenchyma Extravascular transferrin 1.27E-03 Other parenchyma Excreta 5.70E-04 Other parenchyma Urinary bladder content 3.00E-05 RBC Excreta 0.00E+00 3702 3703 (286) Parameter values describing the fate of iron in the first few weeks after entry into 3704 blood plasma were based on results of radioiron studies on reasonably healthy male subjects. 3705 After the parameter values governing the early kinetics of iron had been set, values 3706 controlling long-term retention and excretion were set for consistency with estimated 3707 contents of various iron pools in a male of age 50 y, estimated daily losses of iron along 3708 various excretion pathways, and the assumption that 0.9 mg of iron is absorbed each day 3709 from food. The normal 50-year-old male is assumed to have a total-body iron content of 3710 about 3.9 g, and this is assumed to be divided among major iron pools as follows: 3711 erythrocytes, 2300 mg; liver hepatocytes, 400 mg; liver RE cells, 50 mg, RE cells of bone 3712 marrow, 320 mg; spleen (mainly RE cells), 80 mg; other RE cells, 300 mg; erythroid marrow, 3713 80 mg; plasma transferrin, 2.9 mg; remaining plasma, 0.4 mg; and remainder of the body 3714 (including several of the compartments shown in Fig. 1), about 400 mg (Bothwell et al., 3715 1979). The precise total-body and compartmental contents calculated for age 50 years depend 3716 to some extent on the age at which the calculation is started and the assumed compartmental 3717 contents at that age. The compartment contents given above for a 50-year-old male are based 3718 on a starting age of 15 y, with the initial iron content of a given storage pool being 30% of the 3719 value indicated above for age 50 years and the initial iron content of any other pool being

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3720 80% of the value indicated above for age 50 years. 3721 (287) Iron absorbed from the gastrointestinal or respiratory tract or returning to plasma 3722 after degradation of RBC or wastage iron by the RE system enters a compartment in blood 3723 plasma called other plasma, which represents plasma iron that is not bound to transferrin. 3724 Most of the iron in other plasma transfers to plasma transferrin, but some transfers into the 3725 urinary bladder contents. Iron is removed from plasma transferrin with a half-time of 90 min, 3726 with about 85% moving to erythroid marrow (marrow synthesis), 5% to the hepatic 3727 parenchyma (liver parenchyma 1), and 10% to a compartment representing relatively rapidly 3728 exchanging extravascular spaces (extravascular transferrin). 3729 (288) Iron is removed from marrow synthesis with a half-time of 2 d, with 70% 3730 transferring to RBC and the remaining 30%, representing ineffective erythropoiesis, 3731 transferring to a marrow RE compartment called marrow transit. The removal of aging 3732 erythrocytes from the circulation is depicted as a transfer from RBC to marrow transit, 3733 representing phagocytosis by RE cells, plus a smaller transfer (about 10% of the total) from 3734 RBC to other plasma, representing intravascular breakage of red cells and release of the 3735 hemoglobin into the plasma. Most of the iron entering marrow transit is returned to other 3736 plasma with a half-time of 12 h. To account for relatively long-term storage of iron 3737 throughout the RE system, a small fraction of iron leaving marrow transit is distributed to the 3738 RE storage compartments in marrow, liver, spleen, and other tissues called, respectively, 3739 marrow storage, liver RE, spleen, and other RE. Iron is removed from these storage sites to 3740 marrow transit (and, therefore, largely to other plasma) over a period of months. The use of 3741 marrow transit as a central compartment within the RE system is a simplification of the real 3742 events, in that destruction of red blood cells (including red cell precursors) actually does not 3743 occur entirely in the marrow, and iron entering or leaving RE cells in the liver, spleen, and 3744 other extra-skeletal sites is not actually channeled through the marrow. 3745 (289) In addition to the RE system, an important storage site for iron is the hepatic 3746 parenchyma, represented in this model (for normal iron kinetics) by the compartment liver 3747 parenchyma 1. This compartment receives 5% of the outflow from plasma transferrin. Iron 3748 entering liver parenchyma 1 is returned over a period of months to plasma transferrin, except 3749 for a small amount, representing biliary secretion, that transfers to the compartment 3750 gastrointestinal tract (GI tract). 3751 (290) It is assumed that most (80%) of the iron that transfers from plasma transferrin to 3752 extravascular transferrin returns to plasma over the next day or two, but a portion (20%) is 3753 taken up by a compartment called other parenchyma 1 representing functional or storage iron 3754 not accounted for by explicitly identified tissues and fluids. The compartment other 3755 parenchyma 1 also is used to account for losses of iron due to exfoliation of skin, sweating, 3756 and losses in urine associated with exfoliation of kidney cells. Iron in other parenchyma 1 3757 that is not lost in excreta returns over a period of months to extravascular transferrin. 3758 (291) In addition to the excretion pathways indicated above, iron is lost from the body in 3759 erythrocytes that enter the gut or urinary bladder. According to the model, about two-thirds 3760 of iron losses are in faeces and the remainder is in skin, sweat, and urine in normal adult 3761 males. 3762 3763 7.2.3.3. Treatment of radioactive progeny 3764 3765 (292) Two isotopes of iron addressed in this report have radioactive progeny that 52 3766 contribute significantly to dose coefficients for the parent radionuclide: Fe, with chain 52m 52 60 60m 3767 members Mn (T1/2 = 21.1 min) and Mn (5.59 d); and Fe, with chain members Co 60 3768 (10.5 min) and Co (5.27 y). The models for manganese and cobalt produced in vivo are

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3769 modifications of the models applied in this series of reports to these two elements as parent 3770 radionuclides. The model for internally deposited cobalt is described in the section on cobalt 3771 in the present document. The model for internally deposited manganese will appear in a later 3772 part of this series. Both models were amended by the addition of compartments representing 3773 the spleen and red marrow, which are represented explicitly in the systemic model for iron. 3774 Modifications of the cobalt model were based on biokinetic data for this element developed 3775 by Comar et al., 1946; Comar and Davis, 1947; Barnaby et al., 1968; Smith et al., 1971; 3776 Hollins and McCullough, 1971; Thomas et al., 1976; Kreyling et al., 1986; and Andre et al., 3777 1989. Modifications of the manganese model were based on results of biokinetic or tissue 3778 distribution studies of this element by Fore and Morton, 1952; Koshida et al., 1963; Tipton 3779 and Cook, 1963; Furchner et al., 1966; and Dastur et al., 1971. 3780 (293) The compartment in the iron model called Other plasma is identified with the plasma 3781 compartment in the manganese model. Manganese produced in tissue compartments in the 3782 model for iron is assumed to be transferred to plasma with the following half-times: 1 min for 3783 the blood compartment of the iron model that is not included in the manganese model 3784 (plasma transferrin), 83.2 d for RBC (based on a mean lifetime of 120 d for RBC), and 2 d for -1 3785 all other iron compartments. Manganese is assumed to leave plasma at the rate 1000 d , with 3786 30% going to liver, 5% to kidneys, 5% to pancreas, 1% to right colon contents, 0.2% to 3787 urinary bladder contents, 0.5% to bone surface, 0.02% to RBC, 0.1% to brain, 0.3% to spleen, 3788 0.1% to red marrow, and the remaining 57.78% to other soft tissue. The liver is divided into 3789 two compartments called Liver 1 and Liver 2. Manganese depositing in the liver is assigned 3790 to Liver 1. Manganese is removed from Liver 1 with a half-time of 1 d, with 20% of outflow 3791 going to small intestine (SI) contents via biliary secretion and 80% entering Liver 2. Activity 3792 transfers from Liver 2 to plasma with a half-time of 2 d. Activity entering the pancreas is 3793 removed to plasma with a half-time of 2 d and to SI contents with a half-time of 2 d. The 3794 transfer from pancreas to SI contents represents secretion in pancreatic juice. Activity 3795 transfers from kidneys to plasma with a half-time of 2 d and from brain to plasma with a half- 3796 time of 150 d. The removal half-time from RBC is 83.2 d, as assumed for manganese 3797 produced by decay of iron in RBC. Activity depositing on bone surfaces is divided equally 3798 between cortical and trabecular surface and leaves bone surface with a half-time of 40 days, 3799 with 99% returning to plasma and 1% entering the corresponding bone volume compartment. 3800 Activity is removed from cortical or trabecular volume at the reference turnover rate for the 3801 specific bone type in adults as given in ICRP Publication 89 (2002). Other soft tissue is 3802 divided into compartments ST0, ST1, and ST2 representing fast, intermediate, and slow 3803 turnover of manganese. ST1 receives 14.6% of activity leaving plasma, ST2 receives 4%, 3804 and ST0 receives 39.18% (the amount remaining after all other deposition fractions in the 3805 model were assigned). Activity is returned from ST0, ST1, and ST2 to plasma with half- 3806 times of 30 min, 2 d, and 40 d, respectively. 3807 (294) Cobalt produced in tissue compartments in the model for iron is assumed to be 3808 transferred to the central blood compartment in the cobalt model (identified with Other 3809 plasma in the iron model) with the following half-times: 1 min for RBC and Plasma 3810 transferrin, 2 d for compartments of the liver, 30 d for spleen and compartments of red 3811 marrow, and 7 d for all other compartments. The subsequent biokinetics of cobalt entering or 3812 produced in the central blood compartment is described by the systemic model for internally 3813 deposited cobalt (see the section on cobalt in the present document), with the following 3814 modifications for application to cobalt as a daughter of iron. The spleen and red marrow are 3815 each added to the model as individual compartments that exchange cobalt with the central 3816 blood compartment. These compartments are assumed to receive 0.5% and 1% of outflow 3817 from the central blood compartment, respectively. Depositions in the compartments of Other

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3818 soft tissue with relatively fast and intermediate turnover rates are reduced from 9% and 5%, 3819 respectively, in the original model to 8% and 4.5%, respectively. Cobalt is removed from the 3820 spleen and red marrow to the central blood compartment with a half-time of 30 d. 3821 3822 7.2.3.4. Differences with gender 3823 3824 (295) The pre-menopausal adult female typically absorbs a greater portion of dietary iron 3825 and has faster turnover of body iron than the adult male due to higher iron requirements. The 3826 mass of total body iron typically is 50-100% greater in the adult male due to the combination 3827 of a larger body mass and a substantially larger mass of storage iron than the adult female. 3828 Despite the higher fractional uptake of iron from diet by females, the mass of storage iron in 3829 the pre-menopausal adult female typically is only about one-fourth of that in the adult male 3830 due to lower dietary intake of iron by females and substantial losses of iron via menstruation 3831 (Bothwell et al., 1979). 3832 3833 7.3. Individual monitoring 3834 59 59 3835 (296) Fe is a high energy γ emitter. Monitoring of Fe is in general accomplished 3836 through Whole Body Counting. Urine bioassay monitoring is also used in monitoring for 59 3837 Fe. 3838 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 59Fe Urine Bioassay γ-ray spectrometry 1 Bq/L 0.1 Bq/L 59Fe Whole Body γ-ray spectrometry, 80 Bq 20 Bq Counting in vivo 3839 3840 3841 References 3842 3843 Albert, R.E., Lippmann, M., Spiegelman, J., Strehlow, C., Briscoe, W., Wolfson, P., and Nelson, N. 3844 (1967) The clearance of radioactive particles from the human lung. In: Inhaled Particles and 3845 Vapours II, Proceedings of an International Symposium Organised by the British 3846 Occupational Hygiene Society, Cambridge, 28 September – 1 October 1965, (Ed. Davies, 3847 C.N.), Pergamon Press, Oxford, pp. 361-378. 3848 André S, Métivier H, Masse R. (1989). An interspecies comparison of the lung clearance of inhaled 3849 monodisperse cobalt oxide particles. Part 3: Lung clearance of inhaled cobalt oxide particles 3850 in baboons. J. Aerosol. Sci. 20: 205-217. 3851 Barnaby C. F, Smith T, Thompson B D. 1968. Dosimetry of the radioisotopes of cobalt. Phys. Med. 3852 Biol. 13: 421-433. 3853 Barton J.C., Edwards,C.Q. 2000. Hemochromatosis. New York : Cambridge University Press. 3854 Bellmann, B., Muhle, H., Creutzenberg, O., Dasenbrock, C., Kilpper, R., MacKenzie, J.C., Morrow, 3855 P.E. & Mermelstein, R. 1991. Lung clearance and retention of toner, utilizing a tracer 3856 technique, during chronic inhalation exposure in rats. Fundam. Appl. Toxicol. 17, 300-313. 3857 Bothwell, T.H., Charlton, R.W., Cook, J.D., Finch, C.A., eds: Iron metabolism in man. Oxford: 3858 Blackwell Scientific Publications, 1979 pp.256-283. 3859 Brozovic. (1975). Absorption of iron. In: Intestinal Absorption in Man (Ed.McColl, I; Sladen, G.) 3860 New York : Academic press, pp 263-314. 3861 Cohen, D., Arai, S.F., Brain,J.D. 1979. Smoking impairs long-term dust clearance from the lung. 3862 Science 204, 514-517.

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3863 Collier, C.G., Stradling, G.N., Foster, P.P., Hodgson, A. (1994). The biokinetics of corrosion products 3864 from a water cooled reactor after deposition in the rat lung. Radiation Protection Dosimetry 3865 53, 173-177. 3866 Comar C L, Davis G K. 1947. Cobalt metabolism studies. IV. Tissue distribution of radioactive cobalt 3867 administered to rabbits, swine, and young calves. J. Biol. Chem. 170: 379-389. 3868 Comar, C. L.; Davis, G. K.; Taylor, R. F. 1946. Cobalt metabolism studies : Radioactive cobalt 3869 procedures with rats and cattle. Arch. Biochem. 9:149-158. 3870 Cook JD, Dassenko SA, Whittaker P. 1991. Calcium supplementation: effect on iron absorption. Am J 3871 Clin Nutr 53: 106-11. 3872 Dastur, D. K.; Manghani, D. K.; Raghavendran, K. V. (1971). Distribution and fate of 54Mn in the 3873 monkey: studies of different parts of the central nervous system and other organs. J. Clin. 3874 Invest. 50:9-20. 3875 Fletcher CV, Acosta EP, Strykowski JM. 1994 Gender differences in human pharmacokinetics and 3876 pharmacodynamics. J Adolesc Health.;15(8):619-629. 3877 Freedman, P.A., Robinson, S.E., Street, M.R. 1988. Magnetopneumographic study of human alveolar 3878 clearance in health and disease. In: Inhaled Particles VI, Proceedings of an International 3879 Symposium and Workshop on Lung Dosimetry Organised by the British Occupational 3880 Hygiene Society in Co-operation with the Commission of the European Communities, 3881 Cambridge, 2–6 September 1985, (Eds. Dodgson, J., McCallum, R.I., Bailey, M.R., and 3882 Fisher, D.R), Pergamon Press, Oxford, United Kingdom. Ann. Occup. Hyg., 32 (Suppl. 1), 3883 809–820. 3884 Fore, H.; Morton, R. A. (1952). Manganese in rabbit tissues. Biochem. J. 51:600-603. 3885 Freiman, H., Tauber, S., Tulsky, E. (1963). Iron absorption in the healthy aged. Geriatrics. 716-720. 3886 Furchner, J. E.; Richmond, C. R.; Drake, G. A. (1966). Comparative metabolism of radionuclides in 3887 mammals – III. Retention of manganese-54 in the mouse, rat, monkey and dog. Health Phys. 3888 12:1415-1423. 3889 Gibb, F.R., Morrow, P.E. (1962). Alveolar clearance in dogs after inhalation of an iron 59 oxide 3890 aerosol. J. Appl. Physiol 17, 329-433. 3891 Green R., Charlton,R.W., Seftel,H., Bothwell, T., Mayet, F., Adams, B., Finch, C.; Layrisse, M. 1968. 3892 Body iron excretion in man. A collaborative study. Am. J. Med. 45 : 336-353. 3893 Hollins J G, McCullough R S. (1971). Radiation dosimetry of internal contamination by inorganic 3894 compounds of cobalt: An analysis of cobalt metabolism in rats. Health Phys. 21: 233-246. 3895 ICRP (1980). International Commission on Radiological Protection. Limits on Intakes of 3896 Radionuclides for Workers. ICRP Publication 30, Pt.2. Ann. ICRP 4. (3/4), 17-18 Elsevier 3897 Oxford.. 3898 ICRP (1994). Human Respiratory Tract Model for Radiological Protection. ICRP Publication 66 3899 Ann. ICRP 24 (1-3) Elsevier Oxford. 3900 ICRP (1995) International Commission on Radiological Protection. Age-dependent Doses to 3901 Members of the Public from Intake of Radionuclides: Part 3, Ingestion dose coefficients . 3902 ICRP Publication 69. Ann. ICRP 25. (1) Elsevier Oxford. 3903 ICRP (2002). International Commission on Radiological Protection. Basic Anatomical and 3904 Physiological Data for Use in Radiological Protection Reference Values. ICRP Publication 3905 89. Ann. ICRP 32. (3-4) Elsevier Oxford. 3906 ICRP (2006) Human Alimentary Tract Model for Radiological Protection. ICRP publication 100. 3907 Ann. ICRP 36 (1-2) Elsevier Oxford. 3908 Kalliomäki P-L, Lakomaa E, Kalliomäki K, Kiilunen, M., Kivelä, R., Vaaranen, V. (1983c). Stainless 3909 steel manual metal arc welding fumes in rats. Br. J. Ind. Med. 40, 229-234. 3910 Kalliomäki P-L, Tuomisaari M, Lakomaa E-L, Kalliomäki K, Kivelä, R. (1983b). Retention and 3911 clearance of stainless steel shieldgas welding fumes in rat lungs. Am Ind. Hyg. Assoc. 44, 3912 649-654. 3913 Kalliomäki, P.-L., Aitio, A., Hyvärinen, H.K., Kalliomäki, K. and Lakomaa, E.L. (1986b) Lung 3914 clearance, transportation and excretion of metals in rats after intratracheal instillation of 3915 activated welding fumes. In: Health Hazards and Biological Effects of Welding Fumes and

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3916 Gases. Proceedings of the International Conference. Copenhagen, 18-21 February 1985. pp. 3917 345–348 (Eds. Stern, R.M., Berlin A., Fletcher A. C. and Järvisalo, J.) Excerpta Medica, 3918 Amsterdam. 3919 Kalliomäki, P.-L., Aitio, A., Lakomaa, E.L., Kalliomäki, K. (1987) Kinetics of the metal 3920 components of intratracheally instilled mild and stainless steel welding fumes in rats. J. 3921 Aerosol Sci. 18, 737–740. 3922 Kalliomaki, P.L., Hyvarinen, H.K., Aitio, A., Lakoma, E.L., Kalliomaki, K. (1986a) Kinetics of the 3923 metal components of intratracheally instilled stainless steel welding fume suspensions in rats. 3924 Br. J. Ind. Med. 43, 112-119. 3925 Kalliomäki, P.-L., Kalliomäki, K., Rahkonen, E. and Aittoniemi, K. (1983a) Follow-up study on the 3926 lung retention of welding fumes among shipyard welders. Ann. Occup. Hyg. 27, 449–452. 3927 Kalliomäki, P.-L., Kalliomäki, K., Rahkonen, E. and Juntilla, M. L. (1985) Magnetopneumography – 3928 lung retention and clearance of manual metal arc welding fumes based on experimental and 3929 human data. In: Proceedings of the Fifth World Conference on Biomagnetism, pp. 416–421 3930 (Eds. Weinberg, H., Stroink, G. and Katila, T.) Pergamon Press, New York. 3931 Kalliomäki, P.-L., Korhonen, O., Vaaranen, V., Kalliomäki, K. and Koponen, M. (1978) Lung 3932 retention and clearance of shipyard arc welders. Int. Arch. Occup. Environ. Health. 42, 3933 83–90. 3934 Koshida, Y.; Kato, M.; Hara, T. (1963). Autoradiographic observations of manganese in adult and 3935 embryo mice. Q. J. Exp. Physiol. 48:370-378. 3936 Kreyling W G, Ferron G A, Haider B. (1986). Metabolic fate of inhaled Co aerosols in beagle dogs. 3937 Health Phys. 51: 773-795. 3938 Lay, J.C., Bennett, W.D., Kim, C.S., Devlin, R.B., Bromberg, P.A. (1998) Retention and intracellular 3939 distribution of instilled iron oxide particles in human alveolar macrophages. Am. J. Respir. 3940 Cell Mol. Biol. 18, 687-695. 3941 R. W. Leggett, J. C. Barton, K. F. Eckerman. Mathematical models of metal metabolism in 3942 hemochromatosis. In: J. C. Barton and C. Q. Edwards, eds. Hemochromatosis. New York: 3943 Cambridge University Press; 2000. 3944 Lynch, S.R. (1984). Iron. In: Absorption and Malabsorption of Mineral Nutrients. (Ed. Solomons, N; 3945 Rosenberg, I.) Alan R. Liss Inc : New York, pp 89-124 3946 Möller W., Häussinger K., Winkler-Heil R., Stahlhofen W., Meyer T., Hofmann W. and Heyder J. 3947 (2004) Mucociliary and long-term particle clearance in the airways of healthy non-smoker 3948 subjects. J Appl Physiol. 97: 2200–2206. 3949 Möller W., Häussinger K., Ziegler-Heitbrock, L. and Heyder J. (2006) Mucociliary and long-term 3950 particle clearance in airways of patients with immotile cilia. Respiratory Research 7: 10. 3951 Möller, W. (1991) Untersuchung über das Verhalten von magnetischen Teilchen in der Lunge des 3952 Menschen mit einem supraleitenden SQUID-Magnetometer (PhD thesis). J.W. 3953 Goethe-Universität, Frankfurt am Main, Germany. 3954 Möller, W., Barth, W., Kohlhäufl, M., Häussinger, K., Stahlhofen, W., Heyder, J. (2001) Human 3955 alveolar long-term clearance of ferromagnetic iron oxide microparticles in healthy and 3956 diseased subjects. Exp. Lung Res. 27, 547-568. 3957 Morris, E. (1983) An overview of current information of dietary iron to humans. Proceedings of the 3958 Bioavailability of Essential and Toxic Trace Elements Conference, New Orleans, Louisiana 3959 (USA), 17 Apr 1982. Federation Proceedings - Fed of Am Societies for Experimental Biology 3960 (USA) 42 (6). 1716-1720. 3961 Morrow, P.E., Gibb, F.R., and Gazioglu, K.M. (1967a). A study of particulate clearance from the 3962 human lungs. Am. Rev. Respir. Dis., 96, 1209-1221. 3963 Morrow, P.E., Gibb, F.R., Davies, H., Fisher, M. (1968) Dust removal from the lung parenchyma: an 3964 investigation of clearance stimulants. Toxicol. Appl. Pharmacol. 12, 372-396. 3965 Morrow, P.E., Gibb, F.R., Gazioglu, K. (1967b) The clearance of dust from the lower respiratory tract 3966 of man. An experimental study. In: Inhaled Particles and Vapours II, Proceedings of an 3967 International Symposium Organised by the British Occupational Hygiene Society,

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3968 Cambridge, 28 September – 1 October 1965, (Ed. Davies, C.N.), Pergamon Press, Oxford, pp. 3969 351–359. 3970 Morrow, P.E., Gibb, F.R., Johnson, L. (1964). Clearance of insoluble dust from the lower respiratory 3971 tract. Health Phys. 10, 543-555. 3972 Muhle, H., Bellmann, B. (1986). Pulmonary clearance of inhaled particles in dependence of particle 3973 size. Journal of Aerosol Science 17, 346-349. 3974 Munro, H. N., Linder, M .C. (1978). Ferritin: structure, biosynthesis, and role in iron metabolism. 3975 Physiol Rev 58, 317-96. 3976 Philipson, K., Falk, R., Gustafsson, J., Camner, P. (1996) Long-term lung clearance of 195Au-labelled 3977 Teflon particles in humans. Experimental Lung Research, 22, 65-83. 3978 Ramsden, D. Waite, D.A., (1972). Inhalation of insoluble iron-oxide particles in the sub-micron 3979 range. IN: Assessment of Radioactive Contamination in Man. Proceedings of a Symposium 3980 Stockholm, 22-26 November, 1971, pp. 65-81. International Atomic Energy Agency, Vienna. 3981 Saito, H.; Sargent, T.; Parker, H. G.; Lawrence, J. H. (1964). Whole-body iron loss in normal man 3982 measured with a gamma spectrometer. J. Nucl. Med. 5:571-580. 3983 Smith T, Thompson B D, Barnaby C F. (1971). Measurement of 60Co organ burdens in rats and their 3984 use in calculations of equilibrium dose rates to various organs of man. Health Phys. 20: 195- 3985 204. 3986 Stahlhofen, W. and Möller, W. (1991) The behaviour of inhaled spherical iron oxide particles in 3987 human lungs: magnetometric studies. In: Environmental Hygiene III, pp. 1–4 (Eds. 3988 Seemayer, N. H. and Hadnagy, W.) Springer-Verlag, Berlin, Germany. 3989 Stahlhofen, W. and Möller, W. (1991) The behaviour of inhaled spherical iron oxide particles in 3990 human lungs: magnetometric studies. In: Environmental Hygiene III, pp. 1–4 (Eds. 3991 Seemayer, N. H. and Hadnagy, W.) Springer-Verlag, Berlin, Germany. 3992 Teucher B, Olivares M, Cori H. (2004) Enhancers of iron absorption: ascorbic acid and other organic 3993 acids. Int J Vitam Nutr Res.;74(6):403-419. 3994 Thomas R G, Furchner J E, London J E, Drake G A, Wilson J S, Richmond C R.1976). Comparative 3995 metabolism of radionuclides in mammals--X. Retention of tracer-level cobalt in the mouse, 3996 rat, monkey and dog. Health Phys. 31: 323-333. 3997 Tipton, I. H.; Cook, M. J. (1963). Trace elements in human tissue. Part II. Adult subjects from the 3998 United States. Health Phys. 9: 103-145. 3999 Trubowitz, S.; Davis, S. 1982. The human bone marrow. Anatomy, Physiology and pathophysiology. 4000 CRC Press, Boca Raton, FL USA. 4001 Underwood, E. (1977). Iron. In: Trace Elements in Human and Animal Nutrition. Academic Press, 4002 New York. 4003 Waite, D.A., Ramsden, D. (1971a) The inhalation of insoluble iron oxide particles in the sub-micron 4004 range. Part I – Chromium-51 labelled aerosols. AEEW-R740, Atomic Energy Authority, 4005 Winfrith, Dorset, United Kingdom. 4006 Waite, D.A., Ramsden, D. (1971b) The inhalation of insoluble iron oxide particles in the sub-micron 4007 range. Part II – -237 labelled aerosols. AEEW-R741, Atomic Energy Authority, 4008 Winfrith, Dorset, United Kingdom. 4009 Wehner, A.P., Wilerson, C.L., Stevens, D.L. (1984). Lung clearance of neutron-activated Mount St. 4010 Helens volcanic ash in the rat. Environ. Res. 35, 211-217. 4011 Wehner, A.P., Wilkerson, C.L. (1981). Determination of pulmonary deposition, translocation and 4012 clearance using neutron activation techniques. Z. Erkr. Atmungsorgane. 157, 238-246. 4013 Werner, E., Roth P., Hansen, C., (1987) Intestinal absorption of metals, in Gerber, G.B., Metivier H., 4014 Smith, H. (Eds), Age related factors in radonuclides metabolism and dosimetry. Proc. CEC 4015 Workshop, Angers, France, 1986, Martinus Nijhoff, Lancaster, pp. 27-33. 4016 Whiting SJ. (1995) The inhibitory effect of dietary calcium on iron bioavailability: a cause for 4017 concern? Nutr Rev. Mar;53(3):77-80. 4018 Woodhead JC, Drulis JM, Nelson SE, Janghorbani M, Fomon SJ. (1991) Gender-related differences 4019 in iron absorption by preadolescent children. Pediatric research, 29(5):435-439. 4020 4021

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4022 8. COBALT (Z = 27) 4023 4024 8.1. Chemical Forms in the Workplace 4025 4026 (297) Cobalt is a transition metal, which occurs mainly in oxidation states II and III. 4027 Cobalt may be encountered in industry in a variety of chemical forms, including metal dusts, 4028 oxides (CoO, Co3O4) and soluble salts such as nitrates and chlorides. 4029 (298) Cobalt-60 is an important activation product produced in nuclear power plants, and 4030 could also be present in fragments of irradiated fuel. 57 60 4031 (299) Significant quantities of Co and Co are used as sealed sources in medicine 4032 (nuclear medicine, radiotherapy) and in the food industry for sterilization. 4033 4034 Table 8-1. addressed in this report 4035 Isotope Physical half-life Decay mode Co-55 17.53 h EC, B+ Co-56 77.23 d EC, B+ Co-57 271.74 d EC Co-58 70.86 d EC, B+ Co-58m 9.04 h IT Co-60 5.271 y B- Co-60m 10.467 m IT, B- Co-61 1.65 h B- Co-62m 13.91 m B- 4036 4037 8.2. Routes of Intake 4038 4039 8.2.1. Inhalation 4040 4041 Absorption Types and parameter values 4042 (300) Cobalt-60 is relatively easy to measure, and there have been a number of reported 4043 studies of its lung retention following accidental inhalation, usually of an oxide. Information 4044 is available from experimental studies of cobalt in a variety of forms, including nitrate, 4045 chloride, and oxides. 4046 (301) Absorption parameter values and Types, and associated fA values for particulate 4047 forms of cobalt are given in Table 8-2. 4048 4049 Cobalt nitrate (Co(NO3)2) 57 4050 (302) Kreyling et al. (1986) followed the biokinetics of Co for 1000 days after inhalation 57 4051 of Co-labelled Co(NO3)2 by dogs. Most of the initial lung deposit (ILD) was rapidly cleared 4052 from the lungs and excreted from the body, mainly in urine. Lung retention was described by 4053 a three-component exponential function with biological half-times of 0.8 days (89%), 27 days 4054 (8%) and 400 days (3%). From the results of a complementary gavage experiment with 4055 Co(NO3)2 it was calculated by the task group that fractional absorption from the alimentary 4056 tract fA = 0.3. [In carrying out assessments here, the systemic model for cobalt described by 4057 Leggett (2008) was used, but to fit the nitrate data, it was necessary to increase the transfer 4058 rates from blood to urine and intestine.] Assuming that the cobalt retained in the lungs was 4059 bound, rather than particulate (see below), and hence that fr = 1, analysis here gave parameter –1 –1 4060 values of sr = 1 d , fb = 0.03 and sb = 0.0017 d (giving assignment to Type F). The

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4061 estimated value of sb reflects the biological half-time of the slowest term in the three- 4062 exponential representation of lung retention. 4063 (303) Although specific parameter values for cobalt nitrate based on in vivo data are 4064 available, they are not adopted here, because inhalation exposure to it is unlikely. Instead, 4065 cobalt nitrate is assigned to Type F. However, the data are used as the basis for the default 4066 rapid dissolution rate for cobalt, and with the data on cobalt chloride (see below), are used as 4067 the basis for bound state parameter values for cobalt. Hence specific parameter values for 4068 cobalt nitrate would be the same as default Type F cobalt parameter values. 4069 4070 Cobalt chloride CoCl2 58 4071 (304) Morrow et al. (1968) followed lung retention for 7 days after inhalation of CoCl2 4072 by dogs. Few details are given, but a lung retention half time of 0.01 d was reported, giving fr –1 4073 ~1, sr = 70 d , and assignment to Type F. 4074 (305) Menzel et al. (1989) followed lung retention for 6 days after inhalation of stable 4075 CoCl2 by rats. By that time about 5% of the amount present at the end of exposure remained, 4076 but the authors recognised that some clearance took place during exposure. Assuming that the 4077 cobalt retained in the lungs was bound, rather than particulate, and hence that fr = 1.0, –1 4078 analysis here gave parameter values of sr = 4 d and fb ≤0.1: sb could not be determined 4079 because of the short duration of the measurements. 57 4080 (306) Kreyling et al. (1987) followed the biokinetics of Co for 120 days after 57 4081 intratracheal instillation of CoCl2 into hamsters, to investigate the retention of cobalt in the 4082 lungs and extra-pulmonary airways observed by Kreyling et al. (1986, see above). Additional 4083 information on this experiment is provided by Patrick et al. (1994). Most of the ILD cleared 57 4084 rapidly: ~1% ILD was present in the body after one month, with high concentrations of Co 4085 in tracheal and bronchial cartilage, and 0.15% ILD was present in the lungs after 120 days. 4086 From results of a complementary gavage experiment with CoCl2 it was calculated here that fA 57 4087 = 0.08. At one month after administration, the concentration of Co in the lungs was about 4 4088 and 40 times the average in the body for gavage and instillation respectively. Thus there was 4089 some systemic uptake into the lungs following gavage. However, assuming a similar fraction 4090 was transferred from blood to lungs after instillation, it would account for only a small 4091 fraction of that retained in lungs in the instillation experiment. Assuming that the cobalt 4092 retained in the lungs was bound, rather than particulate, and hence fr = 1, analysis here gave –1 –1 4093 parameter values of sr = 1.4 d , fb = 0.015 and sb = 0.015 d . 4094 (307) Patrick et al. (1994) conducted an interspecies comparison of the lung clearance of 57 4095 ionic cobalt, primarily to determine whether differences in absorption of Co following 57 4096 inhalation of Co3O4 (Bailey et al., 1989; Kreyling et al., 1991, see below) could be 4097 explained by differences in binding of dissolved cobalt. To complement the studies by 57 4098 Kreyling et al. (1986, 1987) in dogs and hamsters (see above), the biokinetics of Co were 57 4099 followed for 100 days after intratracheal instillation of CoCl2 into guinea pigs, rats (two 4100 strains), and a baboon. Autoradiography of the tracheas of rats and a guinea pig 30 days after 57 57 4101 instillation of CoCl2 into the lungs showed that the Co was mainly concentrated in 57 4102 cartilage rings. For one strain of rat, data are available to show that the proportion of Co 4103 retained in the lungs at 21 days after systemic injection was 1.2% of the total body content 57 4104 (Patrick et al., 1989), compared to 20% at 30 days after CoCl2 was instilled into the lungs. 57 4105 This indicates that while some of the Co retained in the lungs was from the systemic 4106 circulation, most came directly from deposition in the lungs. Assuming that the cobalt 4107 retained in the lungs was bound, rather than particulate, and hence fr = 1, analysis here gave –1 4108 values of sr in the range 0.6–0.9 d , and the following parameter values for the bound state: 4109

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-1 fb sb (d ) Guinea pig 0.06 0.013 HMT rat 0.03 0.009 F-344 rat 0.016 0.012 4110 4111 (308) Although specific parameter values for cobalt chloride based on in vivo data are 4112 available, they are not adopted here, because inhalation exposure to it is unlikely. Instead, 4113 cobalt chloride is assigned to Type F. Estimates of the default rapid dissolution rate cover a –1 4114 wide range (from ~1 to 70 d ), but the lower values, which are based on more detailed 4115 information, are similar to the default rapid dissolution rate chosen for cobalt (see below). 4116 The data are used, with data on cobalt nitrate (see above), as the basis for bound state 4117 parameter values for cobalt. Hence specific parameter values for cobalt nitrate would be 4118 similar to default Type F cobalt parameter values. 4119 4120 Cobalt oxide 60 4121 (309) Barnes et al. (1976) followed the biokinetics of Co in dogs for 128 days after 4122 inhalation of cobaltosic oxide (Co3O4), and for 64 days after inhalation of cobaltous oxide 4123 (CoO). The oxides were produced from Co nitrate aerosol heated at 850°C and 1400°C, 4124 respectively before inhalation. Lung clearance of CoO was faster than that of Co3O4: after 8 4125 days 10% versus 85% ILD remained in the lungs, and after 64 days 4% versus 60% ILD, 4126 indicating Type F and Type M behaviour respectively. For both oxides, there was high fecal 60 4127 excretion of Co during the first 3-4 days, which represented material cleared from the upper 4128 respiratory tract, while urinary excretion exceeded fecal excretion after 5 days, reflecting the 4129 greater importance of dissolution than particle transport as a clearance mechanism. The 60 4130 authors considered it noteworthy that the CoO formed at 1400°C was more soluble than the 60 4131 Co3O4 formed at 850°C, because generally aerosols formed at higher temperatures are less 4132 soluble than aerosols formed at lower temperatures. 4133 (310) Detailed studies have been conducted of the lung clearance kinetics of various 4134 physical forms of cobaltosic oxide (Co3O4), which has been used extensively as a test 4135 material to investigate factors that affect particle dissolution in the lungs (e.g. Kreyling et al., 4136 1986, 1988). Kreyling et al., (1986) also found that cobalt oxide aerosols formed at higher 4137 temperatures are more soluble than aerosols formed at lower temperatures: the in vivo 4138 dissolution / absorption of a mixed cobalt oxide consisting of Co3O4 and CoO (formed at 4139 950°C) was significantly faster than for pure Co3O4 particles (formed at 800°C) of similar 4140 size. 4141 (311) These studies included two direct intercomparisons of clearance in different 4142 mammalian species, one of which involved human volunteers, baboon, dog, guinea pig, rat, 4143 hamster and mouse (Bailey et al., 1989), and the other baboon, dog and rat (Kreyling et al., 4144 1991). In these numerous experiments, different parameters were varied, including the 4145 specific surface area, which influences the dissolution rate of the compound (ranging from 2 -1 4146 0.6 to 30 m g ), the AMAD (ranging from 0.8 to 3.5 µm), and the initial lung deposit, ILD, 4147 (ranging from 1 to 2000 kBq, depending on species). 4148 (312) Generally, lung retention was longer in humans and baboons than in the other 4149 species (dogs, guinea pigs, three strains of rats, hamsters, and mice). Absorption from the 4150 human lung was consistent with assignment to Type M, since in that study (Bailey et al., 4151 1989) the test material was designed by means of its physical and chemical parameters to be 2 -1 –1 4152 moderately soluble (specific surface area >6 m g ); ss ranging from 0.0013 to 0.005 d . 2 -1 4153 When the test material was selected to be less soluble (specific surface area <6 m g ), 4154 absorption in baboons and dogs was consistent with assignment to Type S (Kreyling et al.,

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–1 4155 1988; 1991): ss ranging from 0.0008 to 0.03 d . The in vivo rate of dissolution / absorption in 4156 dogs was linearly related to the specific surface area of the particles ranging from 0.6 to 30 2 -1 4157 m g (Kreyling, 1990). Human and baboon data followed the same linear correlation 4158 (Kreyling, 1992). The rate-determining step was shown to be intracellular particle dissolution 4159 in alveolar macrophages in all species (Kreyling et al., 1990; Kreyling, 1992). The results of 4160 two in vitro dissolution tests with lung serum simulant (Collier et al., 1992), gave ss ranging –1 4161 from 0.0002 to 0.0036 d . 57 4162 (313) In more recent studies, Co3O4 (inhaled by dogs) was used as a moderately soluble 4163 test particle to investigate the effects of chronic exposure to sulphur-related environmental air 4164 pollution on respiratory defence mechanisms, including particle dissolution (Kreyling et al., 4165 1992a, 1999; Heyder et al., 2009). It was found that the in vivo dissolution rate decreased 4166 during exposure to the acidic sulphate component, but increased during exposure to the 4167 sulphite component and also during combined exposure to the acidic sulphate component (6 4168 hours daily) and sulphite component (18 hours daily). 60 4169 (314) Newton and Rundo (1971) followed retention of Co in the chest and/or whole body 4170 in five men for 0.4 to 11 years after accidental inhalation of the irradiated metal or its oxide. 4171 Estimated half-lives for the long-term clearance from the chest of cobalt were up to 17 years. 4172 Using the updated HRTM with the new particle transport model for the AI region (Gregoratto 4173 et al., 2010), for three subjects (followed for 2.5 – 9 years), good fits to the data were 4174 obtained here with absorption type S. For the subject followed for 11 years, analysis here 4175 showed that a slow dissolution rate lower than that of Type S was needed to fit the data: the –5 –1 4176 best estimate was ss = (0±5) x10 d . 60 4177 (315) Gupton and Brown (1972) followed retention of Co for 4 years in the chest of a 60 4178 man who was exposed to Co-oxide by inhalation during a period of ~6 months prior to the 4179 initial count, and following which there was no subsequent exposure. Analysis here showed 4180 that retention is predicted adequately by assuming absorption type S, but a better fit is –4 –1 4181 obtained with a higher dissolution rate ss = (8±2) x10 d . 60 4182 (316) Beleznay and Osvay (1994) followed whole body retention of Co in six workers 4183 for about 4 years, starting one day after a short exposure to an aerosol leaking from a hot cell 60 4184 in which a high activity Co source was being manipulated. The authors considered that the 4185 aerosol was probably composed of metallic cobalt and cobaltic or cobaltosic oxide formed at 4186 300-400°C on the surface of the high activity cobalt wire. Longitudinal profile scans on one th 4187 subject showed that on the 15 day a major part of the deposited activity was in the chest, but th 4188 on the 80 day this had decreased considerably, with an increase in systemic activity. The 60 4189 authors interpreted the long-term retention of Co in the body as mainly systemic. Analysis 4190 here showed agreement with the data for model predictions assuming absorption type M (ss = -1 4191 0.005 d ). 4192 4193 Fused aluminosilicate particles (FAP) 4194 (317) FAP or “fused clay” particles have been extensively used as relatively insoluble 4195 particles in inhalation studies, both of biokinetics and of radiation effects. A natural clay 4196 mineral (montmorillonite) is labelled by ion exchange, and the labelled clay particles heated 4197 to about 1100˚C, to form aluminosilicate glass microspheres in which the label is 4198 incorporated. It has been demonstrated that when cobalt is incorporated into FAP, only a 4199 small fraction may be absorbed rapidly. The rest is retained within the particles and is 57 4200 absorbed slowly. Kreyling et al. (1988) followed the lung clearance of Co for 3 years after 57 -1 4201 inhalation of Co-FAP by dogs and estimated a dissolution rate, ss, of 0.0005 d . Kreyling et 60 60 4202 al. (1992a) followed the biokinetics of Co for 600 days after inhalation of Co-FAP by -1 4203 dogs and estimated a dissolution rate of 0.0009 ± 0.0004 d . From measurements following

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57 – 4204 inhalation of Co-FAP in rats the long term dissolution rate, ss, was estimated to be 0.0008 d 1 –1 4205 , while an in vitro dissolution test gave ss = 0.00018 d (Collier et al., 1988, 1992). Most of 4206 these results give assignment to Type S. 4207 4208 Polystyrene (PSL) 4209 (318) As with FAP, it has been demonstrated that when cobalt is incorporated into a 4210 polystyrene matrix, most of it is retained within the particles and is absorbed extremely 4211 slowly, making it an exceptionally useful material for studying long-term particle transport –1 4212 from the lungs. Kreyling et al. (1992b) estimated a rate of dissolution of <0.00003 d for 57 4213 Co-labelled polystyrene inhaled by dogs, but few details were given. Kreyling et al. (1999) 58 60 4214 and Heyder et al. (2009) used Co-and Co-labelled polystyrene as insoluble test particles to 4215 investigate in dogs the effects of chronic exposure to sulphur-related environmental air 4216 pollution on respiratory defence mechanisms, including particle clearance from the alveolar -1 4217 region. Kreyling et al. (1999) estimated dissolution rates of 0.00001 ± 0.00002 d and -1 4218 0.00002 ± 0.00002 d respectively. All these results give assignment to Type S. 4219 4220 Contaminated dusts (‘residues’) formed at nuclear power plant (NPP) 60 4221 (319) Raghavendran et al. (1978) followed retention of Co in four workers at the Bhaba 4222 Atomic Research Centre for between 400 and 1250 days. Profile scans showed most activity 4223 to be in the chest. Retention in the chest was fit by a one- or two-component exponential 4224 function, with long-term half-lives in range 500-18,000 days, indicating Type S behaviour. 4225 (320) Hegde et al. (1979) reported information on chest measurements up to about 400 60 4226 days for five inhalation cases of Co in BWR (Boiling Water Reactor) power station 4227 workers. Results for four workers were summarised with an average value of 664 days for the 4228 biological half-time. Predictions assuming Type S behaviour are in good agreement with the 4229 data. 60 4230 (321) Ramsden (1984) followed two cases of lung retention of Co for about 1500 days 4231 after inhalation of mixed corrosion oxide products from water reactor circuitry. Analysis 4232 here, using the updated HRTM, showed that a slow dissolution rate lower than that of Type S –5 –1 4233 was needed to fit the data: the best estimate was ss = (1±0.5) x10 d . 4234 (322) Davis et al. (2007) and Gregoratto et al. (2010) analysed the results of measurements 60 4235 (urine and faeces during the first two weeks, and whole body to 15 years) of Co in seven 4236 workers who inhaled particles of unknown form in the same incident at a NPP. The dataset is 4237 extraordinary in that a group of workers had a simultaneous, brief single inhalation exposure, 4238 and they have been followed for so long. In order to account for the later whole body 4239 retention data in each subject it was necessary to assume slower particle transport from the 4240 alveolar region, than that assumed in the HRTM (ICRP, 1994). This study is one of those on 4241 which the alveolar-interstitial model in the updated HRTM is based (ICRP, 2012). Specific 4242 absorption parameter values were fit to the results for each subject by both Davis et al. (2007) 4243 and Gregoratto et al. (2010). Most were similar to those for default Type S, but to fit the early 4244 urine data, the fractional absorption in the alimentary tract could be no more than about 0.1%, 4245 and a slow dissolution rate lower than that of Type S was needed to fit the data: the best –1 4246 estimate was ss <0.0001 d . 60 4247 (323) The biokinetics of Co were followed for 6 months after intratracheal instillation 60 4248 into rats of a complex radionuclide bearing dust (72% Co activity) from the ventilation grid 4249 of a NPP reactor fuel hall (Stradling et al., 1996, 1997). Absorption parameter values: fr = –1 –4 –1 4250 0.30; sr = 1.5 d and ss = 5 10 d derived by ICRP (2002a, Section E4.4), are consistent 4251 with assignment to Type M. However, since several human studies following intakes at NPP 4252 indicate Type S behaviour, these specific values do not seem representative and are not

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4253 recommended for use in preference to default Type S. 60 4254 (324) The biokinetics of Co were followed for 280 days after intratracheal instillation 60 4255 into rats of a suspension of corrosion 'crud' particles (oxide bearing debris, 60% Co activity) 4256 from the primary containment of a water cooled reactor (Collier et al., 1994). Few details are 60 4257 given, but it was assessed here that the results are consistent with assignment of the Co 4258 present to Type S. 60 4259 (325) Molokanov et al. (2010) reported in vivo lung measurements of Co up to 200 days, 4260 and several urine and faecal data at about 200 days, for four NPP workers who accidentally 4261 inhaled a cobalt compound. No early data are available, but the slow clearance and the small 4262 amount in the urine indicate that the material was insoluble. A good fit to the data was 4263 obtained here with default Type S absorption but with an increased value for the slow –1 4264 absorption rate, ss = 0.0003 d . 4265 4266 Other compounds 4267 (326) Clearance studies of cobalt in the rat after inhalation of neutron-activated fly ash 4268 (Griffis et al., 1981) or volcanic ash (Wehner et al., 1984) indicated leaching of cobalt out of 4269 the particle matrix consistent with assignment to Type M. 4270 (327) Although numerous studies have been carried out on the toxicity of inhaled cobalt- 4271 containing alloys, no data are available from them on the clearance kinetics of cobalt. The 4272 data obtained from diamond polishers (Van den Oever et al., 1990) or after exposure of rats 4273 (Brune and Beltesbrekke, 1980) suggest, however, long-term retention in the lungs indicative 4274 of Type M or S behaviour. 4275 4276 Rapid dissolution rate for cobalt 4277 (328) Most of the estimated values of the rapid dissolution rate, sr, from studies involving 4278 inhalation or instillation into the lungs of cobalt nitrate and chloride were in the range 0.6 – 4 –1 –1 4279 d . The exception was the value of 70 d , based on a reported lung retention half time of 58 4280 0.01 day following inhalation of CoCl2 by dogs (Morrow et al., 1968): but few details were –1 4281 given. Based on the other studies, a value of sr of 1 d is applied here to all Type F forms of –1 4282 cobalt. Because it is lower than the general default value of 3 d for Type M and S materials, 4283 it is also applied to Type M and S forms of cobalt. 4284 4285 Extent of binding of cobalt to the respiratory tract 4286 (329) Experimental evidence, described in the sections on cobalt nitrate and chloride, 4287 consistently shows long term retention of a few percent of the ILD of cobalt deposited in the 4288 lungs in soluble form. 4289 (330) Studies of the kinetics of cobalt following inhalation of cobalt nitrate (soluble) and 4290 oxides (moderately soluble) by dogs, and following instillation of cobalt chloride into the 4291 lungs of hamsters, showed much larger amounts in the tracheo-bronchial (TB) airways than 4292 expected for material transiting the TB following clearance by particle transport from the 4293 alveolar region (Kreyling et al., 1986, 1987). Furthermore, the relative amount in TB within 4294 the lungs increased with the solubility of the material. Cobalt was also found to be distributed 4295 in the lungs after intravenous injection of oxide particles (Co3O4) in dogs (Kreyling et al., 4296 1986). Measurements showed a decreasing activity in liver with time while increasing in 4297 lungs (and other soft tissues and bones). This suggests that it was not particles injected into 4298 blood which were directly absorbed by the lungs, but non-particulate Co, released into blood 4299 from liver (where particulate matter is incorporated and digested by Kupffer cells) and then 4300 absorbed in the lungs. 4301 (331) Studies were conducted to localise further the distribution of the cobalt retained in

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4302 the lungs. A study of the detailed location of cobalt in the lungs of dogs at 14 days after 4303 instillation of Co(NO3)2 into one lung lobe showed that the retained cobalt was mainly 4304 located in the airway cartilage (Godleski and Kreyling, 1990). Autoradiographs of rats and 4305 guinea pigs at 100 days after instillation of CoCl2 (Patrick et al., 1994) showed the highest 4306 concentrations of cobalt to be in cartilaginous structures of the trachea and bronchi. 4307 (332) There is therefore strong evidence for a bound state for cobalt, which can be 4308 quantified (although the location of the bound cobalt, in cartilaginous structures, is different 4309 from that assumed in the HRTM). Based on this evidence, retention and excretion data for 4310 cobalt nitrates and chlorides were analysed assuming that the cobalt retained in the lungs was 4311 bound, rather than particulate, and hence fr = 1.0. For cobalt chloride instilled into the lungs 4312 of rats and guinea pigs, and followed for 100 days, values of fb averaged 0.03 (range 0.016 to –1 –1 4313 0.06), and values of sb averaged 0.011 d (range 0.009 to 0.013 d ). For cobalt nitrate 4314 inhaled by dogs and followed for a much longer period (up to 1500 days) the bound fraction –1 4315 was estimated here to be fb = 0.03, clearing at a rate sb of =0.0016 d . 4316 (333) On the basis of these results, a bound fraction with fb = 0.03 and a rate of uptake sb = –1 4317 0.002 d is adopted here for cobalt. No experimental evidence was found to show that cobalt 4318 in soluble form deposited in the conducting airways is retained in a bound state. There is 4319 evidence that much of the cobalt deposited in the lungs in soluble form that is not absorbed 4320 rapidly is retained in airway cartilage. However, this is located some distance below the 4321 epithelial tissue which forms the designated source region for material bound in the airway 4322 regions (BB and bb). Locating the bound activity in the source region within the epithelium 4323 could substantially overestimate doses to the BB and bb regions. It is therefore assumed here 4324 that these bound state parameter values apply only in the AI region. 4325 4326 4327 4328

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4329 4330 Table 8-2. Absorption parameter values for inhaled and ingested cobalt 4331 Absorption parameter valuesa Absorption from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorptio Assigned forms n Type F Cobalt nitrate, chloride 1 1 – 0.1 M All unspecified formsd 0.2 1 0.005 0.02 S Cobalt oxide, FAP, PSL 0.01 1 1x10-4 0.001

Ingested materials All chemical forms 0.1 Insoluble oxides 0.05 a –1 4332 It is assumed that for cobalt the bound fraction fb is 0.03 with an uptake rate sb = 0.002 d . The values of sr 4333 for Type F, M and S forms of cobalt (1 d–1,) are element-specific. 4334 b Materials (e.g. cobalt nitrate) are listed here where there is sufficient information to assign to a default 4335 absorption Type, but not to give specific parameter values (see text). 4336 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 4337 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 4338 absorption Type and the fA value for ingested soluble forms of cobalt (0.1). 4339 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 4340 or if the form is known but there is no information available on the absorption of that form from the 4341 respiratory tract. 4342 4343 8.2.2. Ingestion 4344 60 4345 (334) Human volunteer studies with Co chloride (Paley and Sussman, 1963; Smith et al., 4346 1972) showed that when the cobalt was present in trace quantities (less than 1 μg Co), 4347 absorption was 0.05 or less but when larger amounts of cobalt were administered (1-12 mg), 4348 absorption was 0.1-0.3. A higher value of 0.44 (from 1.2 mg Co) was recorded by Valberg et 4349 al. (1969), and this was increased to 0.7 in volunteers suffering from iron deficiency. 4350 Similarly, Paley and Sussman (1963) noticed that fasting for 3 hours or longer increased the 4351 absorption by a factor 2. 4352 (335) The absorption of Co in forms encountered in the workplace may be considerably 4353 lower than these values for relatively soluble inorganic forms. Chevalier and Gonin (1993) 60 4354 estimated the absorption of Co ingested as large particles of stellite following their 4355 inhalation; large particles deposited in the upper airways are rapidly swallowed and 4356 absorption was assumed to take place solely from the gastrointestinal tract. The absorption -3 -4 4357 values obtained for 5 subjects were in the range of about 10 to 10 . Bailey et al. (1989) 57 4358 measured the absorption of Co as cobaltosic oxide (Co3O4), as part of a comparison of the 4359 behaviour of inhaled materials in different mammalian species. Estimates of absorption after 4360 intragastric administration of oxide particles with geometric mean diameters of 0.8 μm or 1.7 4361 μm were in the range of about 0.01 to 0.05 for mice, hamsters, rats, guinea pigs and baboons. 57 4362 Comparing the behaviour of Co nitrate and a mixed oxide containing Co3O4 and CoO in 57 4363 dogs, Kreyling et al. (1986) obtained results for urinary excretion of Co after intravenous 4364 injection and ingestion which suggested absorption of about 0.3 for the nitrate and 0.06 for 57 4365 the oxide. Collier et al (1991) compared whole body retention and urinary excretion of Co 4366 in rats from 3 weeks to 48 weeks of age after intravenous injection as the nitrate or 4367 intragastric administration as Co3O4 (1 μm particles). The results suggested absorption in the

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-3 -2 4368 range of 4x10 to 4x10 with the greatest values in the youngest animals. 4369 (336) In ICRP Publication 30 (1979), an f1 of 0.05 was recommended for oxides, 4370 hydroxides and for all other inorganic forms ingested in trace quantities. For inorganic forms 4371 other than oxides and hydroxides ingested in the presence of carrier material, a value of 0.3 4372 was recommended, although the ingestion of large masses of soluble material would only be 4373 expected in exceptional circumstances. In ICRP Publication 67 (1993), a value of 0.1 was

4374 adopted for dietary intakes by adult members of the public. In this report, an fA value of 0.1 is 4375 adopted for direct ingestion of all chemical forms but insoluble oxides for which an fA value

4376 of 0.05 is recommended. 4377 4378 8.2.3. Systemic Distribution, Retention and Excretion 4379 4380 8.2.3.1. Summary of the database 4381 4382 Data for human subjects 4383 (337) Smith et al. (1972) studied the behavior of cobalt in 11 healthy adult subjects (10 60 4384 males and one female) after intravenous injection with CoCl2. More than 90% of the 4385 injected amount was removed from plasma during the first 30 min. Over the next 30 h 60 4386 activity in plasma declined with a half-time of about 1 d. The concentration of Co in 4387 plasma was 1-2 orders of magnitude higher than that in red blood cells, but the investigators 60 4388 suggested that the measurement techniques may have underestimated Co in red blood cells. 4389 Measurements of urinary and faecal excretion in six of the subjects during the first 2-8 d after 4390 administration revealed that activity was eliminated primarily in urine. The ratio of faecal to 4391 urinary excretion during the study period averaged about 0.15. Long-term retention in the 4392 total body was estimated for three subjects by external measurements. Average retention for 4393 two subjects followed over 1000 d could be described reasonably well by a four-exponential 4394 function with the following biological half-times and component sizes: 0.5 days (44%); 6 4395 days (32%); 60 days (13%) and 800 days (11%). External measurements on one subject soon 4396 after injection indicated that the liver accumulated roughly one-third of the injected amount. 4397 External measurements for 8 subjects indicate that the liver contained roughly 20% (10-30%) 4398 of the total-body burden at times from a few days up to 1000 d after injection. 4399 (338) Letourneau et al. (1972) used external whole-body measurements to estimate the rate 58 4400 of loss of Co from each of 16 male subjects over an approximately one-year period (305- 58 4401 386 d) following intravenous injection of CoCl2. Estimated retention was slightly lower on 4402 average than determined in the study by Smith et al. (1972), although there was overlap in the 4403 range of retention data found in the two studies. On average, about 35-40% of the injected 4404 activity was lost with a biological half-time of a few hours, 25% with a halftime <2 d, 20% 4405 with a half-time of ~8 d, 10-15% with a half-time of ~50 d, and 9% with a half-time of ~600 4406 d. The size of the long-term component ranged from 5-13%, compared with 9-16% in three 4407 subjects of Smith et al. (1972) studied for at least 275 d. 4408 (339) Jansen et al. (1996) used positron emission tomography to study the early 55 4409 biokinetics of Co in two adult males, ages 26 and 30 y, after intravenously injection with 55 4410 CoCl2. Whole-body scans were made immediately (~0.5 h), at 24 h, and at 48 h after 4411 injection. The liver and urinary bladder were estimated to contain about 50% and 40%, 4412 respectively, of the administered activity in the first scan. These values are qualitatively 4413 consistent with other human or animal studies in that they indicate rapid transfer of cobalt to 4414 the liver and urinary bladder but are higher than estimated in most studies. 60 4415 (340) Newton and Rundo (1971) studied the behavior of Co in five men for periods up to 4416 11 y after accidental inhalation of the irradiated metal or its oxide. They estimated a long-

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4417 term clearance half-time on the order of 7 y for systemic cobalt. Measurements on one of the 60 4418 subjects about 3 y after intake established the presence of Co in the skeleton. Activity was 4419 not detectable in the liver. 60 4420 (341) Beleznay and Osvay (1994) measured retention of Co in six workers from 10-1850 60 4421 d after they accidentally inhaled Co aerosols during manipulation of a high-activity source. 4422 A retention component of 25-78 d was interpreted as activity leaving the deep lungs. A long- 4423 term component of retention determined in five of the workers followed for extended periods 4424 was interpreted as the slowest component of systemic retention of cobalt. The biological 4425 half-time of the long-term component varied from ~500 d to ~1200 d and averaged ~900 d. 4426 (342) The collective data for human subjects indicate that the long-term half-time for 4427 cobalt taken into the body in inorganic form tends to increase with the length of the 4428 observation period: 600 d for observations over 305-386 d (Letourneau et al., 1972); 800 d 4429 for observations over for about 1000 d (Smith et al., 1972); 900 d for observations up to 5 y 4430 (Beleznay and Osvay, 1994); and 7 y for observations up to 11 y (Newton and Rundo, 1971). 4431 This suggests that there is a component of retention with a biological half-time of many 4432 years. As described later, animal studies indicate that the skeleton retains a small portion of 4433 deposited cobalt for an extended period. 4434 4435 Data on laboratory animals 4436 (343) The biokinetics of cobalt has been studied in mice, rats, hamsters, guinea pigs, dogs, 4437 monkeys, and baboons. Differences between species are indicated. For example, Thomas et 4438 al. (1976) compared the biokinetics of cobalt in the mouse, rat, monkey, and dog following 60 4439 intravenous, intragastric, and oral administration of CoCl2. The long-term retention half- 4440 time was longer in the mouse (495 d) than in the rat (309 d), monkey (183 d), or dog (180 d). 4441 The investigators noted that the pattern was different than normally encountered in retention 4442 of trace metals in that larger animals usually have longer retention times. 60 4443 (344) In dogs exposed by inhalation to Co aerosols (Barnes et al., 1976), the kidneys and 60 4444 liver showed much higher concentrations of Co than skeleton at early times but the relative 4445 concentration in the skeleton increased over a period of months. The contents of liver, 4446 skeleton, and kidneys decreased in the order liver > skeleton > kidneys at early times and in 57 4447 the order skeleton > liver > kidneys after 2-4 months. In dogs exposed to Co aerosols 4448 (Kreyling et al., 1986), the skeleton and muscle each contained several times more activity 4449 than liver, and kidneys contained roughly the same amount as liver, at 1-5 y after exposure. 60 4450 (345) In rats given a single dose of CoCl2 by gastric intubation, the liver initially was the 4451 main repository, but by 2-4 months the main measured repository was skeleton, followed by 60 4452 muscle, liver, and kidney (Smith, al., 1971). In rats chronically exposed to Co in drinking 4453 water, the liver remained the dominant repository over 170 d, followed by skeleton and 60 60 4454 muscle (Smith et al., 1971). Retention of Co by rats continuously exposed to Co in 4455 drinking water was consistent with the long-term whole-body retention component derived 4456 from single-administration studies (Smith et al., 1971). 57 4457 (346) At 8 d after ingestion of CO3O4 particles by baboons, the skeleton and kidneys 4458 contained 0.6-1.1 times and 0.09-0.15 times, respectively, as much activity as the liver. At 6 57 4459 mo after inhalation of CO3O4 by baboons, the skeleton and kidneys contained 0.6-3 and 0.1- 4460 0.3 times as much activity as the liver, respectively (Andre et al., 1989). 4461 (347) Animal studies reveal that the systemic biokinetics of cobalt depends on the 4462 chemical form injected into blood (Nishimura et al., 1976; Inaba et al., 1982). Nishimura et 60 58 4463 al., (1976) compared the behavior of intravenously injected CoCl2 and Co- 60 4464 cyanocobalamin in rats. At 21 d after administration of CoCl2, 26.4% of the body burden 4465 was found in the liver and 13.1% in the kidneys, and cumulative excretion was mainly in

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58 4466 urine. At 21 d after intravenous administration of Co-cyanocobalamin, the kidneys 58 4467 contained 38.8% of the body burden and the liver contained 14.6%; excretion of Co was 4468 mainly in faeces; and loss from the body was considerably slower than for inorganic cobalt. 57 4469 (348) In studies involving various animal species, more than half of Co injected as 4470 Co(NO3)2 was excreted in urine in the first 24 h and more than two-thirds was excreted in 4471 urine during the first week (Andre et al., 1989; Bailey et al., 1989; Collier et al., 1989; Talbot 4472 and Morgan, 1989). Cumulative faecal excretion over the first week accounted for about 4- 4473 28% of the injected cobalt. Other animal studies also indicate that urine is the primary route 4474 of excretion of injected cobalt (Comar and Davis, 1947; Barnaby et al., 1968; Onkelinx, 4475 1976; Thomas et al., 1976; Gregus and Klaassen, 1986; Kreyling et al., 1986). Excretion of 4476 cobalt in bile amounting to 2-7% of the initial systemic burden has been observed in dogs and 4477 rats (Sheline et al., 1945; Cikrt and Tichy, 1981; Gregus and Klaasen, 1986). 60 4478 (349) The distribution of Co was examined by autoradiography in tissues of pregnant 60 4479 mice intravenously injected with CoCl2 (Flodh, 1968). Sacrifice times were 1 h, 4 h, 24 h, 4 4480 d, and 16 d after injection. Except where otherwise indicated, the following description refers 60 4481 to the mother rather than the fetus. At 1 h the concentration of Co in blood was only about 4482 one-eighth that in liver. Disappearance from blood was gradual after 1 h but largely complete 60 4483 by 24 h. Cartilage showed a high concentration of activity at 1 h. The concentration of Co 4484 in cartilage increased with time and was 4 times higher than in liver by 4 d. From 24 h 4485 onward the cartilage in the trachea and larynx had the highest concentration. Bones of the 4486 skull, the periosteum of the vertebrae, and the pelvic bone also accumulated cobalt. The liver 4487 showed a high concentration at all times studied. Accumulation was high in the kidneys with 4488 a peak at 4 h. Activity was localized mainly in the inner parts of the cortex. After 4 d the 4489 kidney concentration was still as high as the liver. Accumulation in the mammary glands was 4490 high, about the same concentration as in the liver and kidneys. In the fetus, the radioactivity 4491 was localized mainly in the skeleton, with relatively high uptake in hyaline cartilage and 4492 cranial bones. According to the investigators, the distribution of inorganic cobalt in the 58 4493 mother was different from that seen in autoradiographic studies involving Co-labeled 4494 vitamin B12. 4495 (350) In animal studies involving administration of inorganic compounds of radiocobalt, 4496 relatively high concentration of cobalt generally have been found in the liver, kidneys, 4497 skeleton, and skeletal muscle. The skeleton typically contains more than any other single 4498 organ or tissue by a few months after acute intake, indicating tenacious retention of a portion 4499 of the deposited activity. Following intraperitoneal, intravenous, or oral administration of 60 4500 CoCl2 to rats, the skeletal content decreased by a factor of 6-12 between days 1 and 30 and 4501 then showed little decline over the next few months (Barnaby et al., 1968; Thomas et al., 4502 1976). Skeletal muscle showed a longer average retention time than most soft tissues 4503 including liver and kidneys. 4504 (351) In hamsters, rats, and guinea pigs, liver and kidneys contained about 20-40% and 3- 57 4505 4%, respectively, of the total body activity at 3 wk after intravenous injection of Co(NO3)2 4506 (Collier et al., 1989). In rats, liver, skeleton, and muscle each contained about 20-25% and 4507 the kidneys contained about 7-8% of the total-body activity over 10-72 d after intraperitoneal 58 4508 injection of CoCl2 (Hollins and McCullough, 1971). At 386 d after intraperitoneal injection 58 4509 of CoCl2, the skeleton, liver, and kidneys contained about 65%, 7%, and 2%, respectively, 4510 of total-body activity (Hollins and McCullough, 1971). 57 4511 (352) The systemic distribution of Co-labeled cobalt at 100 d after intraperitoneal 4512 injection of CoCl2 into rats depended strongly on the administered mass (Edel et al., 1994). 57 4513 After administration of 5 μg of cobalt the highest concentrations of Co were found in spleen 4514 and pancreas, followed by skull and femur. After administration of 1 mg the skull and femur

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4515 showed far higher concentrations than other tissues. 4516 4517 8.2.3.2. Biokinetic model for systemic cobalt 4518 4519 (353) The model structure for systemic cobalt used in this report (Figure 8-1) is the same 4520 as the generic model structure for bone-volume-seeking radionuclides except that 4521 compartments within blood are not identified explicitly for cobalt. Although cobalt is not 4522 considered a bone-seeking radionuclide, that model structure provides a convenient 4523 framework in which to model the biokinetics of cobalt for radiation protection purposes. 4524

4525 4526 Figure 8-1. Structure of the systemic model for cobalt. 4527 4528 (354) Transfer coefficients (Table 8-3) were based as far as feasible on data from 4529 controlled human studies involving administration of inorganic forms of cobalt. Model 4530 predictions of total-body retention, including different phases of loss from the body, were 4531 required to be consistent with central estimates based on combined data of Smith et al. (1972) 60 58 4532 and Letourneau et al. (1972) for human subjects injected with CoCl2 and CoCl2, 4533 respectively. Parameter values for blood were set for consistency with blood retention data 60 4534 of Smith et al. (1972) for subjects injected with CoCl2. Urinary and faecal excretion rates 4535 and uptake and retention by liver were based mainly on measurements by Smith et al. (1972) 60 55 4536 and Jansen et al. (1996) for subjects injected with CoCl2 and CoCl2, respectively. The 4537 data for human subjects were supplemented with information on the time-dependent 4538 distribution of cobalt among liver, kidneys, skeleton, and other tissues in laboratory animals 4539 receiving inorganic forms of radiocobalt by inhalation, ingestion, or injection. For example, 4540 the initial distribution of systemic cobalt and the shift with time in its distribution were 4541 modeled after general patterns indicated by data on several animal species. Derivations of 4542 parameter values describing uptake and retention in specific repositories are summarized 4543 below. 4544

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4545 4546 Table 8-3. Transfer coefficients (d-1) for systemic cobalt. 4547 Compartments Transfer Coefficient (d-1) Blood 1 to Liver 1 7.00E+01 Blood 1 to Urinary bladder contents 6.00E+01 Blood 1 to Right colon contents 4.00E+00 Blood 1 to ST0 1.80E+01 Blood 1 to ST1 1.00E+01 Blood 1 to ST2 4.00E+00 Blood 1 to Cortical bone surf 6.00E+00 Blood 1 to Trabecular bone surf 6.00E+00 Blood 1 to Kidneys 1 9.00E+00 Blood 1 to Kidneys 2 1.00E+00 Blood 1 to Blood 2 1.20E+01 Blood 2 to Blood 1 6.93E-01 Liver 1 to SI cont 9.24E-02 Liver 1 to Blood 1 3.47E-01 Liver 1 to Liver 2 2.31E-02 Liver 2 to Blood 1 1.90E-03 ST0 to Blood 1 9.90E-02 ST1 to Blood 1 1.39E-02 ST2 to Blood 1 9.50E-04 Cortical bone surf to Blood 1 8.42E-02 Cortical bone surf to Cortical bone vol 1.49E-02 Trabecular bone surf to Blood 1 8.42E-02 Trabecular bone surf to Trabecular bone vol 1.49E-02 Cortical bone vol to Blood 1 8.21E-05 Trabecular bone vol to Blood 1 4.93E-04 Kidneys 1 to Urinary bladder contents 4.62E-01 Kidneys 2 to Blood 1 1.90E-03 4548 surf = surface, vol = volume, SI = small intestine 4549 4550 Blood 4551 (355) Blood is divided into two compartments called Blood 1 and Blood 2. Cobalt atoms 4552 entering blood are assigned to Blood 1, which is a rapid-turnover plasma pool. Blood 2 is a 4553 more slowly exchanging pool that contains the preponderance of activity in blood except for 4554 a short period soon after acute uptake of radiocobalt. These compartments are used to 4555 reproduce observed rates of disappearance of cobalt from blood and are difficult to identify 4556 with specific components of blood. The relatively slow loss of a portion of injected cobalt 4557 from blood may be associated with retention by certain plasma proteins and red blood cells 4558 (RBC), although data of Smith et al. (1972) indicate that RBC contained at most a few 60 4559 percent of the blood content of Co during the first 30 h after intravenous injection of 60 4560 CoCl2 into human subjects. -1 4561 (356) Activity leaves Blood 1 at the rate 200 d , corresponding to a half-time of ~5 min, 4562 with 6% of outflow going to Blood 2 and the remaining 94% divided among tissue 4563 compartments, urinary bladder contents, and colon contents. Activity moves from Blood 2 4564 back to Blood 1 with a half-time of 1 d. 4565

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4566 Liver and faecal excretion 4567 (357) The liver is represented as two compartments, Liver 1 and Liver 2, representing 4568 short- and long-term retention, respectively. Liver 1 receives 35% of activity leaving Blood 1. 4569 Activity is removed from Liver 1 with a half-time of 1.5 d, with 20% going to the small 4570 intestine contents in bile, 5% going to Liver 2, and 75% returning to blood. Activity transfers 4571 from Liver 2 to Blood 1 with a half-time of 1 y. Endogenous faecal excretion of cobalt arises 4572 from biliary secretion as indicated above, plus secretion from Blood 1 to the right colon. The 4573 latter transfer amounts to 2% of cobalt leaving Blood 1. 4574 4575 Kidneys and urinary excretion 4576 (358) The kidneys are divided into two compartments, called Kidneys 1 and Kidneys 2. 4577 Kidneys 1 receives cobalt from blood after filtration through the glomerulus, representing 4578 4.5% of outflow from Blood 1, and loses cobalt to the urinary bladder contents with a half- 4579 time of 1.5 d. The urinary bladder contents receive an additional 30% of outflow from 4580 Blood 1 that is filtered at the glomerulus but not retained in the kidneys. Kidneys 2 is a slow- 4581 turnover pool that receives 0.5% of outflow from Blood 1 and returns cobalt to Blood 1 with 4582 a half-time of 1 y. 4583 4584 Skeleton 4585 (359) Uptake and retention of cobalt in the total skeleton can be modeled on the basis of 4586 data from animal studies, but the distribution of cobalt between cortical and trabecular bone 4587 or between bone surfaces and bone volume has not been established. It is assumed that 3% of 4588 cobalt atoms leaving Blood 1 deposit on trabecular bone surfaces and 3% deposit on cortical 4589 bone surfaces. Cobalt leaves bone surfaces with a half-time of 7 d, with 15% going to the 4590 corresponding bone volume compartment and 85% returning to Blood 1. Cobalt is removed 4591 from trabecular or cortical bone volume at the rate of bone turnover. Reference values for 4592 bone turnover rates are given in ICRP Publication 89 (2002b). 4593 4594 Other tissues 4595 (360) Remaining soft tissues are divided into three compartments called ST0, ST1, and 4596 ST2, with relatively fast, intermediate, and relatively slow turnover, respectively. These 4597 compartments receive 9%, 5%, and 2% of outflow from Blood 1 and return cobalt to Blood 1 4598 with half-times 7 d, 50 d, and 2 y, respectively. 4599 (361) The above parameters yield reasonable consistency between model predictions of 4600 retention and excretion and observations in controlled human studies. Model predictions are 4601 also consistent with the following aspects of the biological behavior of inorganic cobalt 4602 indicated by radiocobalt studies on human subjects and laboratory animals: 4603 • The peak content of liver is roughly one-third (model prediction, ~35%) of the 4604 intravenously injected amount and occurs during the first hour after injection. 4605 • A high rate of urinary of excretion of cobalt occurs during the first hour or two after 4606 absorption or intravenous injection into blood (Apostoli et al., 1994; Jansen et al., 4607 1996). 4608 • The liver contains roughly 20% (model predictions, 15-27%) of the total body burden 4609 at times from a few days up to 1000 d after injection. 4610 • The kidneys and liver initially show similar concentrations of cobalt, but the kidney 4611 concentration is about twice that of liver at times remote from injection. 4612 • The skeleton contains less cobalt than the liver during the early weeks after injection 4613 but gradually becomes the dominant systemic repository for cobalt. 4614

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4615 8.2.3.3. Treatment of radioactive progeny 4616 4617 (362) The only cobalt isotopes addressed in this report that have dosimetrically important 58m 58 60m 60 4618 chain members are Co, which decays to Co, and Co, which decays to Co. In these 4619 cases the biokinetics of the radioactive progeny is presumably identical to that of the parent. 4620 4621 8.3. Individual monitoring

4622 57 4623 Co 57 57 4624 (363) Co is a high energy γ emitter. Monitoring of Co is in general accomplished 57 4625 through Whole Body Counting. Urine bioassays are also used in monitoring for Co. If 4626 needed lung monitoring may be performed. Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 57Co Urine Bioassay γ-ray 1 Bq/L 0.2 Bq/L spectrometry 57Co Whole Body γ-ray 30 Bq 30 Bq Counting spectrometry 57Co Lung Counting γ-ray 4-5Bq 4 Bq spectrometry 4627 58 4628 Co 58 58 4629 (364) Co is a high energy γ emitter. Monitoring of Co is in general accomplished 58 4630 through Whole Body Counting. Urine bioassays are also used in monitoring for Co. If 4631 needed lung monitoring may be performed. Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 58Co Urine Bioassay γ-ray 0.4 Bq/L 0.03Bq/L spectrometry 58Co Whole Body γ-ray 30-40 Bq 9 Bq Counting spectrometry 58Co Lung Counting γ-ray 4 Bq spectrometry 4632 60 4633 Co 60 60 4634 (365) Co is a high energy γ emitter. Monitoring of Co is in general accomplished 60 4635 through Whole Body Counting. Urine bioassays are also used in monitoring for Co. If 4636 needed lung monitoring may be performed.

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4637 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 60Co Urine Bioassay γ-ray 0.4 Bq/L 0.1 Bq/L spectrometry 60Co Whole Body γ-ray 30-40 Bq 10 Bq Counting spectrometry (shielded room) 60Co Lung Counting γ-ray 8 Bq spectrometry 4638 4639 References 4640 4641 André, S., Métivier, H., Masse, R., 1989. An interspecies comparison of the lung clearance of inhaled 4642 monodisperse cobalt oxide particles. Part 3: Lung clearance of inhaled cobalt oxide particles 4643 in baboons. J. Aerosol Sci. 20, 205-217. 4644 Apostoli, P., Porru, S., Alessio, L., 1994. Urinary cobalt excretion in short time occupational exposure 4645 to cobalt powders. Sci. Total Environ. 150, 129-132. 4646 Bailey, M.R., Kreyling, W.G., André, S., Batchelor, A., Black, A., Collier, C.G., Drosselmeyer, E., 4647 Ferron, G.A., Foster, P.P., Haider, B., Hodgson, A., Métivier, H., Moores, S.R., Morgan, A., 4648 Müller, H. L., Patrick, G., Pearman, I., Pickering, S., Ramsden, D., Stirling, C., Talbot, R.J., 4649 1989. An interspecies comparison of the lung clearance of inhaled monodisperse cobalt oxide 4650 particles – Part 1: Objectives and summary of results. J. Aerosol Sci. 20, 169–188. 4651 Barnaby, C. F., Smith, T., Thompson, B.D., 1968. Dosimetry of the radioisotopes of cobalt. Phys. 4652 Med. Biol. 13, 421-433. 4653 Barnes, J.E., Kanapilly, G.M., Newton, G.J., 1976. Cobalt-60 oxide aerosols: Methods of production 4654 and short-term retention and distribution kinetics in the beagle dog. Health Phys. 30, 391– 4655 398. 4656 Beleznay, E., Osvay, M., 1994. Long-term clearance of accidentally inhaled 60Co aerosols in humans. 4657 Health Phys. 66, 392-399. 4658 Brune, D., Beltesbrekke, H., 1980. Pulmonary deposition following inhalation of chromium-cobalt 4659 grinding dust in rats and distribution in other tissues. Scand. J. Dent. Res. 88, 543–551. 4660 Chevalier, C., Gonin, M., 1993. The gastrointestinal absorption factor for cobalt: a study of 4661 contamination cases from French Nuclear Power Plants. Radiat. Prot. Dosim. 48, 363-365. 4662 Cikrt, M., Tichy, M., 1981. Biliary excretion of cobalt in rats. J. Hyg. Epidemiol. Microbiol. 4663 Immunol. 25, 264-368. 4664 Collier, C.G., James, A.C., Ellender, M., 1988. The effect of alpha irradiation on retention of particles 4665 in the rat lung. Inhaled particles VI. Ann. occup. Hyg. 32(1), 1007–1015. 4666 Collier, C.G., Pearce, M.J., Hodgson, A., Ball, A., 1992. Factors affecting the in vitro dissolution of 4667 cobalt oxide. Environ.Health Persp. 97, 109–113. 4668 Collier, C.G., Stradling, G.N., Foster, P.P., Hodgson, A., 1994. The biokinetics of corrosion products 4669 from a water cooled reactor after deposition in the rat lung. Radiat. Prot. Dosim. 53(1–4), 4670 173–177. 4671 Collier, C.G., Hodgson, A., Gray, S.A., Moody, J.C., Ball, A., 1991. The lung clearance kinetics of 57 4672 Co3O4 in rats of various ages. J. Aerosol Sci., 22, 537-549. 4673 Collier, C.G., Bailey, M.R., Hodgson, A., 1989. An interspecies comparison of the lung clearance of 4674 inhaled monodisperse cobalt oxide particles. Part 5: Lung clearance of inhaled cobalt oxide 4675 particles in hamsters, rats and guinea pigs. J. Aerosol Sci. 20, 233-247. 4676 Comar, C.L., Davis, G.K., 1947. Cobalt metabolism studies. IV. Tissue distribution of radioactive 4677 cobalt administered to rabbits, swine, and young calves. J. Biol. Chem. 170, 379-389; 1947.

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4678 Davis, K., Marsh, J.W., Gerondal, M., Bailey, M.R., Le Guen B., 2007. Assessment of intakes and 4679 doses to workers followed for 15 years after accidental inhalation of 60Co. Health Phys. 92, 4680 332-344. 4681 Edel, J., Pozzi, G., Sabbioni, E., Pietra, R., Devos, S., 1994. Metabolic and toxicological studies on 4682 cobalt. Sci. Total Environ. 150, 233-244. 4683 Flodh, H., 1968. Autoradiographic studies on distribution of radiocobalt chloride in pregnant mice. 4684 Acta Radiol. 7, 121-128. 4685 Godleski J.J., Kreyling W.G., 1990. Localization of cobalt in the matrix of airway cartilage. Am. Rev. 4686 Respir. Dis. 141, A525. 4687 Gregoratto, D., Bailey M.R., Marsh J.W., 2010. Modelling particle retention in the alveolar-interstitial 4688 region of the human lungs. J. Radiol. Prot. 30, 491-512. 4689 Gregus, Z., Klaassen, C.D., 1986. Disposition of metals in rats. A comparative study of fecal, urinary, 4690 and biliary excretion and tissue distribution of eighteen metals. Toxicol. Appl. Pharmacol. 85, 4691 24-38. 4692 Griffis, L.C., Snipes, M.B., Brooks, A.L., 1981. Clearance by the rat of inhaled fly ash from fluidized- 4693 bed coal combustion. J. Toxicol. Environ. Health, 7, 117–124. 4694 Gupton, E.D., Brown, P.E., 1972. Chest clearance of inhaled cobalt-60 oxide. Health Phys., 23, 4695 767-769. 4696 Hegde, A.G., Thakker, D.M., Bhat, I.S., 1979. Long-term clearance of 60Co. Health Phys., 36, 732– 4697 734. 4698 Heyder, J., Beck-Speier, I., Ferron, G.A., Josten, M., Karg, E., Kreyling, W.G., Lenz, A.-G., Maier, 4699 K.L., Reitmeier, P., Ruprecht, L., Takenaka, S., Wohland, T., Ziesenis, A., Schulz, H., 2009. 4700 Long-term responses of canine lungs to acidic particles. Inhalation Toxicology, 21, 920–932. 4701 Hollins, J.G., McCullough, R.S., 1971. Radiation dosimetry of internal contamination by inorganic 4702 compounds of cobalt: An analysis of cobalt metabolism in rats. Health Phys. 21, 233-246. 4703 ICRP, 1979. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Pt.1. Pergamon 4704 Press, Oxford. Ann. ICRP 2, (3/4). 4705 ICRP, 1993. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 2, 4706 Ingestion dose coeffcients . ICRP Publication 67. Pergamon Press, Oxford. Ann. ICRP 23, 4707 (3/4). 4708 ICRP, 1994. Human Respiratory Tract Model for Radiological Protection. ICRP Publication 66. 4709 Pergamon Press, Oxford. Ann. ICRP 24, (1–3). 4710 ICRP, 2002a. Guide for the practical application of the ICRP Human Respiratory Tract Model. 4711 Annals of the ICRP 32, (1-2). 4712 ICRP, 2002b. Basic anatomical and physiological data for use in radiological protection: Reference 4713 values. ICRP Pub. 89. Oxford: Pergamon Press. 4714 Inaba, J., Nishimura, Y., Kimura, K.-I., Ichikawa, R., 1982. Whole-body retention and tissue 4715 distribution of 60Co in rats after oral administration of freshwater fish contaminated with 60Co. 4716 Health Phys. 43, 247-250. 4717 Jansen, H.M., Knollema, S., van der Duin, L.V., Willemsen, A.T., Wiersma, A., Franssen, E.J., 4718 Russel, F.G., Korf, J., Paans, A.M., 1996. Pharmacokinetics and dosimetry of cobalt-55 and 4719 cobalt-57. J Nucl Med. 37, 2082-2086. 4720 Kreyling, W.G., 1990. Aerosol particle parameters maintaining lung clearance by intracellular 4721 dissolution and translocation. J. Aerosol Sci. 21, 371–374. 4722 Kreyling, W.G., 1992. Intracellular particle dissolution in alveolar macrophages. Environ. Hlth. 4723 Perspect. 97, 121–126. 4724 Kreyling, W.G., Godleski, J.J., Kariya, S.T., Rose, R.M., Brain, J.D., 1990. In vitro dissolution of 4725 uniform cobalt oxide particles by human and canine alveolar macrophages. American Journal 4726 of Respiratory Cell and Molecular Biology 2, 413–422. 4727 Kreyling, W.G., Ferron G.A., Fürst, G., Heilmann, P., Neuner, M., Ruprecht, L., Schumann, G., 4728 Takenaka, S., Heyder, J., 1992a. Early response of the canine respiratory tract following long- 4729 term exposure to a sulfur(IV) aerosol at low concentration: III. Macrophage mediated long- 4730 term particle clearance. Inhalation Toxicology 4, 197–233.

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4731 Kreyling, W.G., André, S., Collier, C.G., Ferron, G.A., Métivier, H., Schumann, G., 1991. 4732 Interspecies comparison of lung clearance after inhalation of monodisperse, solid cobalt oxide 4733 aerosol particles. J. Aerosol Sci., 22, 509–535. 4734 Kreyling, W.G., Bloom, S.B., Brain, J.D., 1987. The uptake of soluble cobalt in the extrapulmonary 4735 airways of hamsters. In: Deposition and Clearance of Aerosols in the Human Respiratory 4736 Tract (Ed. Hofmann, W.) Proceedings of the 2nd International Symposium Sept 18-20, 1986 4737 at Salzburg, Austria, Facultas Universitätsverlag GmbH Wien pp. 57-62. 4738 Kreyling, W.G., Dirscherl, P., Ferron, G.A., Neuner, M., Schumann, G., Takenaka, S., Ziesenis, A., 4739 Heyder, J., 1999. Health effects of sulfur-related environmental air pollution: III. Nonspecific 4740 respiratory defense capacities, Inhalation Toxicology 11(5), 391–422. 4741 Kreyling, W.G., Ferron, G.A., Haider, B., 1986. Metabolic fate of inhaled Co aerosols in beagle dogs. 4742 Health Phys. 51, 773–795. 4743 Kreyling, W.G., Ferron, G.A., Schumann, G., Heilmann, P., 1992b. Macrophage mediated particle 4744 transport from the lungs. J. Aerosol Med., 5, 285. 4745 Kreyling, W.G., Schumann, G., Ortmaier, A., Ferron, G.A., Karg, E., 1988. Particle transport from the 4746 lower respiratory tract. J. Aerosol Med., 1, 351–369. 4747 Leggett R.W., 2008. The biokinetics of inorganic cobalt in the human body. Science of the Total 4748 environment 389, 259–269. 4749 Letourneau, E.G., Jack, G.C., McCullough, R.S., Hollins, J.G., 1972. The metabolism of cobalt by the 4750 normal human male: Whole body retention and radiation dosimetry. Health Phys. 22, 451- 4751 459. 4752 Menzel, D.B., Wolpert, R.L., Francovitch, R.J., Shoaf, C.R., Boger, J.R., Tayyeb, M.I., 1989. 4753 Respiratory tract burdens of cobalt from inhalation of soluble aerosols: simulation by a two- 4754 compartment model. Inhalation Toxicology, 1, 49–69. 4755 Molokanov, A.A., Bushmanov, A., Kukhta, B.A., Yatsenko, V.N., 2010. A numerical statistical 4756 method application experience for the interpretation of Со-60 special monitoring data for 4757 nuclear power-plant workers. 3rd European IRPA Congress, 14-18 June 2010, Helsinki, 4758 Finland. 4759 Morrow, P.E., Gibb, F.R., Davies, H., Fisher, M., 1968. Dust removal from the lung parenchyma: an 4760 investigation of clearance stimulants. Toxicol. Appl. Pharmacol. 12, 372-396. 4761 Newton, D., Rundo, J., 1971. The long-term retention of inhaled cobalt-60. Health Phys. 21, 377-384. 60 58 4762 Nishimura, Y., Inaba, J., Ichikawa, R., 1976. Whole-body retention of CoCl2 and Co- 4763 cyanocobalamin in young and adult rats. J. Radiat. Res. 17, 240-246. 4764 Onkelinx, C., 1976. Compartment analysis of cobalt (II) metabolism in rats of various ages. Toxicol. 4765 Appl. Pharmacol. 38, 425-438. 4766 Paley, K.R., Sussman, E.S., 1963. Absorption of radioactive cobaltous chloride in human subjects. 4767 Metabolism 12(11), 975-982. 4768 Patrick, G., Kreyling, W.G., Poncy, J.-L., Collier, C.G., Godleski, J.J., Duserre, C., Stirling, C., 4769 Brain, J.D., 1994. Interspecies comparison of the clearance of ionic cobalt from the lung. 4770 Inhalation Toxicology, 6, 225–240. 4771 Patrick, G., Batchelor, A. L., Stirling, C. 1989. An interspecies comparison of the lung clearance of 4772 inhaled monodisperse cobalt oxide particles. Part VI: Lung clearance of inhaled cobalt oxide 4773 particles in SPF Fischer rats. J. Aerosol Sci. 20: 247-255. 4774 Raghavendran, K., Satbhai, P.D., Abhyankar, B., Unnikrishnan, K., Somasundaram, S., 1978. Long- 4775 term retention studies of 131I, 137Cs and 60Co in Indian workers, Health Phys. 34, 185-188. 4776 Ramsden, D., 1984. A modified lung model to match observed lung and urinary data following the 4777 inhalation of plutonium oxide - the problems of long term retention in the pulmonary lymph 4778 nodes. In: Smith, H., Gerber, G. (Eds.), Lung Modelling for Inhalation of Radioactive 4779 Materials, EUR 9384, pp. 281–286. Commission of the European Communities, 4780 Luxembourg. 4781 Sheline, G.E., Chaikoff, I.L., Montgomery, M.L., 1945. The elimination of administered cobalt in 4782 pancreatic juice and bile of the dog, as measured with its radioactive isotopes. Amer. J. 4783 Physiol. 145, 285–290.

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4784 Smith T., Thompson, B.D., Barnaby, C.F., 1971. Measurement of 60Co organ burdens in rats and their 4785 use in calculations of equilibrium dose rates to various organs of man. Health Phys. 20, 195- 4786 204. 4787 Smith, T., Edmonds, C., Barnaby, C., 1972. Absorption and retention of colbalt in man by whole body 4788 counting. Health Physics. 22, 359-367. 4789 Stradling, G.N., Pellow, P.G., Hodgson, A., Fell, T.P., Phipps, A., Pearce, M., Rance, E., Ellender, 4790 M., Taskaeva, M., Penev, I., Guentchev, T., 1996. Dose coefficient and assessment of intake 4791 of a radionuclide bearing dust formed at the Kozloduy Nuclear Power Plant, NRPB-M679. 4792 Chilton, National Radiological Protection Board. 4793 Stradling, G.N., Pellow, P. G., Hodgson, A., Fell, T. P., Phipps, A., Pearce, M., Taskaeva, M., Penev, 4794 I., Guentchev, T., 1997. Assessment of intake of a complex radionuclide bearing dust formed 4795 at a nuclear power plant. J. Radioanal. Nucl. Chem. 226, 7–14. 4796 Talbot, R.J., Morgan, A., 1989. An interspecies comparison of the lung clearance of inhaled 4797 monodisperse cobalt oxide particles. Part 8: Lung clearance of inhaled cobalt oxide particles 4798 in mice. J. Aerosol Sci. 20, 261-265. 4799 Thomas, R.G., Furchner, J. E., London, J.E., Drake, G.A., Wilson, J.S., Richmond, C.R., 1976. 4800 Comparative metabolism of radionuclides in mammals--X. Retention of tracer-level cobalt in 4801 the mouse, rat, monkey and dog. Health Phys. 31, 323-333. 4802 Valberg, L.S., Ludwig, J., Olatunbosun, D., 1969. Alteration in cobalt absorption in patients with 4803 disorders of iron metabolism. Gastroenterology 56(2), 241-251. 4804 Van den Oever, R., Roosels, D., Douwen, M., Vanderkeel, J., Lahaye, D., 1990. Exposure of diamond 4805 polishers. Ann. Occup. Hyg., 34, 609–614. 4806 Wehner, A.P., Wilkerson, C.L., Stevens, D.L., 1984. Lung clearance of neutron-activated Mount St. 4807 Helens volcanic ash in the rat. Environ. Res., 35, 211–217. 4808

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4809 9. ZINC (Z = 30) 4810 4811 9.1. Chemical Forms in the Workplace 4812 4813 (366) Zinc is a transition metal, which occurs mainly in oxidation state II. Zinc may be 4814 encountered in industry in a variety of chemical and physical forms, including metal dusts, 4815 oxides, phosphates, sulphides or as soluble salts (sulphates, nitrates, chlorides), and 4816 chromates. 4817 (367) Zinc-65 is a major activation product in nuclear power plants and could be present in 4818 corrosion particles. 4819 4820 Table 9-1. addressed in this report 4821 Isotope Physical half-life Decay mode Zn-62 9.186 h EC, B+ Zn-63 38.47 m EC, B+ Zn-65a 244.06 d EC, B+ Zn-69 56.4 m B- Zn-69m 13.76 h IT, B- Zn-71m 3.96 h B- Zn-72 46.5 h B- 4822 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 4823 are given on accompanying electronic disk. 4824 4825 9.2. Routes of Intake 4826 4827 9.2.1. Inhalation 4828 4829 Absorption Types and parameter values 4830 (368) Little information was found on the behaviour of inhaled zinc in man, and it is 4831 difficult to estimate the contribution of absorption to lung clearance in such cases, because 4832 the systemic excretion of zinc is predominantly by the faecal route. Information is available 4833 from experimental studies of several compounds of zinc, or associated with corrosion 4834 products. 4835 (369) Absorption parameter values and Types, and associated fA values for particulate 4836 forms of zinc are given in Table 9-2. 4837 4838 Zinc oxide 4839 (370) Following inhalation of zinc oxide by rats, Oberdörster et al. (1979) observed a lung 4840 retention half-time of about 6 hours, with 7% of the initial lung deposit (ILD) retained at 24 4841 hours. Rosaminth and Breining (1974) administered zinc oxide to rats by instillation five 4842 times over 14 days, and less than 2% of the total ILD was retained 7 days later. Hirano et al. 4843 (1989) also administered zinc oxide to rats by instillation and observed a lung retention half- 4844 time of about 15 hours, with negligible retention after 5 days. The results of all three studies 4845 (with stable zinc oxide) are consistent with the assignment to Type F. 4846 4847 Zinc chromate 51 4848 (371) Following intratracheal instillation of zinc Cr-chromate to rats, 25% ILD remained 4849 at 30 minutes, and from 30 minutes to 6 days the retention half-time was 1.9 days, consistent

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4850 with assignment to Type F (Bragt and van Dura, 1983). 4851 4852 Zinc nitrate 65 4853 (372) Morrow et al. (1968) followed lung clearance of Zn for 70 days after inhalation of 65 4854 Zn(NO3)2 by dogs and rats, but few details are given. Lung retention in dogs was described 4855 by a two-component exponential function with half-times of 4 days (53%: clearance rate 0.17 -1 -1 4856 d ) and 120 days (clearance rate 0.0058 d ), giving lung retention at 30 d to be 40% ILD, 4857 consistent with assignment to Type M. 4858 4859 Zinc phosphate 65 4860 (373) Morrow et al. (1968) followed lung clearance of Zn for 65 days after inhalation of 65 4861 Zn3(PO4)2 by dogs and rats, but few details are given. Lung retention in dogs was described 4862 by a two-component exponential function with half-times of 7 days (58%: clearance rate -1 -1 4863 0.099 d ) and 330 days, (clearance rate 0.0021 d ), giving lung retention at 30 d to be 42% 4864 ILD, consistent with assignment to Type M. 4865 4866 Corrosion Products (contaminated dusts or ‘residues’ formed at nuclear power plant (NPP) 65 4867 (374) The biokinetics of Zn were followed for 280 days after intratracheal instillation 65 4868 into rats of a suspension of corrosion 'crud' particles (oxide bearing debris, 11% Zn activity) 4869 from the primary containment of a water cooled reactor (Collier et al., 1994). Few details are 4870 given, but it was assessed by the task group that the results are consistent with assignment of 65 4871 the Zn present to Type S. 4872 4873 Other compounds 4874 (375) In one case of accidental human exposure to dust from an experimental hole in a 65 4875 reactor, Zn was rapidly cleared from the lungs except for a small component that was 4876 retained for a period of several months, indicating Type F (Newton and Holmes, 1966). 65 4877 Measurements have also been reported following accidental intakes of Zn from metallic 4878 zinc (Andrasi and Feher, 1967) and reactor graphite dust (Sedlet and Fairman, 1970), but 4879 there is insufficient information to assign the material to absorption Types, since excretion of 4880 systemic zinc is predominantly faecal. 4881 4882 Rapid dissolution rate for zinc 4883 (376) There is insufficient experimental information to estimate the rapid dissolution rate 4884 for zinc. There is therefore no justification for choosing a rate different from the general –1 4885 default value of 30 d , which is applied here to all Type F forms of zinc. 4886 4887 Extent of binding of zinc to the respiratory tract 4888 (377) Evidence from the zinc oxide studies outlined above suggests that there is probably 4889 little binding of zinc. It is therefore assumed that for zinc the bound state can be neglected, 4890 i.e. fb = 0.0. 4891

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4892 Table 9-2. Absorption parameter values for inhaled and ingested zinc 4893 Absorption parameter Absorption from valuesa the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorption Assigned forms Type F Oxide, chromate 1 30 - 0.5 M Nitrate, phosphate, all unspecified 0.2 3 0.005 0.1 compoundsd S Corrosion products 0.01 3 1x10-4 0.005 Ingested materials All forms 0.5 a 4894 It is assumed that for zinc the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M and S 4895 forms of zinc (30, 3 and 3 d–1, respectively) are the general default values. 4896 b Materials (e.g. zinc oxide) are listed here where there is sufficient information to assign to a default 4897 absorption Type, but not to give specific parameter values (see text). 4898 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 4899 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the -1 4900 absorption Type and the fA value for ingested soluble forms of zinc (5x10 ). 4901 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 4902 or if the form is known but there is no information available on the absorption of that form from the 4903 respiratory tract. 4904 4905 9.2.2. Ingestion 4906 69m 4907 (378) Studies in which Zn was administered as chloride to three fed volunteers showed 4908 gastrointestinal absorption of zinc of about 0.2 (Molokhia et al., 1980). 4909 (379) Zinc absorption in humans is influenced by numerous factors including fasting, meal 4910 composition, the amount of daily dietary zinc and the state of health. Experiments performed 4911 on five fasting volunteers showed fractional absorption values ranging from 0.4 to 0.8 4912 (Molokhia et al., 1980). Similar experiments performed on 75 fasting subjects given carrier- 65 4913 free Zn, showed similar fractional absorption values, ranging from 0.4 to 0.86 (Aamodt et 4914 al., 1981). 4915 (380) When stable or radioactive zinc isotopes were incorporated into meals fed to normal 4916 adult subjects, the mean absorption values ranged between 0.05 and 0.5, with a value of about 4917 0.3 being typical (ICRP, 1993). It has been suggested that some foods, such as milk and beef 4918 may enhance dietary zinc uptake (Evans and Johnson, 1980; Solomons et al., 1982), while 4919 bran and phytate reduce it (Turnland et al., 1984; Sandstrom and Cedarblad, 1980). 4920 (381) Experiments performed with eight healthy subjects showed that when the amount of -1 4921 dietary zinc intake decreased from 15 to 2 mg.day , this resulted in an increase of fractional 4922 zinc absorption from 0.6 to about 0.9 (Istfan et al., 1983). Similarly, studies performed with 68 70 4923 Zn or Zn sulfate given to eight fed volunteers together with doses of aqueous zinc 4924 decreasing from 30 to 2 mg, showed that fractional absorption values increased from 0.37 to 4925 0.73 (Tran et al., 2004). 4926 (382) Zinc absorption has been reported to be reduced in the elderly (Turnlund et al., 4927 1982) and in the cirrhotic (Mills et al., 1983). 4928 (383) In Publication 30 (ICRP, 1980), an absorption value of 0.5 was recommended for all 4929 forms of Zn. The same value was adopted in Publication 67 (ICRP, 1993) for dietary intakes.

4930 An fA of 0.5 is also used in this report for all chemical forms.

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4931 4932 9.2.3. Systemic Distribution, Retention and Excretion 4933 4934 9.2.3.1. Overview of zinc biokinetics and balance in adult humans 4935 4936 (384) Zinc is an essential trace element required for normal growth, protein production, 4937 and function of numerous enzymes in mammals (NAS, 1979; Walravens, 1979; Vallee and 4938 Falchuk, 1993; Lowe et al., 2009). Dietary intake of zinc by adults generally is in the range -1 4939 7-20 mg d (Buchet et al., 1983; van Dokkum et al., 1989; Bro et al., 1990; Anke et al., 1991; 4940 Becker and Kumpulainen, 1991; Ysart et al., 2000; Hunt and Meacham, 2001; Jaiswal et al., 4941 2002; Conacher, 2003; Noel et al., 2003; Suzuki et al., 2003). Gastrointestinal uptake 4942 averages about 30-35% but varies with the level of zinc in diet, timing of intake relative to 4943 meals, and other factors (Hambidge et al., 1998; Krebs and Hambidge, 2001; Lowe et al., 4944 2009). 4945 (385) Fecal loss is the primary route of excretion of zinc. Endogenous fecal excretion 4946 appears to arise largely from pancreatic secretions into the small intestine contents, with 4947 smaller amounts transferred into the gastrointestinal contents in liver bile, saliva, and other 4948 secretions (McClain, 1990; Hambidge et al., 1998). Daily excretion in urine typically is 4949 about 0.3-0.5 mg (Spencer et al., 1973; Elinder et al., 1978; Wastney et al., 1991; 4950 Schuhmacher et al., 1994; Scott and Turnlund, 1994). The amount of zinc lost in sweat under 4951 normal conditions appears to be of the same order as losses in urine (Jacob et al., 1981; 4952 Johnson et al., 1993). 4953 (386) Following acute entry of labeled zinc into blood, 60% or more of the label rapidly 4954 accumulates in the liver (Siegel et al., 1961; Spencer et al., 1965; Aamodt et al., 1979). 4955 Relatively high concentrations are also seen in the kidneys and pancreas at early times (Siegel 4956 et al., 1961; Spencer et al., 1965). Over a period of weeks the label shifts largely to skeletal 4957 muscle and bone, which have low rates of accumulation but long retention of zinc 4958 (McKenney et al., 1962; Khristov, 1970; Aamodt et al., 1982). 65 4959 (387) External measurements Zn in human subjects following intravenous or oral 4960 administration indicate two main components of systemic retention with half-times on the 4961 order of 1-3 wk (15-30%) and 300-450 d (70-85%) (Richmond et al., 1962; Spencer et al., 4962 1965; Aamodt et al., 1982). Biokinetic studies on human subjects have not been sufficiently 4963 long to identify small components of retention with extremely long half-times that may arise, 4964 for example, from binding of zinc to bone mineral. 4965 (388) The mass of stable zinc in the total body of adult humans is on the order of 2 g 4966 (ICRP, 1975; NAS, 1979; Zhu et al., 2010). Muscle contains about 55-65% and bone about 4967 20-30% of the body’s zinc. 4968 4969 Summary of the database 4970 4971 Human studies 65 4972 (389) Siegel et al. (1961) measured Zn concentrations in tissue samples taken at autopsy 65 4973 1-174 d after intravenous injection of Zn as chloride into 14 terminal patients with various 4974 malignancies. The liver, pancreas, spleen, prostate, seminal vesicles, lung, urinary bladder, 65 4975 and skeletal muscle were sampled. Widely differing concentrations of Zn were found in 4976 different tissues. The highest levels were found in the liver, in which the concentration 4977 reached about 0.05% of the administered activity per gram of tissue in the first few days after 4978 administration. This value was about 2-8 times that in the pancreas, which contained the 4979 second highest concentrations at early times, and about 10-30 times that in muscle, which

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4980 contained the lowest concentrations at early times. Turnover was relatively slow in the liver 4981 and relatively fast in the pancreas. The concentration in the pancreas was reduced by about 4982 two-thirds within a week, while the concentration in the liver remained high after 81 d. 4983 (390) Richmond et al. (1962) measured uptake, excretion, and whole-body retention of 65 4984 acutely ingested Zn in one healthy female subject (A) of age 31 y and three healthy male 4985 subjects (B, C, D) of ages 29, 45, and 48 y, respectively. Measurements for Subjects A-D 4986 were continued up to 431, 664, 416, and 579 d after intake, respectively. Excretion of 4987 absorbed activity was primarily in faeces. Whole-body retention in each subject could be 4988 represented as a sum of three exponential terms representing fast, intermediate, and slow 4989 turnover. Assuming the term with fast turnover (half-time <30 h) represented fecal excretion 4990 of unabsorbed activity, about 20% (range 16-27%) of absorbed activity was lost with a mean 4991 biological half-time of 16 d (4.5-26 d) and 80% (73-84%) was lost with a mean half-time of 4992 420 d (387-478 d). 65 4993 (391) Spencer et al. (1965) investigated the biokinetics of intravenously injected Zn in 19 4994 patients, at least 11 of whom had terminal cancers. Whole blood of a subject described as 4995 representative contained about 22% of the injected amount at 13 min, 11% at 1 h, 5% at 2 h, 4996 4% at 10 d, and 3% at 40 d. Measurements on three subjects indicate that 75-90% of the 4997 activity in total blood was contained in cellular components at 2-29 d after administration of 65 4998 Zn. The main pathway of excretion was via the gastrointestinal tract. In two subjects 4999 followed over 45 d, cumulative fecal and urinary excretion averaged 19.2% and 2.1%, 5000 respectively, of the administered amount. Urinary excretion of activity became extremely 5001 low after the first few days, while a small but nearly constant fraction was excreted daily in 5002 faeces for an extended period. Whole-body retention measurements made on each of two 5003 subjects for approximately 1 y could be closely approximated as a sum of two exponential 5004 terms representing fast and slow components of turnover. The biological half-times of the 5005 fast component, representing about one-fourth of the injected amount, were 13.1 and 11.8 d 5006 in the two subjects. The half-times of the slow components were 334 and 308 d, respectively. 5007 In tissue samples obtained at autopsy from 11 subjects dying from metastatic cancers at 1-71 65 5008 d after administration of Zn, the activity concentration was higher in the liver than other 5009 tissues over the entire period. The kidney showed the next highest concentration, averaging 5010 about half of that in liver, over the entire observation period. Relatively high concentrations 5011 were also seen in the pancreas, spleen, and adrenals over the early days or weeks after 65 5012 administration of Zn. The concentration in the liver at 71 d was still about one-fourth of that 65 5013 at 1 d. Concentrations of Zn in samples of bone and skeletal muscle were relatively low. 5014 The activity concentrations in samples from the vertebrae, ribs, and sternum were 5015 substantially higher than in samples from the femur of the same subject. 65 5016 (392) In a case of accidental inhalation of Zn, whole-body measurements indicated that 5017 27% of the inhaled activity was retained in the body with a half-time of 18 d and 73% was 5018 retained with a half-time of 453 d (Newton and Holmes, 1966). Similar half-times were 5019 estimated from time-dependent activity in faeces. A widespread distribution of activity with 5020 a relatively high concentration in the liver was apparent throughout the study. An estimated 65 5021 20-30% of the total daily excretion of Zn was in urine. 65 5022 (393) Hawkins et al. (1976) studied the biokinetics of orally administered Zn in nine 5023 subjects with skin diseases. The study was motivated by reported findings that some skin 5024 diseases respond dramatically to treatment with zinc, and that low plasma zinc concentrations 65 5025 are associated with some skin diseases. Whole blood and plasma concentrations of Zn were 5026 measured up to 192 d, and whole-body retention was measured externally up to 231 d. 65 5027 Whole-body retention measurements indicated that average absorption of Zn from the gut in 5028 these subjects exceeded 70%. Whole-body retention R(t) of absorbed activity as a function of

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5029 time t (days) in each subject could be represented reasonably well as a sum of two 5030 exponential terms: R(t) = A1exp(-0.693t/B1) + A2exp(-0.693t/B2), where the terms represent 5031 short- and long-term components of retention, respectively. The coefficients A1 and A2 5032 represented on average about 16% and 84% of the absorbed amount, respectively. The 5033 biological half-times B1 and B2 averaged about 23 d and 399 d, respectively. These results are 5034 reasonably consistent with findings of Richmond et al. (1962) for healthy subjects. A 5035 subgroup with venous leg ulcers showed a smaller component of long-term retention and a 5036 shorter long-term biological half-time than the other subjects. External measurements 65 5037 indicated a high concentration of Zn in the liver at early times. 5038 (394) Aamodt and coworkers (Aamodt et al., 1979; Foster et al., 1979) studied the short- 69m 5039 term biokinetics of orally or intravenously administered Zn (T1/2 = 13.8 h) in 17 subjects 5040 with taste or smell dysfunction. Activity was measured over the first five days in total body, 5041 urine, faeces, total blood, plasma, and RBC, and externally over the liver and thigh. The 5042 biokinetics of zinc did not appear to be affected by the mode of administration. Biological 5043 clearance from blood plasma as a function of time t (days) following intravenous 5044 administration was described as a four-exponential retention function, R(t) = 0.79exp(-176t) 5045 + 0.175exp(-73.4t) + 0.022exp(-5.87t)+0.013exp(-0.053t). The liver accumulated about 50% 5046 of the intravenously injected activity during the first 15 min and reached a peak content of 5047 about 60% at 2 h. Activity measured over the thigh increased with a doubling time of about 5048 5.7 d after both oral and intravenous injection. The rate of buildup in the thigh corresponded 5049 roughly to the rate of loss from the liver. Activity in RBC increased over the five-day 5050 observation period to 6.4% of the injected amount and 2.4% of the ingested amount. 5051 (395) Aamodt et al. (1982) studied the effects of oral zinc loading on the biokinetics of 5052 zinc in 50 patients with taste or smell dysfunction for up to 440 d following acute ingestion of 65 5053 Zn (T1/2 = 244 d). The study was conducted in three phases: (1) all patients were studied for 65 5054 21 days after oral intake of Zn as ZnCl2; (2) from 21 to 290-440 d (mean 336 d), all 50 5055 subjects received placebo for ZnSO4, which was later used for zinc loading; (3) over the next 5056 112-440 d (mean 307 d), 14 patients continued on placebo while 36 ingested high levels of -1 5057 stable zinc (100 mg d ) as ZnSO4. Prior to zinc loading, retention of absorbed zinc could be 5058 represented as a sum of two exponential terms with biological half-times of 18.2 d (32%) and 5059 380 d (68%). Retention during the second (placebo) phase was not significantly different for 5060 the 36 subjects subsequently treated with ZnSO4 and the 14 who were continued on placebo 5061 through the third phase of the study. Subjects receiving ZnSO4 during the third phase showed 65 65 5062 accelerated loss of Zn (half-time 235 +/- 8 days). Accelerated loss of Zn from the thigh, 5063 presumably representing mainly loss from muscle, was apparent immediately in these 36 5064 subjects. Accelerated loss from the liver began after a mean delay of 107 days. There was no 5065 apparent effect of zinc loading on loss of activity from RBC. 5066 (396) Wastney et al. (1986) studied zinc metabolism in 32 normal subjects after oral (n = 65 5067 25) or intravenous (n = 7) administration of Zn. Activity was measured in blood, urine, 5068 faeces, whole body, liver, and thigh over a nine-month period of normal intake of stable zinc -1 - 5069 (~10 mg d ) and an additional nine-month period with supplemental zinc intake of 100 mg d 1 5070 . Comparison of kinetic data derived during periods of normal and high intake of zinc 5071 suggested up to five sites of regulation of zinc concentrations in the body: absorption from 5072 the gut, endogenous secretion into the gut, urinary excretion, exchange between plasma and 5073 RBC, and release by muscle. 5074 (397) Wastney et al. (1992) assessed changes in zinc metabolism with age based on 65 5075 biokinetic studies of intravenously or orally administered Zn in 26 healthy men and 21 5076 healthy women in the age range 20-84 y. The studies covered a nine-month period in with 5077 dietary intake of stable zinc was approximately 10 mg/day, followed by a nine-month period

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5078 in which intake was approximately 110 mg/day. Zinc-65 kinetics was analyzed by 5079 compartmental analysis using measurements of zinc isotopes in plasma, red blood cells, 65 5080 urine, faeces, liver, thigh, and whole body. Significant changes with age in Zn kinetics 5081 were determined for urinary excretion, exchange between plasma and red blood cells, 5082 absorption, and endogenous secretion. 5083 (398) Miller et al. (1994) describe a four-compartment approximation of the model of 5084 Wastney et al. (1986). The simplified model consists of a plasma compartment and three 5085 satellite compartments representing fast, intermediate, and slow turnover of tissue zinc. The 5086 transfer coefficients from plasma to the fast, intermediate, and slow pools and to excretion -1 5087 pathways derived from the collective injection data are 85, 40, 4, and 2.4 d , respectively. 5088 Removal half-times from the fast, intermediate, and slow pools back to plasma based on the 5089 injection data are approximately 112 min, 18 h, and 108 d, respectively. The plasma 5090 clearance curve based on these parameter values closely approximates the curve determined 5091 in the study by Aamodt and coworkers (Aamodt et al., 1979; Foster et al., 1979) describe 5092 above. 5093 (399) Zinc metabolism and balance were studied in 11 healthy men with adequate or low 5094 levels of dietary zinc (Johnson et al., 1993). In terms of the mass of zinc excreted daily, 5095 urinary zinc decreased with decreasing zinc intake while surface losses, presumably 5096 representing mainly losses in sweat, were unaffected by the level of zinc in diet. On average, 5097 urinary losses represented 6-7% of dietary zinc during periods of adequate zinc intake and 5098 13-16% during periods of low intake. Fecal excretion represented about two-thirds of dietary 5099 zinc during periods of adequate dietary zinc and 39-48% in periods of low intake. Surface 5100 losses represented 4-6% of dietary intake during periods of adequate zinc intake and 12-36% 5101 during periods of low intake. The estimated surface losses during periods of adequate dietary 5102 zinc are reasonably consistent with results of a study by Jacobi et al. (1981) in which an effort 5103 was made to collect total-body sweat from 13 male subjects living in a controlled 5104 environment for several months. 5105 (400) Lowe et al. (1997) developed a model of the short-term biokinetics of zinc based on 5106 stable isotope studies on six healthy women of mean age 30 y. Oral and intravenous tracers 67 70 5107 enriched in Zn and Zn, respectively, were administered simultaneously following a seven- 5108 day zinc equilibration period involving a controlled diet. Plasma and urine samples were 5109 collected over the first 7 d and fecal samples over the first 11 d. A seven-compartment model 5110 was developed to describe the kinetics of both tracers as well as that of naturally occurring 5111 zinc. The model structure was used to derive the following central estimates from the 5112 measurements: fractional absorption from the gastrointestinal tract, 0.28; daily endogenous 5113 secretion, 2.8 mg; daily endogenous excretion, 2.0 mg; fractional turnover rate of the plasma -1 5114 pool, 131 d ; sizes of extravascular compartments representing fast and slow equilibration 5115 with plasma, 7.2 mg and 77 mg, respectively; fractional turnover rates of these rapidly and -1 -1 5116 slowly equilibrating pools, 22 d and 1.5 d , respectively; and size and turnover rate of an -1 5117 extravascular pool with very slow turnover, 1083 mg and 0.014 d , respectively. 5118 Extrapolation of model predictions to infinity based on average parameter values indicated 5119 that cumulative fecal and urinary excretion represented 97.3% and 2.7%, respectively, of the 5120 oral tracer and 91.4% and 8.6%, respectively, of the intravenous tracer. 5121 (401) King et al. (2001) used stable zinc tracers to compare the biokinetics of zinc in five 5122 men, ages 21-35 y, during normal zinc intake and following acute zinc depletion. The study 5123 was divided into two metabolic periods: a 16-d baseline period with dietary zinc of 12.2 mg -1 -1 5124 d and a 41-d depletion period with intake of 0.23 mg d . Stable isotope tracers of zinc were 5125 administered on days 6 or 7 of the baseline period and at the end of the depletion period (day 5126 35). Baseline kinetic data indicated average gastrointestinal absorption of about 26%, a

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-1 -1 5127 plasma zinc concentration of 0.71 µg ml , fecal excretion of 9.8 mg d (about 80% of dietary -1 5128 zinc), urinary excretion of 0.46 mg d (about 4% of dietary zinc), and total-body content of 5129 about 1600 mg. The modeled rate of transfer of zinc from plasma to other compartments was -1 5130 approximately 144 d . After zinc depletion, gastrointestinal absorption was virtually 5131 complete, plasma zinc fell on average by 65%, and fecal and urinary excretion fell by 96% 5132 and 74%, respectively. 5133 (402) Pinna et al. (2001) studied the effects of low dietary zinc (4.6 mg/d) on the mass of 5134 exchangeable zinc pools and its turnover time in seven healthy men confined during a 20-wk 5135 clinical study. The estimated mass of exchangeable zinc was maintained when dietary zinc 5136 was reduced to roughly one-third the recommended daily allowance over a 10-wk period. 5137 Data analysis based on a three-compartment model indicated that the masses of plasma zinc 5138 and total exchangeable zinc were 3.25 and 148 mg, respectively, over the different phases of 5139 the study. Plasma zinc turned over 5.3 times per hour on average. There was a modest 5140 reduction in plasma zinc at 3 wk after the start of the low zinc diet period, but plasma zinc 5141 returned to baseline values after 10 wk of zinc restriction. 5142 (403) The concentration of stable zinc in autopsy samples of ribs from Japanese subjects 5143 increased with age from early adulthood to age 60 y (Yoshinaga et al., 1989). There was no 5144 clear change with age after age 60 y. 5145 (404) Aitken (1976) measured the zinc content of trabecular and cortical bone from 16 5146 male and 12 female cadavers. The mean zinc to calcium ratio was 0.63 µg/mg for trabecular 5147 bone and 0.45 µg/mg for cortical bone. There was a significant increase with age in the zinc 5148 to calcium ratios of both trabecular and cortical bone. 5149 (405) Alhava et al. (1977) determined the concentration of zinc in cancellous bone of the 5150 iliac crest from 66 male and 28 female cadavers. The concentration was statistically related 5151 to age despite a large variability in subjects of nearly the same age. The concentration 5152 reached a maximum during the fifth decade of life in both men and women. Men who died 5153 suddenly had a higher concentration than those with a chronic disease. 5154 (406) Typical (reference) contents of zinc in the total body and specific tissues and fluids 5155 of adult humans are listed in Table 9-3. Concentrations in plasma and RBC are based on 5156 analyses of samples from living subjects (NAS, 1979; Wastney et al., 1991; Scott and 5157 Turnlund, 1994). The other listed concentrations are rounded values based on a review of 5158 reported measurements of zinc in tissues collected postmortem, in many cases from subjects 5159 who had apparently been in good health up to the time of sudden accidental death (Tipton and 5160 Cook, 1963; Tipton and Shafer, 1964; Tipton et al., 1965; Strehlow and Kneip, 1969; Soman 5161 et al., 1970; Forssén, 1972; Hamilton et al., 1972; McBean et al., 1972; Evenson and 5162 Anderson, 1975; Sumino et al., 1975; Zhu et al., 2010). Median concentrations determined 5163 by Tipton and coworkers (Tipton and Cook, 1963; Tipton et al., 1965) for soft tissues other 5164 than liver were judged to be typical of reported values and were used in Table 9-3. Central 5165 estimates for liver reported by Tipton and coworkers are lower than most reported values and 5166 were replaced by the median of reported values from 14 studies of the zinc concentration in 5167 adult human liver tissue (see Table 6 of Evenson and Anderson, 1975). The zinc 5168 concentration in bone listed in Table 9-3 is based on measurements reported by Tipton and 5169 Shafer (1964), Strehlow and Kneip (1969), and Aitken (1976), which together address zinc 5170 concentrations in bone tissue sampled from several skeletal sites. Conversions of 5171 concentrations to total contents were based on reference masses of tissues and fluids given in 5172 ICRP Publication 89 (2002). 5173 5174

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Table 9-3. Reference zinc contents in tissues and total-body of adult humans.

Sex-averaged Tissue contents (mg) distribution of stable zinc in the Concentration body (% per organ (μg/g) Adult male Adult female or tissue) Adipose tissue 3 55 67 3.0 Blood plasma 1 3 2.5 0.14 Bone 110 600 440 26 Brain 11 16 14 0.75 Gastrointestinal tract 20 23 22 1.14 Gonads 15 0.5 0.15 0.0164 Heart 30 10 7.5 0.44 Kidneys 50 16 14 0.75 Liver 70 130 100 5.8 Lung 14 7 6 0.33 Muscle 50 1450 870 58 Pancreas 28 4 3.5 0.19 Prostate 83 1.4 -- 0.035 Red blood cells 12 29 19 1.2 Skin 6 20 14 0.85 Spleen 18 3 2.5 0.14 Thyroid 30 0.6 0.5 0.028 Urinary bladder 24 1.2 1 0.055 Total-body zinc (mg) -- 2400 11600 2000 5175 5176 Animal studies 5177 (407) The biokinetics of zinc has been studied in different animal species following acute 5178 or chronic administration of zinc tracers. Although some species differences are indicated, 5179 the animal studies provide insights into aspects of the biokinetics of zinc not clearly defined 5180 by kinetic studies on humans such as its skeletal behavior. Species-specific biokinetic models 5181 for zinc have been developed from isotopic studies on rats (House et al., 1982; Dunn and 5182 Cousins, 1989; House and Wastney, 1997), mice (Wastney and House, 2008), and pigs 5183 (Serfass et al., 1996). 65 5184 (408) Following intravenous injection of Zn into mice, the highest activity concentration 5185 over the first 7 d was found in the pancreas followed by the liver and kidney (Sheline et al., 5186 1943). As much as 50% of the administered activity was eliminated in faeces during the first 5187 7 d. The rate of elimination in urine was substantially lower than that in faeces. 65 5188 (409) Following intravenous injection of Zn into dogs, about 25% of the administered 5189 activity was eliminated in faeces during the first two weeks (Montgomery et al., 1943). 5190 Substantially less was lost in urine. The liver contained about 38% of the administered 5191 amount at 3 h and about 3.5% at 7 d. A maximum of 0.4% of the administered activity 5192 appeared in bile in the first 8 d. As much as 11% of the injected amount was secreted in 5193 pancreatic juice in the first 14 d. Activity was also found in large amounts in the juices 5194 obtained from an isolated loop of the duodenum. 65 5195 (410) The concentration of Zn was measured in rat tissues over 42 d following 5196 intravenous injection (Wakeley et al., 1960). At 1 d after administration the highest 5197 concentration was found in pancreas followed by prostate and liver. Thereafter the 5198 concentration in prostate was at least twice that in any other tissue. Bone showed the next

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5199 highest concentration after the first week. Initial biological half-times for pancreas, liver, 5200 kidneys, and muscle were 0.8 d, 1.25 d, 1.7 d, and 40 d, respectively. 65 5201 (411) Ballou and Thompson (1961) investigated the biokinetics of Zn administered to 5202 rats by intravenous injection, acute oral intake, or chronic feeding. Following intravenous 5203 administration the highest activity concentrations were found in liver, kidneys, and pancreas 5204 at early times and in bone at late times. After chronic feeding for 200-400 d the highest 5205 concentrations were found in hair, bone, and prostate. The concentration did not reach steady 5206 state in these tissues during the feeding studies. 65 5207 (412) Taylor (1961) measured the retention of Zn in the femur, pelvis, and humerus of 5208 rats over a period of 630 d following its intravenous injection into 7-wk-old animals. 5209 Retention in each bone could be described as a single exponential function. The mean 65 5210 removal half-time was 738 d. Measurements of the specific activities of Zn in these three 65 5211 bones and in the ribs at 7 d after injection indicated that the Zn was distributed nearly 5212 uniformly throughout the zinc content of the skeleton. 5213 (413) Haumont (1961) used histochemical methods to examine the distribution of zinc in 5214 bones of young adult dogs and immature rats. High concentrations of zinc were found at 5215 sites undergoing calcification. Zinc was detected in the haversian systems of compact bone 5216 at the border line between calcified and uncalcified tissue, in the cartilaginous partitions of 5217 hypertrophic cells, and in endochondral bone recently deposited in the metaphysis. 65 5218 (414) Calhoun et al. (1970) observed a significantly increased uptake of Zn in healing 5219 bones of rats compared with control rats following its intravenous administration. Uptake of 65 5220 Zn at the injured site appeared to be correlated with bone formation. No statistically 85 45 5221 significant difference was found in the uptake of Sr or Ca in the injured bones and bones 5222 of control animals. 5223 (415) Bergman et al. (1972) examined the importance of zinc to cell proliferation in 5224 endochondral growth sites of bone in white rats using zinc-deficient feeding and 5225 autoradiography. The results of the study suggest that zinc is required in bone formation, 5226 especially in the synthesis of the organic matrix. 65 5227 (416) The time-dependent distribution and excretion of Zn was studied in rats following 5228 a single subcutaneous, intratracheal, or intraperitoneal administration (Khristov, 1970). The 5229 relative contents of tissues as a function of time were similar for all modes of administration. 5230 Highest initial activity concentrations were found in the pituitary, pancreas, and liver. At 25 d 5231 the highest concentrations were found in pituitary and bone. Excluding activity found at the 5232 injection site, total-body retention following subcutaneous injection was approximately 65% 5233 at 1 d, 44% at 10 d, and 37% at 25 d post injection. The liver, muscles, and bones contained, 5234 respectively, about 24%, 22%, and 32% of the retained activity at 1 d; 7%, 34%, and 31% at 5235 10 d; and 4%, 36%, and 52% at 25 d. 65 5236 (417) The uptake and distribution of Zn were measured in rams at 5, 10, and 20 d after 5237 single oral or intravenous injection and in pregnant ewes and a ram 2 wk after the start of 5238 daily feeding (McKenney et al., 1962). The liver and kidney cortex initially contained the 5239 highest concentrations of activity. After 20 d bone and muscle has substantially higher 5240 concentrations than the liver and kidney cortex. The relative concentrations in tissues at 20 d 5241 after single intake were independent of the route of administration. After daily feeding the 5242 highest concentrations were found in decreasing order in liver, kidney cortex, mammary 5243 tissue, pancreas, and spleen. 65 5244 (418) Richmond et al. (1962) measured uptake and retention of Zn after a single oral 65 65 5245 uptake of ZnCl2 by dogs, rats, and mice and after intravenous injection of Zn into rats and 5246 mice. Maximum observation periods were 137, 164, and 540 for mice, rats, and dogs, 5247 respectively. Fecal excretion represented the primary mode of elimination in all animals.

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5248 Detailed studies of the tissue distribution in rats indicated that rates of loss were similar for 5249 tissues other than bone and pelt, which retained zinc more tenaciously than other tissues. 5250 (419) Studies on weanling and 7-week-old mice were conducted to investigate whether 5251 bone serves as a reservoir of available zinc (Murray and Messer, 1981). The results indicated 5252 that availability of bone zinc depended on the rate of bone resorption but not on zinc status 5253 and that the skeleton does not serve as an available reservoir for zinc. Redeposition of zinc in 5254 the skeleton following resorption was extensive and independent of the rate of bone mineral 5255 deposition. In calcium deficiency there was an increased deposition of zinc, suggesting 5256 limited substitution of zinc for calcium in bone mineral. 65 5257 (420) Feaster et al. (1954) studied the behavior of Zn in steers over the first 6 d following 5258 acute oral or intravenous administration. Tissue concentrations at 6 d decreased in the order 5259 pancreas > liver > pituitary, kidneys, rib sternal end, adrenals > mandible > rib shaft, incisors 5260 > whole blood. Accumulation in different bones or portions of bone paralleled their 5261 metabolic activity, with highest accumulation in sites with highest blood flow and trabecular 5262 bone accumulating more zinc than cortical bone per gram of tissue. 65 5263 (421) At 7 and 14 d after intravenous injection of Zn into young horses the tissue 5264 concentrations decreased in the order liver > pancreas > spleen, kidney, heart, lung > rib, 5265 femur, skeletal muscle, skin > whole blood, adipose tissue, tibia, metatarsus (Schryver et al., 5266 1980). Tissue samples from the wall of the gastrointestinal tract contained higher 65 5267 concentrations of Zn than sampled contents of the tract. Addition of stable zinc to the diet 65 5268 increased the rate of elimination of Zn from the body. 5269 (422) House et al. (1982) studied zinc metabolism in male rats by combining nutritional 65 5270 balance methods with an analysis of Zn kinetics. Disappearance of zinc from plasma was 5271 described by a four-exponential retention function. Measurement of zinc in tissues at 5272 different times indicated that plasma zinc exchanged more rapidly with zinc in liver and 5273 kidneys than it did with zinc in testes, skeletal muscle, or bone. The total body zinc content 5274 was about nine times higher than estimates of exchangeable zinc in the body. 5275 (423) Lowe and coworkers (1991, 1993, 1995) found that intravenously injected zinc 5276 isotopes followed similar two-compartment kinetics in rats, dogs, and human subjects over 5277 the first few hours after administration. Investigation into the location of the two metabolic 5278 pools in the rat indicated that the smaller pool consisted mainly of plasma zinc and the larger 5279 pool resided largely within the liver. In normal human subjects the fractional turnover rate of 5280 the smaller pool was fivefold faster than that of the larger pool. 5281 (424) House and Wastney (1997) determined zinc kinetics in 15 tissues of rats and 5282 analyzed the data using modeling techniques. The study revealed the existence of slow and 5283 fast pools of zinc in muscle and bone. 5284 5285 9.2.3.2. Biokinetic model for systemic zinc 5286 5287 (425) The biokinetic model for systemic zinc is taken from a paper by Leggett (2012). The 5288 model structure is shown in Figure 9-1. Baseline transfer coefficients for workers are listed in 5289 Table 9-4. 5290 (426) The model includes three groups of tissues representing rapid (minutes to hours), 5291 intermediate (days), and slow (weeks to years) exchange with plasma, as indicated by a 5292 number of studies of the behavior of zinc tracers in human subjects. Rapid exchange occurs 5293 between plasma and liver, and between plasma and a soft-tissue compartment called ST0. 5294 The kidneys, pancreas, RBC, and a soft-tissue compartment called ST1 have intermediate 5295 rates of exchange with plasma. Also, part of the zinc entering the liver moves to a 5296 compartment called Liver 2 that returns zinc to plasma with a half-time of a few days.

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5297 Muscle, bone, and a soft-tissue compartment called ST2 exchange zinc slowly with plasma. 5298 Each of the soft-tissue compartments ST0, ST1, and ST2 is assumed to be uniformly 5299 distributed in “Other soft tissues”, which represents all soft tissues except liver, kidneys, 5300 pancreas, and muscle. 5301 (427) Bone is divided into four compartments: trabecular bone surface, trabecular bone 5302 volume, cortical bone surface, and cortical bone volume. Bone surface exchanges zinc slowly 5303 with plasma. A small portion (5%) of zinc depositing on bone surface transfers to bone 5304 volume, from which it is removed to plasma at the rate of bone remodeling, assumed to be -1 -1 5305 18% y for trabecular bone and 3% y for cortical bone (ICRP, 2002). 5306 (428) Systemic zinc is assumed to be removed from the body in faeces, urine, and surface 5307 loss representing mainly sweat. Urinary excretion is represented as a transfer from plasma to -1 5308 the urinary bladder contents followed by transfer to urine at the rate 12 d , the generic value 5309 for adults used in ICRP documents on environmental and occupational exposure (ICRP, 5310 1993). Surface loss is represented as a direct transfer from plasma to the environment. 5311 Endogenous fecal excretion of zinc is assumed to arise mainly (80%) from secretion into the 5312 gastrointestinal contents in pancreatic juice, represented as a transfer from pancreas to small 5313 intestine contents. The remaining endogenous fecal excretion is assumed to be equally 5314 divided between biliary secretion, represented as a transfer from liver to small intestine 5315 contents, and all other secretions into the alimentary tract combined, represented as a direct 5316 transfer from plasma to the small intestine contents. 5317 (429) All secretions into the alimentary tract are assumed to be subject to reabsorption to 5318 blood with the same fractional absorption as dietary zinc. Except where otherwise indicated, 5319 model predictions given in the following sections are based on absorption of 35% of zinc 5320 entering the small intestine contents. 5321 (430) Transfer coefficients between plasma and the liver, kidneys, pancreas, and RBC 5322 were set for consistency with observations of accumulation and loss of zinc tracers by these 5323 tissues in tracer studies on human subjects (Siegel et al., 1961; Spencer et al., 1965; Aamodt 5324 et al., 1979, 1982; Wastney et al., 1986). Transfer coefficients between plasma and other 5325 compartments (excluding the generic removal rates from bone volume to plasma, which 5326 represent bone turnover rates) were set for reasonable consistency with results of tracer data 5327 where available; the typical distribution of stable zinc in adult humans as estimated in Table 5328 9-3, assuming long-term ingestion of zinc at a constant rate; and data for laboratory animals 5329 where needed to fill gaps in the database for human subjects. 5330 (431) The total rate of loss of zinc from the body along all excretion pathways combined 65 5331 was set for consistency with observations of whole-body retention of Zn in human subjects 5332 following acute uptake to blood (Richmond et al., 1962; Spencer et al., 1965; Hawkins et al., 5333 1976; Aamodt et al., 1982). Transfer coefficients describing removal of zinc in faeces, urine, 5334 and surface loss were set so that these pathways account for about 80%, 10%, and 10% of 5335 total endogenous excretion of zinc, assuming that 35% of endogenous secretion of zinc into 5336 the gastrointestinal tract is reabsorbed to blood. The relative quantities of zinc predicted by 5337 the model to be excreted in faeces, urine, and surface loss vary to some extent with the 5338 assigned gastrointestinal absorption fraction because this affects the level of reabsorption of 5339 secreted zinc to blood and hence the amount available for excretion along each pathway. 5340 5341

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5342 5343 Figure 9-1. Structure of the biokinetic model for systemic zinc. RBC = red blood cells; SI = small 5344 intestine; ST0, ST1, and ST2 represent fast, intermediate, and slow turnover, respectively, in soft 5345 tissues other than muscle, liver, kidneys, and pancreas. 5346 5347 5348 5349

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Table 9-4. Transfer coefficients in the biokinetic model for zinc.

From To Transfer coefficient (d-1) Plasma Liver 1 60 Plasma Kidneys 4 Plasma Pancreas 3 Plasma Muscle 2 Plasma RBC 1.5 Plasma ST0 40 Plasma ST1 30 Plasma ST2 0.4 Plasma Urinary bladder contents 0.13 Plasma Excreta 0.13 Plasma Small intestine contents 0.2 Plasma Trabecular bone surface 0.15 Plasma Cortical bone surface 0.3 Liver 1 Plasma 10 Liver 1 Small intestine contents 0.067 Liver 1 Liver 2 10 Liver 2 Plasma 0.6 Kidneys Plasma 0.7 Pancreas Plasma 1.5 Pancreas Small intestine contents 1.0 Muscle Plasma 0.005 RBC Plasma 0.14 ST0 Plasma 10 ST1 Plasma 3 ST2 Plasma 0.01 Trabecular bone surface Plasma 0.01 Cortical bone surface Plasma 0.01 Trabecular bone surface Trabecular bone volume 0.00053 Cortical bone surface Cortical bone volume 0.00053 Trabecular bone volume Plasma 0.000493 Cortical bone volume Plasma 0.0000821 5350 5351 9.2.3.3. Treatment of radioactive progeny 5352 5353 (432) Three isotopes of zinc addressed in this report have progeny that are considered in 69m 5354 the derivation of dose coefficients for the parent radionuclide: Zn (T1/2 = 13.8 h) decays to 69 62 62 72 72 5355 Zn (56.4 m), Zn (9.19 h) decays to Cu (9.67 m), and Zn (46.5 h) decays to Ga (14.1 5356 h). Zinc-69 presumably behaves the same as the parent radionuclide from the time it is 62 5357 produced in the body. -62 produced by decay of Zn is assumed to decay at its site of 5358 production. 5359 (433) The systemic model for gallium as a daughter of zinc was based on observations of 5360 the behavior of gallium in human subjects (Nelson et al., 1972; MIRD, 1973; ICRP, 1981; 5361 Priest et al., 1995; Bernstein, 1998), particularly autopsy data for patients administered radio- 5362 gallium during terminal illness (Nelson et al., 1972; MIRD, 1973) and results of a biokinetic 67 5363 study of intravenously administered Ga in a healthy adult (Priest et al., 1995). The model 5364 includes compartments representing blood, liver, kidneys, spleen, pancreas, muscle, 5365 trabecular bone surface, trabecular bone marrow, cortical bone surface, and cortical bone 5366 marrow, and two compartments representing other soft tissue. Gallium is assumed to leave

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-1 5367 blood at the rate 5 d , with 20% depositing on bone surface, 10% in marrow, 6% in liver, 8% 5368 in kidneys, 4% in muscle, 1% in spleen, 0.1% in pancreas, 3% in right colon contents, 10% in 5369 a soft tissue compartment with relatively slow transfer back to blood (half-time of 1 y), and 5370 the remainder (37.9%) in a soft tissue compartment with relatively fast transfer back to blood 5371 (half-time of 0.5 d). The bone and marrow deposits are assumed to be equally divided 5372 between trabecular and cortical bone. Gallium is removed from liver, spleen, pancreas, and 5373 muscle to blood with a half-time of 5 d; from kidneys to urinary bladder contents with a half- 5374 time of 0.5 d; and from bone surface and marrow to blood with a half-time of 2 d. Blood in 5375 the gallium model is identified with the plasma compartment of the zinc model. Gallium 5376 produced in compartments of the systemic model for zinc (Figure 9-1) other than plasma are 5377 assumed to be transferred to the blood compartment of the gallium model with the following 5378 half-times: 1 min for RBC, 5 d for liver compartments, spleen, pancreas and muscle; 0.5 d 5379 for kidneys and compartments of other soft tissue; 2 d for bone surface and marrow 5380 compartments; and the bone turnover half-time for bone volume compartments. 5381 5382 9.3. Individual monitoring 5383 65 65 5384 (434) Zn is a γ emitter. Monitoring of Zn is in general accomplished through Whole 5385 Body Counting or/and urine bioassays. 5386 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 65Zn Urine Bioassay γ-ray spectrometry 1 Bq/L 0.1 Bq/L 65Zn Whole Body γ-ray spectrometry 80 Bq 20 Bq Counting 5387 5388 References 5389 5390 Aamodt, R.L., Rumble, W.F., Babcock, A.K., Foster, D.M., Henkin, R.I., 1982. Effects of oral zinc 5391 loading on zinc metabolism in humans - I: Experimental studies. Metabolism 31, 326-334. 5392 Aamodt, R.L., Rumble, W.F., Johnston, G.S., Foster, D., Henkin, R.I., 1979. Zinc metabolism in 5393 humans after oral and intravenous administration of Zn-69m. Amer. J. Clin. Nutr. 32, 559-569. 5394 Aamodt, R., Rumble, W., Johnston, G., Marley, E., Henkin, R., 1981. Absorption of orally 5395 administered zinc-65 by normal human subjects. Amer. J. Clinical Nutrition. 34, 2648-2652. 5396 Aitken, J.M., 1976. Factors affecting the distribution of zinc in the human skeleton. Calcif. Tiss. Res. 5397 20, 23-30. 5398 Alhavah, E.M., Olkkonen, H., Puittinen, J., Nokso-Koivisto, V.M., 1977. Zinc content of human 5399 cancellous bone. Acta Orthop. Scand. 48, 1-4. 5400 Andrasi, A., Feher, I., 1967. Measurement of the retention and excretion of incorporated 65Zn. Health 5401 Phys. 13, 915–916. 5402 Anke, M., Groppel, B., Krause, U., Arnhold, W., Langer, M., 1991. Trace element intake (zinc, 5403 manganese, copper, molybdenum, and nickel) of humans in Thuringia and Brandenburg 5404 of the Federal Republic of Germany. J. Trace Elem. Electrolytes Health Dis. 5, 69-74. 5405 Ballou, J.E., Thompson, R.C., 1961. Consideration of permissible exposure limits. Health Phys. 6, 6- 5406 18. 5407 Becker, W., Kumpulainen, J., 1991. Contents of essential and toxic mineral elements in Swedish 5408 market-basket diets in 1987. Br. J. Nutr. 66, 151-60. 5409 Bergman, B., Friberg, U., Lohmander, S., Sberg, T., 1972. The importance of zinc to cell 5410 proliferation in endochondral growth sites in the white rat. Scand. J. Dent. Res. 80, 486-492. 5411 Bernstein, L.R., 1998. Mechanisms of therapeutic activity for gallium. Pharmacological Reviews 50,

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5412 665-682. 5413 Bragt, P.C., van Dura, E.A., 1983. Toxicokinetics of hexavalent chromium in the rat after 5414 intratracheal administration of chromates of different solubilities. Ann. Occup. Hyg., 27, 315– 5415 322. 5416 Bro, S., Sandstrom, B., Heydorn, K., 1990. Intake of essential and toxic trace elements in a random 5417 sample of Danish men as determined by the duplicate portion sampling technique. J. Trace 5418 Elem. Electrolytes Health Dis. 4, 147-55. 5419 Buchet, J.P., Lauwerys, R., Vandevoorde, A., Pycke, J.M., 1983. Oral daily intake of , , 5420 manganese, copper, chromium, , calcium, zinc and in Belgium: a duplicate 5421 meal study. Food Chem. Toxicol. 21, 19-24. 5422 Calhoun, N.R., Campbell, S., Smith, J.C., 1970. Accumulation of labeled zinc, strontium, and calcium 5423 in bone injuries. J. Dent. Res. 49, 1083-1085. 5424 Collier, C.G., Stradling, G.N., Foster, P.P., Hodgson, A., 1994. The biokinetics of corrosion products 5425 from a water cooled reactor after deposition in the rat lung. Radiat. Prot. Dosim., 53, 173– 5426 177. 5427 Conacher, H.B.S., 2003. Canadian Total Diet Study, 1993-1996. Food Research Division, Bureau of 5428 Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, 5429 Ontario K1A 0L2. http://www.hc-sc.gc.ca/food-aliment/cs-ipc/fr-ra/e_tds.html; 2003. 5430 Dunn, M.A., Cousins, R.J., 1989. Kinetics of zinc metabolism in the rat: effect of dibutyryl cAMP. 5431 Am. J. Physiol. 256, E420–E430. 5432 Elinder, C.-G., Kjellström, T., Linnman, L., Pershagen, G., 1978. Urinary excretion of cadmium and 5433 zinc among persons from Sweden. Environ. Res. 15, 473-484. 5434 Evans G.W., Johnson, P.E., 1980. Characterization and quantitation of a zinc-binding ligand in human 5435 milk. Pediatr. Res. 14, 876-880. 5436 Evenson, M.A., Anderson, C.T., 1975. Ultramicro analysis for copper, cadmium, and zinc in human 5437 liver tissue by use of atomic absorption spectrophotometry and the heated graphite tube 5438 atomizer. Clin. Chem. 21, 537-543. 5439 Feaster, J.P., Hansard, S.L., McCall, J.T., Skipper, F.H., Davis, G.K., 1954. Absorption and Tissue 5440 Distribution of radiozinc in steers fed high-zinc rations. J. Anim. Sci. 13, 781-788. 5441 Forssén, A., 1972. Inorganic elements in the human body. Occurrence of Ba, Br, Ca, Cd, Cs, Cu, K, 5442 Mn, Ni, Sn, Sr, Y, and Zn in the human body. Ann. Med. Exp. Biol. Fenn. 50, 99-162. 5443 Foster, D.M., Aamodt, R.L., Henkin, R.I., Berman, M., 1979. Zinc metabolism in humans: A kinetic 5444 model. Am. J. Physiol. 237, R340–349. 5445 Hambidge, K.M., Krebs, N.F., Miller, L., 1998. Evaluation of zinc metabolism with use of stable- 5446 isotope techniques: implications for the assessment of zinc status. Am. J. Clin. Nutr. 68 (Suppl), 5447 410S-413S. 5448 Hamilton, E.I., Minski, M.J., Cleary, J.J., 1972. The concentration and distribution of some stable 5449 element in healthy human tissues from the United Kingdom, an environmental study. Sci. Total 5450 Environ. 1, 341-374. 5451 Haumont, S., 1961. Distribution of zinc in bone tissue. J. Histochem. Cytochem. 9, 141-145. 5452 Hawkins, T., Marks, J.M., Plummser, U.M., Greaves, M.W., 1976. Whole-body monitoring and 5453 other studies of zinc-65 metabolism in patients with dermatological disease. Clin. Exp. 5454 Dermatol. 1, 243-252. 5455 Hirano, S., Higo, S., Tsukamoto, N., Kobayashi, E., Suzuki, K.T., 1989. Pulmonary clearance and 5456 toxicity of zinc oxide instilled into the rat lung, Arch. Toxicol., 63, 336–342. 5457 House, W.A., Wastney, M.E., 1997. Compartmental analysis of zinc kinetics in mature male rats. Am. 5458 J. Physiol. 273, R1117–R1125. 5459 House, W.A., Welch, R.M., Van Campen, D.R., 1982. Effect of phytic acid on the absorption, 5460 distribution, and endogenous excretion of zinc in rats. J. Nutr. 112, 941-953. 5461 Hunt, C.D., Meacham, S.L., 2001. Aluminum, , calcium, copper, iron, magnesium, manganese, 5462 molybdenum, phosphorus, potassium, sodium, and zinc: concentrations in common western 5463 foods and estimated daily intakes by infants, toddlers, male and female adolescents, adults, and 5464 seniors in the United States. J. Am. Diet. Assoc. 101, 1058-1060.

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5465 ICRP, 1975. Report of the Task Group on Reference Man, ICRP Publication 23. Pergamon Press, 5466 Oxford. 5467 ICRP, 1980. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Pt.2. Ann. ICRP 5468 4, (3/4). 5469 ICRP, 1981. Limits for intakes of radionuclides by workers, ICRP Publication 30, Annals of the 5470 ICRP, Vol. 6 (2/3), Oxford Pergamon Press. 5471 ICRP, 1993. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 2, 5472 Ingestion dose coeffcients . ICRP Publication 67. Ann. ICRP 23, (3/4). 5473 ICRP, 2002. Basic anatomical and physiological data for use in radiological protection: Reference 5474 values, ICRP Publication 89, Annals of the ICRP, Vol. 32, Nos. 3-4. Pergamon Press, Oxford. 5475 Istfan, N., Janghorbani, M., Young, V., 1983. Absorption of stable zinc-70 in healthy young men in 5476 relation to zinc intake. Amer. J. Clinical Nutrition. 38, 187-194. 5477 Iyengar, G.V., Wolf, W.R., Tanner, J.T., Morris, E.R., 2000. Content of minor and trace elements, and 5478 organic nutrients in representative mixed total diet composites from the USA. Sci. Total 5479 Environ. 256, 215-226. 5480 Jacob, R.A., Sandstead, H.H., Munoz, J.M., Klevay, L.M., Milne, D.B., 1981. Whole body surface 5481 loss of trace metals in normal males. Am. J. Clin. Nutr. 34, 1379-1383. 5482 Jaiswal, D.D., Dang, H.S., Nair, S., Sharma, R.C., 2002. Validating the analytical methodologies for 5483 determining some important trace elements in food consumed in India. Food Nutr Bull. 23(3 5484 Suppl), 185-190. 5485 Johnson, P.E., Hunt, C.D., Milne, D.B., Mull, L.K., 1993. Homeostatic control of zinc metabolism in 5486 men: zinc excretion and balance in men fed diets low in zinc. Amer. J. Clin. Nutr. 57, 557-565. 5487 Khristov, Kh. D., 1970. Behavior of zinc-65 in the rat body. In: Letavet, A. A.; Kurlyandskaya, E. B., 5488 eds. The toxicology of radioactive substances. Translation edited by G. W. Dolphin. Oxford: 5489 Pergamon Press; pp. 12-19. 5490 King, J.C., Shames, D.M., Lowe, N.M., Woodhouse, L.R., Sutherland, B., Abrams, S.A., Turnlund, 5491 J.R., Jackson, M. J., 2001. Effect of acute zinc depletion on zinc homeostasis and plasma zinc 5492 kinetics in men. Am. J. Clin. Nutr. 74, 116–124. 5493 Krebs, N.F., Hambidge, K.M., 2001. Zinc metabolism and homeostasis: The application of tracer 5494 techniques to human zinc physiology. BioMetals 14, 397-412. 5495 Leggett, R. W., 2012. A biokinetic model for zinc for use in radiation protection. Sci. Total Environ. 5496 420, 1-12. 5497 Lowe, N.M., Bremmer, I., Jackson, M.J., 1991. Plasma 65Zn kinetics in the rat. Brit. J. Nutr. 65:445- 5498 455. 5499 Lowe, N. M.; Fekete, K.; Decsi, T. (2009). Methods of assessment of zinc status in humans: A 5500 systematic review. Am. J. Clin. Nutr. 89(Suppl), 2040S–2051S. 5501 Lowe, N.M., Hall, E.J., Anderson, R.S., Batt, R.M., Jackson, M.J., 1995. A stable isotope study of 5502 zinc kinetis in Irish setters with gluten-sensitive enteropathy. Brit. J. Nutr. 74, 69-76. 5503 Lowe, N.M., Shames, D.M., Woodhouse, L.R., Matel, J.S., Roehl, R., Saccomani, M.P., Toffolo, G., 5504 Cobelli, C., King, J.C., 1997. A compartmental model of zinc metabolism in healthy women 5505 using oral and intravenous stable isotope tracers. Am. J. Clin. Nutr. 65, 1810-1819. 5506 Lowe, N.M., Green, A., Rhodes, J.M., Lombard, M., Jalan, R., Jackson, M.J., 1993. Studies of human 5507 zinc kinetics using the stable isotope 70Zn. Clin. Sci. 84, 113-117. 5508 McBean, L.D., Dove, J.T., Halsted, J.A., Smith, J.C., 1972. Zinc concentration in human tissues. Am. 5509 J. Clin. Nutr. 25, 672-676. 5510 McClain, C.J., 1990. The pancreas and zinc homeostasis. J. Lab. Clin. Med. 116, 275-276. 5511 McKenney, J.R., McClellan, R.O., Bustad, L.K., 1962. Early uptake and dosimetry of 65Zn in sheep. 5512 Health Phys. 8, 411-421. 5513 Miller, L.V., Hambidge, K.M., Naake, V.L., Hong, Z., Westcott, J.L., Fennessey, P.V., 1994. Size of 5514 the zinc pools that exchange rapidly with plasma zinc in humans: Alternative techniques for 5515 measuring and relation to dietary zinc intake J. Nutr. 124, 268-276. 5516 Mills, P., Fell, G., Bessent, R., Nelson, L., Russell, R., 1983. A study of zinc metabolism in alcoholic 5517 cirrhosis. Clinical Science. 64, 527-535.

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5518 MIRD, 1973. Summary of current radiation dose estimates to humans from 66Ga, 67Ga, 68Ga, and 72Ga 5519 citrate. J Nucl. Med. 14,755-756. 5520 Molokhia, M., Sturniolo, G., Shields, R., Turnlund, L., 1980. A simple method for measuring zinc 5521 absorption in man using a short lived isotope. Amer. J. Clinical Nutrition, 881-886. 5522 Montgomery, M.L., Sheline, G.E., Chaikoff, I.L., 1943. The elimination of administered zinc in 5523 pancreatic juice, duodenal juice, and bile of the dog as measured by its radioactive isotope. J. 5524 Exptl. Med. 78, 151-159. 5525 Morrow, P.E., Gibb, F.R., Davis, H., Fisher, M., 1968. Dust removal from the lung parenchyma: an 5526 investigation of clearance stimulants. Tox. Applied. Pharm., 12, 372–396. 5527 Murray, E.J., Messer, H.M., 1981. Turnover of bone zinc during normal and accelerated bone loss in 5528 rats. J. Nutr. 111, 1641-1647. 5529 NAS, 1979. Zinc. National Academy of Sciences, National Research Council, Committee on Medical 5530 and Biological Effects of Environmental Pollutants, Subcommittee on Zinc. University Park 5531 Press, Baltimore. 5532 Nelson, B., Hayes, R.L., Edwards, C.L., Kniseley, R.M., Andrews, G.A., 1972. Distribution of 5533 gallium in human tissues after intravenous administration. J. Nucl. Med. 13, 92-100. 5534 Newton, D., Holmes, A., 1966. A case of accidental inhalation of zinc-65 and -110m. Radiat. 5535 Res. 29, 403-412. 5536 Noel, L., Leblanc, J.C., Guerin, T., 2003. Determination of several elements in duplicate meals from 5537 catering establishments using closed vessel microwave digestion with inductively coupled 5538 plasma mass spectrometry detection: estimation of daily dietary intake. Food Addit. Contam. 5539 20, 44-56. 5540 Oberdörster, G., Hochrainer, D., Ma, R.H., 1979. Zinc oxide aerosols: generation, lung clearance and 5541 effects on lung clearance. In: Aerosols in Science, Medicine and Technology – the Biomedical 5542 Influence of the Aerosol, Gesellschaft für Aerosolforschung, 7, 132–137. 5543 Pinna, K., Woodhouse, L.R., Sutherland, B., Shames, D.M., King, J.C., 2001. Exchangeable zinc pool 5544 masses and turnover are maintained in healthy men with low zinc intakes. J. Nutr. 131, 2288– 5545 2294. 5546 Priest, N.D., Newton, D., Day, J.P., Talbot, R.J., Warner, A.J., 1995. Human metabolism of 5547 aluminum-26 and gallium-67 injected as citrates. Hum. Exp. Toxicol. 14, 287-293. 5548 Richmond, C.R., Furchner, J.E., Trafton, G.A., Langham, W.H., 1962. Comparative metabolism of 5549 radionuclides in mammals – I. Uptake and retention of orally administered 65Zn by four 5550 mammalian species. Health Phys. 8, 481-489. 5551 Rosaminth, J., Breining, H., 1974. Die Retention und Elimination von Zink nach wiederholter 5552 intratrachealer Applikation von Zinkoxid bei Ratten. Staub-Reinhalt. Luft. 34, 266–270. 5553 Sandstrom, B., Cederblad, A., 1980. Zinc absorption from composite meals: influence of the main 5554 protein source. Amer. J. Nutrition. 33, 1778-1783. 5555 Schryver, H.F., Hintz, H.F., Lowe, J.E., 1980. Absorption, excretion and tissue distribution of stable 5556 zinc and 65Zn in ponies. J. Anim. Sci. 51, 896-902. 5557 Schuhmacher, M., Domingo, J.L., Corbella, J., 1994. Zinc and copper levels in serum and urine: 5558 relationship to biological, habitual and environmental factors. Sci. Total Environ. 148, 67-72. 5559 Scott, K.C., Turnlund, J.R., 1994. A compartmental model of zinc metabolism in adult men used to 5560 study effects of three levels of dietary copper. Amer. J. Physiol. 267, E165-E173. 5561 Sedlet, J., Fairman, W.D., 1970. Elimination of radioactive cobalt following acute accidental 5562 inhalation. IN Proceedings of the Second IRPA Congress, Brighton 3–8 May 1970. pp. 1205– 5563 1213. Pergamon Press. 5564 Serfass, R.E., Fang, Y., Wastney, M.E., 1996. Zinc kinetics in weaned piglets fed marginal zinc 5565 intake: Compartmental analysis of stable isotopic data. J. Trace Elem. Exp. Med.9, 73-86. 5566 Sheline, G.E., Chaikoff, I.L., Jones, H.B., Montgomery, M.L., 1943. Studies on the metabolism of 5567 zinc with the aid of its radioactive isotope. II. The distribution of administered radioactive zinc 5568 in the tissues of mice and dogs. J. Biol. Chem. 149, 139-151. 5569 Siegel, E., Graig, F.A., Crystal, M.M., Siegel, E.P., 1961. Distribution of 65Zn in the prostate and 5570 other organs of man. Brit. J. Cancer 15, 647-664.

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5624 2000. 1997 UK Total Diet Study--dietary exposures to aluminum, arsenic, cadmium, 5625 chromium, copper, lead, mercury, nickel, , tin and zinc. Food Addit. Contam. 17, 775- 5626 786. 5627 Zhu, H., Wang, N., Zhang, Y., Wu, Q., Chen, R., Gao, J., Chang, P., Liu, Q., Fan, T., Li, J. Wang, J. 5628 2010. Element contents in organs and tissues of Chinese adult men. Health Phys. 98, 61-73. 5629 5630

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5631 10. STRONTIUM (Z = 38) 5632 5633 10.1. Chemical Forms in the Workplace 5634 5635 (435) Strontium is an alkaline earth element, which mainly occurs in oxidation state II. It 5636 is a chemical analogue of calcium. A variety of chemical and physical forms are encountered 85 89 5637 in industry including, chlorides, sulphates, carbonates and titanate (SrTiO3). Sr, Sr and 90 5638 Sr are the three main fission products which may be encountered in the nuclear industry. 5639 Strontium can also be present in fragments of irradiated fuels. 5640 5641 Table 10-1. addressed in this report 5642 Isotope Physical half-life Decay mode Sr-80 106.3 m EC, B+ Sr-81 22.3 m EC, B+ Sr-82 25.36 d EC Sr-83 32.41 h EC, B+ Sr-85a 64.84 d EC Sr-85m 67.63 m IT, EC, B+ Sr-87m 2.815 h IT, EC Sr-89a 50.53 d B- Sr-90a 28.79 y B- Sr-91 9.63 h B- Sr-92 2.66 h B- 5643 a Data for these radionuclides are given in the printed copy of this report. Data for 5644 other radionuclides are given on accompanying electronic disk. 5645 5646 10.2. Routes of Intake 5647 5648 10.2.1. Inhalation 5649 5650 Absorption Types and parameter values 5651 (436) Some information is available on the behaviour of inhaled strontium in man 5652 following accidental intakes of several compounds. Information is available from 5653 experimental studies of strontium as chloride, sulphate, titanate, irradiated fuel fragments, or 5654 in fused aluminosilicate particles (FAP). 5655 (437) Absorption parameter values and Types, and associated fA values for particulate 5656 forms of strontium are given in Table 10-2. 5657 5658 Strontium chloride (SrCl2) 90 5659 (438) Petkau and Pleskach (1972) measured urinary and fecal excretion of Sr for 800 5660 days after a worker’s presumed accidental inhalation of strontium chloride, 13 days before 5661 the first measurement. The lack of information about the intake, or of measurements during 5662 the first week or so after it, limits the conclusions that can be drawn about absorption of the 5663 material. The results of measurements made during the first few months suggest that a large 5664 fraction (>0.5) was readily soluble, but the later data suggest continuing transfer from the –1 5665 lungs, and hence a low (<0.001 d ) slow dissolution rate. 5666 (439) Animal experiments have shown that following administration of strontium chloride, 5667 most of the strontium is rapidly cleared from the respiratory tract. It was reported that at 12 85 85 5668 hours after inhalation of SrCl2 by dogs, the Sr remaining in the lungs was less than 1% of

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85 5669 the total Sr in the body (McClellan and Rupprecht, 1967, McClellan et al., 1972), giving fr –1 5670 ~1. It was calculated by the task group that sr was greater than 8 d . However, it was also 85 5671 noted that a large amount of Sr was excreted in faeces in the first few days post exposure, 5672 apparently as a result of clearance from the upper respiratory tract, ingestion and only partial 5673 gastrointestinal absorption. This shows that in the upper airways the rate of absorption to –1 5674 blood is probably less than the rate of particle transport to the gut (~100 d ). Morrow et al. 85 5675 (1968) measured a lung retention half time of 0.02 d following inhalation of SrCl2 by dogs, –1 85 5676 giving sr = 35 d . Naményi et al. (1986) followed the biokinetics of Sr for 45 days after 85 5677 intratracheal instillation of SrCl2 into rats. Lung retention in healthy control rats was 3.9% –1 5678 of the initial lung deposit (ILD) at 3 hours, from which it was calculated here that sr = 26 d , 85 5679 and about 0.3% ILD at 24 hours. Cuddihy and Ozog (1973) deposited SrCl2 directly onto 5680 the nasal membranes of Syrian hamsters. From the results it was calculated here that fr = 1 –1 5681 and sr = 8 d . This is somewhat slower than in the other strontium chloride experiments, 5682 possibly because of the techniques used, including the anaesthetic, or that clearance from the 5683 nasal passage was slower than from the lungs. Similar observations were made for caesium 5684 and barium chlorides which were also administered by Cuddihy and Ozog (see caesium and 5685 barium inhalation sections). 5686 (440) Based on the results of the experiments outlined above, specific absorption -1 5687 parameter values for strontium chloride were estimated here to be: fr = 1 and sr = 30 d 5688 (consistent with assignment to default Type F). However, although specific parameter values 5689 for strontium chloride based on in vivo data are available, they are not adopted here, because 5690 inhalation exposure to it is so unlikely. Instead, strontium chloride is assigned to Type F. 5691 However, the data are used as the basis for the default rapid dissolution rate for strontium. 5692 Hence specific parameter values for strontium chloride would be the same as default Type F 5693 strontium parameter values. 5694 5695 Strontium sulphate (SrSO4) 90 5696 (441) Following inhalation of SrSO4 by mice and dogs most of the strontium was rapidly 5697 cleared from the lungs, indicating Type F behaviour (Bair, 1961). 5698 5699 Strontium carbonate (SrCO3) 90 5700 (442) Measurements following accidental inhalation by man of SrCO3 indicate Type F 5701 behaviour (Rundo and Williams, 1961). 5702 5703 Strontium titanate (SrTiO3) 5704 (443) Strontium titanate was shown to be tenaciously retained in the human lungs (Fish et 5705 al., 1967) and was assigned to Class Y in ICRP Publication 30. In vitro dissolution tests 90 5706 performed with various forms of SrTiO3 from high-level radioactive waste facilities 5707 (Anderson et al., 1999) showed that at 181 days, 97% of the strontium remained undissolved, 5708 giving assignment to Type S. Absorption parameter values calculated here were fr = 0.009, sr –1 –1 5709 = 0.7 d , and ss = 0.00012 d . In a parallel in vivo study, the biokinetics of strontium and 5710 titanium were followed for 30 days after intratracheal instillation of stable SrTiO3 in rats. 5711 Uptake of strontium by the skeleton was below the detection limit. Lung retention showed a 5712 slow component, accounting for 15% of the instilled material, with a half time of 133 days. It 5713 was assessed that 85% of the material deposited in the AI region was retained at 30 d, 5714 indicating Type S behaviour. A case of accidental inhalation from a source containing 90 5715 SrTiO3 was well fitted with the ICRP Publication 30 strontium model and led the authors to 5716 the assumption of a 10-µm AMAD and the assignment of this compound to inhalation Class 5717 Y (Navarro and Lopez, 1998). Studies on ingested strontium titanate on rats (see below)

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5718 suggest fA ~0.01. Since specific lung absorption parameter values are available only from in 5719 vitro tests, default Type S absorption parameter values and a specific value of fA =0.01 are 5720 used here for strontium titanate. 5721 5722 Irradiated fuel fragments 5723 (444) Measurements following the accidental inhalation of a mixture of fresh fission 5724 products, indicate Type M behaviour of the strontium present (Johnson et al., 1983). Results 5725 of an in vitro study on airborne fission products from the Three Mile Island reactor accident 5726 are consistent with assignment to Type F (Kanapilly et al., 1980). An in vitro study on 5727 aerosols generated during transfer, cutting, storage and shipment of nuclear reactor fuel (Dua –1 –1 5728 et al., 1987) gave absorption parameters fr = 0.4, sr = 0.57 d and ss = 0.0045 d , consistent 5729 with assignment of the strontium present to Type M. 5730 5731 Fused aluminosilicate particles (FAP) 5732 (445) FAP or “fused clay” particles have been extensively used as relatively insoluble 5733 particles in inhalation studies, both of biokinetics and of radiation effects. A natural clay 5734 mineral is labelled by ion exchange, and the labelled clay particles heated to about 1100˚C, to 5735 form aluminosilicate glass microspheres in which the label is incorporated. It has been 5736 demonstrated that when strontium is incorporated into FAP, only a small fraction may be 5737 rapidly absorbed, while the remainder is retained within the particles and absorbed slowly. –1 5738 Estimates of the rate of dissolution of Sr-FAP were in the range 0.0005 – 0.002 d (Snipes et 5739 al., 1972; Kanapilly and Goh, 1973; Bailey et al., 1985a,b), and indicate Type S behaviour. 5740 5741 Polystyrene (PSL) 5742 (446) As with FAP, it has been demonstrated that when strontium is incorporated into a 5743 polystyrene matrix, only a small fraction may be absorbed rapidly, while the rest is retained 85 5744 within the particles and is absorbed slowly. Bohning et al. (1982) used Sr-PSL to follow 5745 lung retention in man for about a year after inhalation. Although absorption to blood of the 5746 label was not measured directly, lung retention at 300 days (37% and 64% ILD in smokers 5747 and non-smokers, respectively) is consistent with assignment to Type S. 5748 5749 5750

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5751 5752 Table 10-2. Absorption parameter values for inhaled and ingested strontium 5753 Absorption parameter Absorption from valuesa the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Specific parameter valuesb Strontium titanate 0.01 3 1x10-4 0.01

Default parameter valuesc,d Absorptio Assigned forms n Type F Strontium chloride, sulphate and 1 30 – 0.25 carbonate M Fuel fragments, all unspecified 0.2 3 0.005 0.05 formse S FAP, PSL 0.01 3 1x10-4 0.0025 Ingested material Strontium titanate 0.01 All other chemical forms 0.25 a 5754 It is assumed that for strontium the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M 5755 and S forms of strontium (30, 3 and 3 d–1, respectively) are the general default values. 5756 b See text for summary of information on which parameter values are based, and on ranges of parameter 5757 values observed for individual materials. For strontium titanate Type S default parameter values are used for 5758 dissolution in the lungs, but a specific value of fA. 5759 c Materials (e.g. strontium chloride) are generally listed here where there is sufficient information to assign to 5760 a default absorption Type, but not to give specific parameter values (see text). 5761 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 5762 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 5763 absorption Type and the fA value for ingested soluble forms of strontium (0.25). 5764 e Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 5765 or if the form is known but there is no information available on the absorption of that form from the 5766 respiratory tract. 5767 5768 Rapid dissolution rate for strontium –1 5769 (447) The value of sr estimated for strontium chloride above, 30 d , is applied here to all 5770 Type F forms of strontium. 5771 5772 Extent of binding of strontium to the respiratory tract 5773 (448) Evidence from the strontium chloride studies outlined above suggests that there is 5774 little binding of strontium. It is therefore assumed that for strontium the bound state can be 5775 neglected, i.e. fb = 0.0. 5776 5777 10.2.2. Ingestion 5778 5779 (449) Due to the presence of Sr isotopes in fall-out material and its long-term retention in 5780 bone as a Ca analogue, the metabolism of strontium has been the subject of a number of human 5781 volunteer studies. Similar fractional absorption values were obtained from studies in which 5782 inorganic forms of radiostrontium was administered orally in solution (Spencer et al., 1960; 5783 Suguri et al., 1963; Shimmins et al., 1967; Sips et al., 1996) and from experiments where 5784 known quantities of radiostrontium incorporated in food were ingested (Fujita et al., 1966; 5785 Carr, 1967). In most cases, mean values were between 0.1 and 0.4, averaging about 0.2.

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85 5786 (450) Likhtarev et al. (1975) measured the absorption of Sr (chemical form not specified) 5787 in nine young adult male volunteers and obtained a mean value of 0.28, with a range of 0.1 – 5788 0.5. LeRoy et al. (1966) measured the absorption of Sr from real and simulated fall-out and 85 5789 after administration of Sr chloride. Ten volunteers ingested samples of local fallout, largely 5790 comprising silicaceous soil constituents (40-700 μm particles). The estimated absorption 5791 averaged 0.03 with a range of 0 - 0.09. For simulated fallout prepared as glass microspheres 5792 (30-40 μm), estimated absorption was 0.16 (range 0.06 - 0.25), compared to 0.17 (0.08 - 0.34) 5793 after administration as the chloride. 5794 (451) Most of these data have been reanalyzed and summarized in a recent review 5795 (Apostoaei, 2002). This author showed that the probability distribution function of f1 values is 5796 well represented by a lognormal curve with a geometric mean of 0.22 and a geometric standard 5797 deviation of 1.44. 5798 (452) A number of factors have been found to increase Sr absorption, including fasting, low 5799 dietary levels of Ca, Mg and P, milk diets and vitamin D (Gruden, 1984; Moon, 1994; Sips et 5800 al., 1996; Bianchi et al., 1999). 5801 (453) Sips et al., (1996) investigated the gastrointestinal absorption of Sr chloride in eight 5802 healthy male volunteers under fasting conditions and obtained a mean value of 0.25 (range 5803 0.13-0.41). Spencer et al. (1972) showed that overnight fasting increased absorption from about 5804 0.25 to 0.55. McAughey et al. (1994) also reported an f1 value of 0.55 (range 0.38 - 0.72) for 4 5805 volunteers after an overnight fast compared with 0.11 in a single volunteer ingesting Sr after 5806 breakfast. Höllriegl et al. (2006) and Li et al. (2006) reported absorption of stable Sr on 13 5807 human volunteers after an overnight fast and found f1 values of about 0.6 (range 0.25-0.97) 5808 when Sr was given as chloride, diluted in aqueous solutions. -1 -1 5809 (454) Similarly, a decrease in the Ca content of the diet from 30-40 to 0-10 mg d kg 5810 increased Sr absorption from an average of 0.2 to 0.4 (Shimmins et al., 1967). By contrast, 5811 gender, age at exposure in adult groups (Apostoaei, 2002; Höllriegl et al., 2006) smoking, 5812 exercise or use of oral contraceptives in young females (Zitterman et al. 1995) do not seem to 5813 change the intestinal absorption of strontium. 5814 (455) Vezzoli et al. (1998) in a study of stable strontium absorption in 47 normocalciuric 5815 volunteers (29 men and 18 women) reported no clear evidence of gender on Sr absorption. 5816 Results from animal studies are generally similar to those from volunteer studies (Coughtrey 5817 and Thorne, 1983), although effects of gender on strontium absorption are controversial. Dahl 5818 et al. (2001) reported higher plasma strontium levels in male rats and monkeys, compared to 5819 females, and concluded that there were no clear gender differences in the gastrointestinal 5820 absorption of strontium. Results for the absorption of Sr administered as the titanate (SrTiO3) 5821 to rats show low levels of absorption of about 0.01 (McClellan and Bustad, 1964). 5822 (456) Radioactive strontium has been shown to accumulate in teeth (Neuzil and Dysart, 5823 1984; Kulev et al., 1994; O’Donnell et al., 1997). Most of this deposit comes from 5824 gastrointestinal absorption and subsequent systemic distribution but a small part may also be 5825 adsorbed directly from the oral cavity onto the dental plaque and enamel during mastication. Ex 5826 vivo experiments performed with enamel removed from rat teeth and transferred to culture 90 5827 medium containing Sr (chemical form not given) showed rapid and large deposition on the 5828 enamel surface (White et al., 1980). Similarly, experiments performed with adult participants 5829 rinsing their mouths twice a day for 2 weeks with a SrCl2 solution, showed that strontium 5830 incorporated into dental plaque and was retained for at least 6 weeks (Spets-Happonen et al. 5831 1998). In vitro uptake of strontium directly into plaque-free bovine enamel and, to a lesser 5832 extent, human enamel has also been shown after experiments where enamel was agitated for 5833 10 min per day for 7 days in a solution containing 2000 ppm of strontium (Curzon and 5834 Spector, 1983). Unfortunately none of these studies provide enough information to derive

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5835 robust parameters for Sr adsorption and retention on teeth. 5836 (457) In Publication 30 (1979), the recommended absorption values were 0.01 for SrTiO3 5837 and 0.3 for all other compounds. In Publication 67 (1993), a value of 0.3 was recommended for 5838 dietary intakes by adults. However, due to the strong link between strontium and calcium 5839 absorption and the known discrimination in favour of calcium, a default fA value of 0.25 is 5840 adopted here for all chemical forms but Sr titanate, for which lower fA value of 0.01 is retained. 5841 5842 10.2.3. Systemic Distribution, Retention and Excretion 5843 5844 10.2.3.1. Summary of the database 5845 5846 (458) Strontium is a chemical and physiological analogue of calcium but has different 5847 biokinetics from calcium due to discrimination between these elements by biological 5848 membranes and hydroxyapatite crystals of bone. For example, strontium is less effectively 5849 absorbed from the intestines and more effectively excreted by the kidney than calcium and is 5850 lost from bone at a higher rate than calcium over the first few months after uptake to blood 5851 (Bauer et al. 1955, Spencer et al. 1960, Barnes et al. 1961, Cohn et al. 1963, Decker et al. 5852 1964, Harrison et al. 1967). 5853 (459) The biokinetics of strontium has been studied extensively in human subjects and 90 5854 laboratory animals. A large database related to the transfer of Sr from food and milk to the 5855 human skeleton was developed in the 1950s and 1960s. Interpretation of these environmental 5856 data is complicated by the facts that measured skeletal burdens were accumulated over an 90 5857 extended period and depend on assumptions concerning fractional uptake of Sr from the 5858 gastrointestinal tract. More easily interpreted data are available from controlled studies on 5859 human subjects. Data on the behavior of strontium in laboratory animals, particularly dogs, 5860 help to clarify the behavior of strontium at early times after intake. Because strontium is a 5861 close physiological analogue of calcium, data from controlled studies of calcium in humans 5862 provide supporting information for selection of parameter values for strontium, particularly 5863 for paths of movement for which comparative information on strontium and calcium transport 5864 is available. 5865 (460) Reviews of the biokinetic database for systemic strontium can be found in ICRP 5866 Publication 20 (1973), ICRP Publication 67 (1993), and an article by Leggett (1992). More 5867 recent human studies are described in articles by Shagina et al. (2003) and Li et al. (2008). 5868 The primary datasets underlying specific parameter values in the model for systemic 5869 strontium used in this report are summarized below. 5870 5871 10.2.3.2. Biokinetic model for systemic strontium 5872 5873 (461) The structure of the model for systemic strontium is shown in Figure 10-1. This is a 5874 simplified version of the generic model for bone-volume seekers. All soft tissues including 5875 the liver and kidneys are included in the three "Other tissue" compartments, ST0, ST1, and 5876 ST2 corresponding to rapid, intermediate, and slow exchange of activity with blood, 5877 respectively. 5878 (462) Blood is treated as a uniformly mixed pool that exchanges activity with soft tissues 5879 and bone surfaces. Soft tissues are divided into three compartments corresponding to fast, 5880 intermediate, and slow return exchange of activity with blood (compartments ST0, ST1, and 5881 ST2, respectively). The liver and kidneys are not addressed separately in the model for 5882 strontium but are included implicitly in the soft tissue compartments. Bone is divided into 5883 cortical and trabecular bone, and each of these bone types is further divided into bone

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5884 surfaces and bone volume. Bone volume is viewed as consisting of two pools, one that 5885 exchanges with activity in bone surface for a period of weeks or months and a second, non- 5886 exchangeable pool from which activity can be removed only by bone restructuring processes. 5887 Activity depositing in the skeleton is assigned to bone surface. Over a period of days a 5888 portion of the activity on bone surfaces moves to exchangeable bone volume and the rest 5889 returns to plasma. Activity leaves exchangeable bone volume over a period of months, with 5890 part of the activity moving to bone surfaces and the rest to non-exchangeable bone volume. 5891 The rate of removal from non-exchangeable bone volume is assumed to be the rate of bone 5892 turnover, with different turnover rates applying to cortical and trabecular bone. Strontium is 5893 assumed to be lost from the body only by urinary or fecal excretion. 5894

5895 5896 Figure 10-1. Structure of the biokinetic model for systemic strontium. 5897 Abbreviations: exch = exchangeable, nonexch = non-exchangeable. 5898 5899 Parameter values 5900 (463) The systemic biokinetic model for strontium given in ICRP Publication 67 (1993) is 5901 reasonably consistent with later information on the biokinetics of strontium and related 5902 elements in adult humans (e.g. Shagina et al., 2003; Li et al., 2008). For example, the model 90 5903 predicts that 2.8-3.2% of total-body Sr is eliminated each year at times 25-45 y after acute 5904 uptake to blood, compared with average values of 2.7-3.2%, depending on age, in adult males 90 5905 of a Russian population exposed to high levels of Sr (Shagina et al., 2003). Average rates 5906 of loss for adult females in that population were estimated as 3.2-3.5% up to age 45 y and 5907 4.4-5.8% at higher ages. The model of ICRP Publication 67 is independent of age and 5908 gender after age 25 y. 5909 (464) The parameter values for strontium applied in ICRP Publication 67 (1993) to an 5910 adult member of the public are adopted in this document for application to workers. These 5911 values are listed in Table 10-1. The basis for each of the parameter values is summarized 5912 below. 5913 (465) Results of controlled studies involving adult humans indicate that whole-body 5914 retention, presumably representing primarily skeletal retention, is higher in young adults (<25

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5915 y) than in middle-aged or elderly persons (Likhtarev et al., 1975; Leggett, 1992). This is 5916 thought to be associated with differences with age in the bone formation rate, which 5917 determines the level of deposition of calcium and related elements in bone and which remains 5918 elevated until about the middle of the third decade of life. The baseline parameter values for 5919 strontium given in this report apply to ages 25 y or greater. Model predictions for younger 5920 adult ages can be derived from the age-specific parameter values given in ICRP Publication 5921 67 (1993), interpolating linearly with age between values provided in that document for ages 5922 15 y and 25 y. 5923 (466) Kinetic analysis of plasma disappearance curves for normal subjects intravenously 5924 injected with calcium or strontium tracers indicates that these elements initially leave plasma 5925 at a rate of several hundred plasma volumes per day and equilibrate rapidly with an 5926 extravascular compartment roughly three times the size of the plasma pool (Heaney, 1964; 5927 Harrison et al., 1967; Hart and Spencer, 1976). At times greater than 1-2 h after injection, a -1 5928 transfer rate from plasma of about 15 d yields a reasonable fit to plasma disappearance 5929 curves for strontium or calcium tracers. The model for strontium used in this report does not 5930 depict the extremely rapid removal of activity during the early minutes but assigns a removal -1 5931 rate from plasma of 15 d . 5932

Table 10-3. Transfer coefficients for systemic strontium

Transfer coefficient Froma Toa (d-1) Blood Urinary bladder contents 1.73 Blood Right colon contents 0.525 Blood Trabecular bone surface 2.08 Blood Cortical bone surface 1.67 Blood ST0 7.50 Blood ST1 1.50 Blood ST2 0.003 Trabecular bone surface Blood 0.578 Trabecular bone surface Exch trabecular bone volume 0.116 Cortical bone surface Blood 0.578 Cortical bone surface Exch cortical bone volume 0.116 ST0 Blood 2.50 ST1 Blood 0.116 ST2 Blood 0.00038 Exch trabecular bone volume Trabecular bone surface 0.0043 Exch trabecular bone volume Nonexch trabecular bone volume 0.0043 Exch cortical bone volume Cortical bone surface 0.0043 Exch cortical bone volume Nonexch cortical bone volume 0.0043 Nonexch cortical bone volume Blood 0.0000821 Nonexch trabecular bone volume Blood 0.000493 a Exch = exchangeable; Nonexch = non-exchangeable; ST0, ST1, and ST2 are compartments within other soft tissues with fast, intermediate, and slow turnover, respectively. 5933 5934 (467) Uptake and retention of radiostrontium in soft tissues and bone have been measured 5935 in several seriously ill human subjects (Comar et al., 1957; Schulert et al., 1959). The data 5936 indicate that soft tissues initially contain about as much strontium as bone, but the soft-tissue 5937 content falls off sharply after a few weeks while the bone content declines only slowly over 5938 the first few months.

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85 45 5939 (468) Soft-tissue contents of Sr and Ca were measured in postmortem tissues of several 5940 human subjects injected with these radionuclides during late stages of terminal illnesses, from 5941 a few hours to four months before death (Schulert et al. 1959). The fraction of injected 5942 activity remaining in soft tissues after clearance of the rapid-turnover pool was roughly the 5943 same for the two radionuclides. It appeared that strontium was removed more slowly than 5944 calcium from the intermediate-term pool. No information on the presumably small, long- 5945 term retention compartment (ST2) could be gained from this relatively short-term study. 5946 (469) The rates of transfer of strontium between plasma and the soft tissue compartments 5947 are set as follows. It is assumed that 50% of strontium leaving plasma moves to the 5948 rapid-turnover soft-tissue compartment ST0; this is the balance after deposition percentages 5949 in other compartments are assigned. The corresponding transfer rate from plasma to ST0 is -1 -1 5950 0.50 × 15 d = 7.5 d . Based on the assumed relative amounts of strontium in ST0 and 5951 plasma, the transfer rate from ST0 to plasma is set at one-third the transfer rate from plasma -1 5952 to ST0, or 2.5 d . Fractional transfer from plasma to ST1 is assumed to be 0.1, the same as -1 -1 5953 for calcium; the corresponding transfer rate is 0.1 x 15 d = 1.5 d ). The removal half-time -1 5954 from ST1 to plasma is set at 6 d for strontium (transfer rate = ln(2)/ 6 d = 0.116 d ), 5955 compared with 4 d for calcium, to account for the slower decline in soft-tissue activity for 5956 strontium than calcium indicated by human injection data. Fractional deposition in the 5957 relatively non-exchangeable soft-tissue pool, ST2, is set at 0.0002 (transfer rate = 0.0002 x 15 -1 -1 5958 d = 0.003 d ) compared with 0.00005 for calcium. This is consistent with the estimate that 5959 soft tissues of the adult contain 1% of the body's natural strontium (Schlenker et al., 1982), 5960 assuming the removal half-time from ST2 to plasma is the same as that used in the model for -1 5961 calcium (5 y, corresponding to a transfer rate of 0.00038 d ). 5962 (470) Data for laboratory animals indicate that fractional deposition on bone surfaces is 5963 similar for calcium, strontium, barium, and radium (Bligh and Taylor, 1963; Kshirsagar et al., 5964 1966; Domanski et al. 1969, 1980). This is consistent with limited data from controlled 5965 studies on human subjects, including measurements of radiocalcium and radiostrontium in 5966 bone samples from subjects injected 3 h or longer before death (Schulert et al., 1959); and 5967 external measurements of the buildup of radiocalcium (Anderson et al., 1970; Heard and 5968 Chamberlain, 1984) and radiobarium (Korsunskii et al., 1981) after intravenous injection. 5969 Based on these data, 25% of calcium, strontium, barium, or radium leaving plasma is 5970 assigned to bone surfaces. The transfer rate from plasma to cortical and trabecular surfaces -1 -1 5971 combined is 0.25 × 15 d = 3.75 d . 5972 (471) The initial distribution between cortical and trabecular bone appears to be similar for 5973 calcium, strontium, barium, and radium (Ellsasser et al., 1969; Wood et al., 1970; Liniecki, 5974 1971; Stather, 1974; Lloyd et al., 1976). Relative deposition on cortical and trabecular bone 5975 surfaces is based on the estimated calcium turnover rate of each bone type. As an average 5976 over adult ages, deposition on trabecular bone is estimated to be 1.25 times that on cortical 5977 bone (Leggett et al., 1982). The transfer rate from plasma to trabecular bone surface is -1 -1 -1 5978 (1.25/2.25) × 3.75 d = 2.08 d and from plasma to cortical bone surface is (3.75 - 2.08) d = -1 5979 1.67 d . 5980 (472) The residence time on human bone surfaces has not been determined with much 5981 precision for any of the alkaline earth elements. The removal half-time of 1 d is estimated for 5982 all four elements. This value is consistent with autoradiographic measurements of surface 5983 activity in human and canine bone samples taken at times ranging from few hours to a few 5984 days after intravenous injection of 45Ca (Riggs et al. 1971, Groer et al. 1972, Groer and 5985 Marshall 1973, ICRP 1973). It is also reasonably consistent with measurements of the early 5986 decline in whole-body retention of intravenously injected radioactive calcium, strontium, 5987 barium, and/or radium in human subjects (Spencer et al. 1960; Bishop et al. 1960; Heaney

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5988 1964; Harrison et al. 1967; Phang et al. 1969; Carr et al. 1973; Likhtarev et al. 1975; 5989 Malluche et al. 1978; Henrichs et al. 1984; Newton et al. 1990, 1991) coupled with 5990 measurements of soft-tissue retention as described earlier. A removal half-time of 1 d refers 5991 to the half-time that one theoretically would observe if recycling of activity to bone surfaces 5992 were eliminated. Given the considerable amount of recycling from plasma to bone surfaces, 5993 the corresponding net or apparent half-time would be 3 d or more. 5994 (473) Parameter values for exchangeable bone volume are estimated from whole-body 5995 measurements for human subjects using data for times after bone surfaces and soft tissues 5996 have largely cleared of activity but before loss from bone resorption becomes an important 5997 consideration. Based on analysis of whole-body retention data for human subjects injected 5998 with radioisotopes of calcium, strontium, barium, or radium (Spencer et al., 1960; Bishop et 5999 al., 1960; Heaney, 1964; Harrison et al., 1967; Maletskos et al., 1969; Phang et al., 1969; 6000 Carr et al., 1973; Likhtarev et al., 1975; Malluche et al., 1978; Henrichs et al., 1984; Newton 6001 et al., 1990, 1991), the fraction of activity that moves from bone surfaces back to plasma is 6002 assumed to be the same for all four elements. Specifically, five-sixths of activity leaving bone 6003 surfaces is assumed to return to plasma and one-sixth is assumed to transfer to exchangeable 6004 bone volume. The transfer rate from trabecular or cortical bone surface to the corresponding -1 6005 exchangeable bone volume compartment is (1/6) × ln(2)/1 d = 0.116 d , and the transfer rate -1 6006 from trabecular or cortical bone surface to plasma is (5/6) × ln(2)/1 d = 0.578 d . 6007 (474) Element-specific removal half-times from the exchangeable bone volume 6008 compartments are based in part on fits to the intermediate-term retention data from human 6009 injection studies. It is also considered that the assigned half-times should increase roughly in 6010 proportion to the likelihood of the element entering nonexchangeable sites in bone mineral, as 6011 suggested by data from in vitro experiments with hydroxyapatite crystals and whole-body 6012 retention patterns for alkaline earth elements in human subjects. A removal half-time of 80 d 6013 is assigned to strontium, compared with 100 d for calcium, 50 d for barium, and 30 d for 6014 radium (Leggett, 1992). Because the data do not allow the derivation of removal half-times 6015 as a function of bone type, the same half-time is applied to cortical and trabecular 6016 exchangeable bone volume compartments. 6017 (475) Discrimination between alkaline earth elements by bone is accounted for by 6018 fractional transfer of activity from exchangeable to nonexchangeable bone volume. It is 6019 assumed that calcium, strontium, barium, and radium are all equally likely to become 6020 temporarily incorporated in bone mineral after injection into plasma but that the likelihood of 6021 reaching a non-exchangeable site in bone crystal decreases in the order calcium > strontium > 6022 barium > radium. Fractional transfers of calcium, strontium, barium, and radium from 6023 exchangeable to nonexchangeable bone volume are set at 0.6, 0.5, 0.3, and 0.2, respectively, 6024 for consistency with whole-body and skeletal retention data on these elements (Spencer et al. 6025 1960; Bishop et al., 1960; Heaney et al., 1964; Harrison et al., 1967; Phang et al., 1969; 6026 Maletskos et al., 1969; Carr et al., 1973; Likhtarev et al., 1975; Malluche et al., 1978; 6027 Henrichs et al., 1984; Newton et al., 1990, 1991) as well as results of in vitro measurements 6028 on hydroxyapatite crystals (Neuman, 1964; Stark, 1968). The derived rate of transfer of 6029 strontium from exchangeable trabecular or cortical bone volume to the corresponding -1 6030 nonexchangeable bone volume compartment is 0.5 × ln(2)/80 d = 0.0043 d and to the -1 6031 corresponding bone surface compartment is 0.5 × ln(2)/80 d = 0.0043 d . 6032 (476) Biological removal from the nonexchangeable bone volume compartments of 6033 cortical and trabecular bone is assumed to result from bone turnover. The average bone -1 -1 6034 turnover rates during adulthood are estimated as 3% y and 18% y for cortical and 6035 trabecular bone, respectively (ICRP, 2002). The corresponding transfer rates from the 6036 nonexchangeable bone volume compartments of cortical and trabecular bone to plasma are

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-1 -1 6037 0.0000821 d and 0.000493 d , respectively. Age-specific rates of bone turnover, including 6038 changes with age during adulthood, are provided in the paper by Leggett (1992) for 6039 application of the model to specific cases. 6040 (477) Clearance of strontium from plasma to urine and faeces has been determined in 6041 several human studies (Spencer et al., 1960; Barnes et al., 1961; Fujita, 1963; Cohn et al., 6042 1963; Samachson, 1966; Harrison et al., 1967; Wenger and Soucas, 1975; Likhtarev et al., 6043 1975; Newton et al., 1990). Based on central estimates derived from results of these studies, 6044 it is assumed that 11.5% of strontium leaving plasma is transferred to the contents of the 6045 urinary bladder contents and subsequently to urine and 3.5% is transferred to the contents of 6046 the right colon contents and subsequently to faeces. Therefore, the transfer rate from plasma -1 -1 6047 to the urinary bladder contents is 0.115 × 15 d = 1.73 d and from plasma to the contents of -1 -1 6048 the right colon contents is 0.035 × 15 d = 0.525 d . 6049 6050 10.2.3.3. Treatment of radioactive progeny 6051 6052 (478) Dosimetrically significant radioactive progeny of strontium isotopes considered in 6053 this report include isotopes of , , and yttrium. Results of animal studies 90 6054 (Arnold et al., 1955; Lloyd, 1961; Mueller, 1972; Stevenson, 1975) indicate that Y 90 6055 produced by decay of Sr in soft tissues tends to migrate from the parent and distribute 90 6056 similarly to intravenously injected yttrium but shows little if any migration from Sr when 6057 produced in bone volume (see the section on yttrium in this report for summaries of reported 6058 data). No information was found on the behavior of rubidium produced in the body by decay 6059 of a strontium parent. The krypton produced by serial decay of strontium and 6060 rubidium isotopes presumably migrates from these radionuclides over a period of minutes to 6061 hours and escapes from the body to an extent determined by the half-life of the krypton 6062 isotope. 6063 (479) The model used in this report for yttrium as a daughter of strontium is based on the 6064 model for yttrium as a parent described elsewhere in this report, but additional assumptions 6065 are made to address structural differences in the strontium and yttrium models. Yttrium 6066 produced in a compartment of bone is assumed to follow the same kinetics as if deposited in 6067 the compartment as a parent radionuclide. No distinction is made between the exchangeable 6068 and non-exchangeable bone volume compartments of the strontium model when applied to 6069 yttrium, i.e. each compartment is treated simply as the bone volume compartment for the 6070 corresponding bone type in the yttrium model. Yttrium produced in a soft-tissue 6071 compartment of the strontium model (ST0, ST1, or ST2) is assumed to transfer to blood with 6072 a half-time of 3 d (the shortest half-time for Other soft tissue in the model for yttrium as a 6073 parent) and then to follow the kinetics of yttrium as a parent radionuclide. 6074 (480) The model for rubidium as a daughter of strontium is a considerably condensed 6075 version of a proposed model for rubidium as a parent radionuclide (Leggett and Williams, 6076 1988). The model is based on the same principles as the model for cesium, a chemical and 6077 physiological analogue of rubidium, described elsewhere in this report. That is, the 6078 biokinetics of systemic rubidium is predicted on the basis of the distribution of cardiac 6079 output, experimentally determined tissue-specific extraction fractions, and the steady-state 6080 distribution of stable rubidium in the body. The reference division of cardiac output in the 6081 adult male tabulated in ICRP Publication 89 (2002) is applied here. The present version of 6082 the model depicts blood plasma as a central compartment that exchanges rubidium with red 6083 blood cells (RBC), trabecular bone surface, cortical bone surface, muscle, and a compartment 6084 representing all other soft tissue. Rates of transfer of rubidium from plasma are as follows: 6 -1 -1 -1 -1 6085 d to RBC, 255 d to muscle, 7 d to cortical bone surface, 7 d to trabecular bone surface,

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-1 -1 -1 6086 855 d to other tissue, 3.9 d to urinary bladder contents, 1.2 d to right colon contents, and -1 6087 0.1 d to excreta (sweat). Transfer rates from RBC or tissues to plasma are as follows: 0.35 -1 -1 -1 -1 6088 d from RBC, 1.14 d from muscle, 1.68 d from bone surface compartments, and 10.3 d 6089 from other tissue. Rubidium produced by decay of strontium in blood is assigned to plasma. 6090 Rubidium produced in exchangeable or non-exchangeable bone volume compartments of the 6091 strontium model are transferred to plasma at the rate of bone turnover. Rubidium produced in 6092 soft tissue compartments of the strontium model (ST0, ST1, or ST2) are transferred to plasma -1 6093 at the rate 10.3 d . 6094 (481) The model for krypton produced by serial decay of strontium and rubidium in 6095 systemic compartments is similar to the model applied in this report to produced in 6096 vivo by decay of a parent radionuclide. Krypton is assumed to follow the bone model for 6097 radon introduced in ICRP Publication 67 (1993) but is assigned a higher rate of removal from 6098 soft tissues to blood than is assumed for radon. Specifically, krypton produced in 6099 nonexchangeable bone volume, exchangeable bone volume, or bone surface transfers to -1 -1 -1 6100 blood at the rate 0.36 d , 1.5 d , or 100 d , respectively. Krypton produced in a soft-tissue 6101 compartment transfers to blood with a half-time of 15 min, compared with an assumed half- 6102 time of 30 min for radon produced by in soft tissues. Krypton entering -1 6103 blood is assumed to be removed from the body (exhaled) at the rate 1000 d , corresponding 6104 to a half-time of 1 min. Partial recycling of krypton to tissues via arterial blood is not 6105 depicted explicitly but is considered in the assignment of the effective half-times in tissues. 6106 The model is intended to yield a conservative average residence time of krypton atoms in the 6107 body assuming introduction into arterial blood and subsequent tissue uptake. It is recognized 6108 that the residence time of krypton in the body following production in tissues depends on the 6109 distribution of the parent radionuclide. 6110 6111 10.3. Individual Monitoring 6112 85 6113 Sr 85 6114 (482) Sr monitoring techniques include in vivo techniques (whole body and if necessary 6115 lung counting) as well as urine bioassay. 6116 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 85Sr Urine Bioassay γ-ray spectrometry 5 Bq/L 1 Bq/L 85Sr Whole Body γ-ray spectrometry 50 Bq 20 Bq Counting 85Sr Lung Counting γ-ray spectrometry 5 Bq 6117 89 6118 Sr 89 6119 (483) Sr is determined by urine bioassay, by beta counting following chemical 6120 separation. 6121 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 89Sr Urine Bioassay Beta proportional 1 Bq/L 0.05 Bq/L counting 6122 90 6123 Sr

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90 6124 (484) Sr intakes are in general estimated by beta counting of urine excreta samples, after 90 6125 chemical separation. Sr is determined directly when Liquid Scintillation Counting is used. 90 90 6126 When beta proportional counter is used Sr content is commonly determined based on Y 90 6127 content, after a delay of at least seven days to allow for Y ingrowth. 6128 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 90Sr Urine Bioassay Beta proportional 0.4 Bq/L 0.05 Bq/L counting 90Sr Urine Bioassay Liquid Scintillation 0.4 Bq/L 0.1 Bq/L Counting 6129 6130 References 6131 6132 Anderson, J., Kahn, B., Labone, T., Brown, L., Harris, F., 1999. Solubility of various forms of 6133 strontium titanate in lungs: in vitro and in vivo studies. Health Phys., 76(6), 628-634. 6134 Anderson, J., Tomlinson, R.W.S., Ramsay, I.D., Clarke, M.B., Osborn, S.B., 1970. Radiocalcium 6135 uptake in the bones of the foot. Br. J. Radiol., 43, 168-172. 6136 Apostoaei, A. I., 2002. Absorption of strontium from the gastrointestinal tract into plasma in healthy 6137 human adults. Health Phys., 83, 56-65. 6138 Arnold, J. S.; Stover, B. J.; Van Dilla, M. B. (1955). Failure of Y-90 to escape from skeletally-fixed 6139 Sr-90. Soc. Exp. Biol. Med. 90:260-263. 6140 Bailey, M.R., Fry, F.A., James, A.C., 1985a. Long-term retention of particles in the human respiratory 6141 tract. J. Aerosol Sci., 16, 295–305. 6142 Bailey, M.R., Hodgson, A., Smith, H., 1985b. Respiratory tract retention of relatively insoluble 6143 particles in rodents. J. Aerosol Sci., 16, 279–293. 6144 Bair, W.J., 1961. Deposition, retention, translocation and excretion of radioactive particles. In: 6145 Inhaled Particles and Vapours, Proceedings of an International Symposium organized by the 6146 British Occupational Hygiene Society, Oxford 1960, (Ed. Davies, C.N.). pp. 192–208, 6147 Pergamon Press, Oxford. 6148 Barnes, O.W., Bishop, M., Harrison, G.E., Sutton, A., 1961. Comparison of the plasma concentration 6149 and urinary excretion of strontium and calcium in man. Int. J. Radiat. Biol., 3, 637-646. 6150 Bauer, G.C.H., Carlsson, A., Lindquist, B., 1955. A comparative study of the metabolism of 90Sr and 6151 45Ca. Acta Physiol. Scand., 35, 56-66. 6152 Bianchi, M.L., Ardissino, G.L., Schmitt, C.P., Daccó, V., Barletta, L., Claris-Appiani, A., Mehls, O., 6153 1999. No difference in intestinal strontium absorption after an oral or an intravenous 6154 1,25(OH)2D3 bolus in normal subjects. J Bone Mineral Res., 14(10), 1789-1795. 6155 Bishop, M., Harrison, G.E., Raymond, W.H.A., Sutton, A., Rundo, J., 1960. Excretion and retention 6156 of radioactive strontium in normal man following a single intravenous injection. Int. J. Radiat. 6157 Biol., 2, 125-142. 6158 Bligh, P.H., Taylor, D.M., 1963. Comparative studies of the metabolism of strontium and barium in 6159 the rat. Biochem. J. 87, 612-618. 6160 Bohning, D.E., Atkins, H.L., Cohn, S.H., 1982. Long-term particle clearance in man: Normal and 6161 impaired. Ann. Occup. Hyg., 26, 259-271. 6162 Carr, T., 1967. An attempt to quantitate the short term movement of strontium in the human adult. In: 6163 Stontium Metabolism. (Ed. Lenihan, J, Loutit, J, Martin, J.) Academic Press, London, pp. 6164 139-148. 6165 Carr, T.E.F., Harrison, G. E.; Nolan, J., 1973. The long-term excretion and retention of an intravenous 6166 dose of Ca-45 in two healthy men. Calcif. Tissue Res., 12, 217-226. 6167 Cohn, S.H., Lippincott, S.W., Gusmano, E.A., Robertson, J.S., 1963. Comparative kinetics of 47Ca 6168 and 85Sr in man. Radiat. Res., 19, 104-119.

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6222 Höllriegl, V., Li, W.B., Oeh, U., 2006. Human biokinetics of strontium--part II: Final data evaluation 6223 of intestinal absorption and urinary excretion of strontium in human subjects after stable 6224 tracer administration. Radiat Environ Biophys., 45, 179-85. 6225 ICRP, 1973. Alkaline Earth Metabolism in Adult Man, Publication 20. Oxford, Pergamon Press. 6226 ICRP, 1979. Limits on Intakes of Radionuclides for Workers, ICRP Publication 30, Part 1. Ann. ICRP 6227 2, (3/4). 6228 ICRP, 1989. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 1, 6229 ICRP Publication 56, Ann. ICRP 20, (2). 6230 ICRP, 1993. Age-dependent Doses to Members of the Public from Intake of Radionuclides: Part 2, 6231 Ingestion Dose Coefficients, ICRP Publication 67. Annals of the ICRP 23 (3/4). 6232 ICRP, 2002. Supporting Guidance 3. Guide for the Practical Application of the ICRP Human 6233 Respiratory Tract Model. Ann. ICRP 32(1-2). 6234 Johnson, J.R, Dunford, D.W., Kramer, G.H., 1983. Summary of a strontium-89 contamination case. 6235 Radiat. Prot. Dosim., 5, 247–249. 6236 Kanapilly, G.A., Stanley, J.A., Newton, G.J., Wong, B.A., DeNee, P.B., 1980. Characterization of an 6237 aerosol sample from Three Mile Island reactor auxiliary building. Inhalation Toxicology 6238 Research Institute Annual Report 1979–1980, LMF–84, pp. 5–9. Lovelace Biomedical & 6239 Environmental Research Foundation, Albuquerque, New Mexico. Available from National 6240 Technical Information Service, Springfield, Virginia. 6241 Kanapilly, G.M., Goh, C.H.T., 1973. Some factors affecting the in vitro rates of dissolution of 6242 respirable particles of relatively low solubility. Health Phys., 25, 225–237. 6243 Korsunskii, V.N., Tarasov, N.F., Naumenko, A.Z., 1981. Clinical evaluation of Ba-133m as an 6244 osteotropic agent. ORNL/TR-86/30 (7 pgs); Translated from the Russian UDC 616.71-006- 6245 073.916, Meditsinskaya Radiologiya No. 10, pp. 45-48. 6246 Kshirsagar, S.G., Lloyd, E., Vaughan, J., 1966. Discrimination between strontium and calcium in 6247 bone and the transfer from blood to bone in the rabbit. Br. J. Radiol., 39, 131-140. 6248 Kulev, Y.D., Polikarpov, G.G., Prigodey, E.V., Assimakopoulos, P.A., 1994. Strontium-90 6249 concentrations in human teeth in south Ukraine, 5 years after the Chernobyl accident. Sci 6250 Total Environ., 155(3), 215-219 6251 Leggett, R.W., 1992. A generic age-specific biokinetic model for calcium-like elements, Radiat. Prot. 6252 Dosim., 41, 183-198. 6253 Leggett, R.W., Eckerman, K.F., Williams, L.R., 1982. Strontium-90 in bone: a case study in 6254 age-dependent dosimetric modeling, Health Phys., 43, 307-322. 6255 LeRoy, G., Rust, J., Hasterlik, J., 1966. The consequences of ingestion by man of real and simulated 6256 fall-out. Health Phys., 12, 449-473. 6257 Li, W.B., Höllriegl, V., Roth, P., Oeh, W., 2008. Influence of human biokinetics of strontium on 6258 internal ingestion dose of 90Sr and absorbed dose of 89Sr to organs and metastases. Radiat. 6259 Environ. Biophys., 47, 225-239. 6260 Li, W.B., Höllriegl, V., Roth, P., Oeh, U., 2006. Human biokinetics of strontium. Part I: intestinal 6261 absorption rate and its impact on the dose coefficient of 90Sr after ingestion. Radiat. Environ. 6262 Biophys., 45, 115-24. 6263 Likhtarev, I. A., Dobroskok, I. A., Ilyin, L. A., Krasnoschekova, G. P., Likhtareva, M., Smirnov, B. I., 6264 Sobolev, E. P., Shamov, V.P., Shapiro, E.L., 1975. A study of certain characteristics of 6265 strontium metabolism in a homogeneous group of human subjects. Health Phys., 28, 49-60. 6266 Liniecki, J., 1971. Kinetics of calcium, strontium, barium and radium in rabbits. Health Phys., 21, 6267 367-376. 6268 Lloyd, E., 1961. The relative distributions of radioactive yttrium and strontium and the secondary 6269 deposition of Y-90 built up from Sr-90. Int. J. Radiat. Biol. 3:457-492. 6270 Lloyd, R.D., Mays, C.W., Atherton, D.R., 1976. Distribution of injected Ra-226 and Sr-90 in the 6271 beagle skeleton. Health Phys. 30:183-189; 1976. 6272 Maletskos, C.J., Keane, A.T., Telles, N.C., Evans, R.D., 1969. Retention and absorption of Ra-224 6273 and Th-234 and some dosimetric considerations of Ra-224 in human beings. In: Delayed

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6274 effects of bone-seeking radionuclides, ed. by C.W. Mays, W.S.S. Jee, R.D. Lloyd, B.J. 6275 Stover, J.H. Dougherty, G.N. Taylor, Salt Lake City, UT: University of Utah Press; pp. 29-49. 6276 Malluche, H.H., Werner, E., Ritz, E., 1978. Intestinal absorption of calcium and whole-body calcium 6277 retention in incipient and advanced renal failure. Miner. Electrolyte Metab., 1, 263-270. 6278 McAughey, J.J., Vernon, L., Haines, J., Sanders, T., Clark, R., 1994. Fractional gut absorption of 6279 strontium, barium and following administration of stable isotope tracers. In: Proc. 6280 9th Int. Conf. on Heavy Metals in the Environment. Toronto, 1993. 6281 McClellan, R.O., Boecker, B.B., Jones, R.K., Barnes, J.E., Chiffelle, T.L., Hobbs, C.H., Redman, 6282 H.C., 1972. Toxicity of inhaled radiostrontium in experimental animals. In Biomedical 6283 Implications of Radiostrontium Exposure. Proceedings of a symposium held at Davis, 6284 California, February 22–24, 1971 (Goldman, M. and Bustad, L. K. Eds.) AEC Symposium 6285 Series 25 (CONF-710201) pp. 149–167. U. S. Atomic Energy Commission. Available from 6286 National Technical Information Service, Springfield, Virginia. 6287 McClellan, R.O., Bustad, L.K., 1964. Gastrointestinal absorption of 85Sr titanate. In: Hanford 6288 Biology Research Annual Report for 1963. Washington (HW 80500). pp.100-101. 6289 McClellan, R.O., Rupprecht, F.C. (Eds.), 1967. Toxicity of inhaled 90Sr in Beagle dogs. Fission 6290 Product Inhalation Program Annual Report 1966–1967, LF–38, pp. 1–17. Lovelace 6291 Foundation for Medical Education and Research, Albuquerque, New Mexico. Available from 6292 National Technical Information Service, Springfield, Virginia. 6293 Moon, J., 1994. The role of vitamin D in toxic metal absorption: a review. J. Am. Coll. Nutr. 13, 559- 6294 564. 6295 Morrow, P.E., Gibb, F.R., Davies, H., Fisher, M., 1968. Dust removal from the lung parenchyma: an 6296 investigation of clearance stimulants. Toxicol. App. Pharmacol., 12, 372–396. 6297 Mueller, W.A., 1972. Y-90 distribution in male mice after injection of Sr-90, and consequences for 6298 dose burden of bone, soft tissue, and gonads. In: Comar, C. L., president, Second international 6299 conference on strontium metabolism. Glasgow and Strontian. 16-19 August 1972, pp. 137- 6300 143. 6301 Naményi, J., Gachályi, A., Varga, L., 1986. Decorporation of 85Sr by radioadsorbents from the lungs 6302 of rats with bronchial disorders. Health Phys., 51, 539–544. 6303 Navarro, T., Lopez, M.A., 1998. Accidental contamination with 90Sr: a case study. Radiat. Prot. 6304 Dosim., 79 (1-4), 67-70. 6305 NCRP, 2007. National Council on Radiation Protection and Measurements. Management of 6306 radionuclide-contaminated wounds: assessment, dosimetry and treatment. Publication No. 6307 1xy. 6308 Neuman, W.F., 1964. Blood-bone exchange. In: Bone biodynamics, ed. by H. M. Frost. Boston: 6309 Little, Brown, and Co, 393-408. 6310 Neuzi,l E.F., Dysart, M.E., 1984. The determination of 90Sr and 228Ra in human teeth by age groups 6311 and in other substances. Int. J. Appl. Radiat. Isot., 35(12), 1113-1115. 6312 Newton, D., Harrison, G.E., Kang, C., Warner, A.J., 1991. Metabolism of injected barium in six 6313 healthy men. Health Phys., 61, 191-201. 6314 Newton, D., Harrison, G.E., Rundo, J., Kang, C., Warner, A.J., 1990. Metabolism of Ca and Sr in late 6315 adult life. Health Phys., 59:433-442. 6316 O'Donnell, R.G., Mitchell, P.I., Priest, N.D., Strange, L., Fox, A., Henshaw, D.L., Long, S.C., 1997. 6317 Variations in the concentration of plutonium, strontium-90 and total alpha-emitters in human 6318 teeth collected within the British Isles. Sci. Total Environ., 201(3), 235-243. 90 6319 Petkau, A., Pleskach, S.D., 1972. A case of accidental aspiration of SrCl2. Health Phys. 22, 87–90. 6320 Phang, J.M., Berman, M., Finerman, G.A., Neer, R.M., Rosenberg, L.E., Hahn, T.J., 1969. Dietary 6321 Perturbation of calcium metabolism in normal man: compartmental analysis. J. Clin. Invest., 6322 48, 67-77. 6323 Riggs, B.L., Marshall, J.H., Jowsey, J., Heaney, R.P., Bassingthwaighte, J.B., 1971. Quantitative Ca- 6324 45 autoradiography of human bone. J. Lab. Clin. Med., 78, 585-598. 90 6325 Rundo, J., Williams, K., 1961. A case of accidental inhalation of SrCO3. Br. J. Radiol. 34, 734–740.

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6326 Samachson, J., 1966. The gastrointestinal clearance of strontium-85 and calcium-45 in man. Radiation 6327 Research, 27, 64-74. 6328 Schlenker, R.A., Keane, A.T., Holtzman, R.B., 1982. The retention of Ra-226 in human soft tissue 6329 and bone; implications for the ICRP 20 alkaline earth model. Health Phys., 42, 671-693. 6330 Schulert, A.R., Peets, E.A., Laszlo, D., Spencer, H., Charles, M., Samachson, J., 1959. Comparative 6331 metabolism of strontium and calcium in man. Int. J. Appl. Radiat. Isotop., 4, 144-153. 6332 Shagina, N.B., Tolstykh, E.I., Zalyapin, V.I., Degteva, M.O., Kozheurov, V.P., Tokareva, E.E., 6333 Anspaugh, L.R., Napier, B.A., 2003. Evaluation of age and gender dependencies of the rate of 6334 strontium elimination 25-45 years after intake: Analysis of data from residents living along 6335 the Techa River. Radiat. Res., 159, 239-246. 6336 Shimmins, J., Smith, D., Nordin, B., Burkinshaw, L., 1967. A comparison between calcium-45 and 6337 strontium-85 absorption, excretion and skeletal uptake. In: Strontium Metabolism. (Ed. 6338 Lenihan, J; Loutit, J; Martin, J.) Academic Press, London, pp149-159. 6339 Sips, A.J., VanderVijgh, W.J., Barto, R., Netelenbos, J.C., 1996. Intestinal absorption of strontium 6340 chloride in healthy volunteers: pharmacokinetics and reproducibility. Br. J. Clin. Pharmacol., 6341 41, 543-549. 6342 Snipes, M.B., Barnes, J.E, Boecker, B.B., Hahn, F.F., Hobbs, C.H., Mauderly, J.L, McClellan, R.O., 6343 Pickrell, J.A., 1972. Toxicity of inhaled 90Sr fused clay in Beagle dogs III. Fission Product 6344 Inhalation Program Annual Report 1971–1972, LF–45, pp. 177–188. Lovelace Foundation 6345 for Medical Education and Research, Albuquerque, New Mexico. Available from National 6346 Technical Information Service, Springfield, Virginia. 6347 Spencer, H., Li, M., Samachson, J., laszlo, D., 1960. Metabolism of Strontium-85 and Calcium-45 in 6348 Man. Metabolism; 9, 916-925. 6349 Spencer, H., Kramer,L., Norris,C. and Samachson,J. 1972. Certain aspects of radiostrontium 6350 metabolism in man. In : Proceedings of the 2nd Int. Symp. On Strontium Metabolism (J.M.A. 6351 Lenihan, Ed.) 335-346. 6352 Spets-Happonen, S., Seppa, L., Korhonen, A., Alakuijala, P., 1998. Accumulation of strontium and 6353 fluoride in approximal dental plaque and changes in plaque microflora after rinsing with 6354 chlorhexidine-fluoride-strontium solution. Oral Diseases, 4, 114-119. 6355 Stark, G., 1968. Studies on synthetic hydroxyapatite crystals with regard to metabolism of calcium, 6356 strontium, barium and radium in bone. I. The discrimination against calcium. Biophysik., 5, 6357 42-54. 6358 Stather, J.W., 1974. Distribution of P-32, Ca-45, Sr-85 and Ba-133 as a function of age in the mouse 6359 skeleton. Health Phys., 26, 71-79. 6360 Stevenson, A F.G., 1975. The influence of age and sex on the activity ratio of yttrium-90 to strontium- 6361 90 in the rat skeleton after incorporation of strontium-90. Health Phys. 29:285-290. 6362 Suguri, S., Ohtani, S., Oshino, M., Yanagidhita, K., 1963. The behaviour of strontium-85 in a normal 6363 man following a single ingestion application of the whole body counter for the retention. 6364 Health Phys., 9, 529-535. 6365 Vezzoli, G., Baragetti, I., Zerbi, S., Caumo, A., Soldati, L., Bellinzoni, P., Centemero, A., Rubinacci, 6366 A., Moro, G., Bianchi, G., 1998. Strontium absorption and excretion in nomocalciuric 6367 subjects: relation to calcium metabolism. Clin. Chem., 44 (3), 586-590. 6368 Wenger, P., Soucas, K., 1975. Retention and excretion curves of persons containing 90Sr and 226Ra 6369 after a chronic contamination. Health Phys., 28, 145-152. 6370 White, B.A., Deaton, T.G., Bawden, J.W., 1980. In vivo and in vitro study of 90Sr in developing rat 6371 molar enamel. J Dent Res. Dec., 59(12), 2091-2099. 6372 Wood, S.K., Farnham, J.E., Marshall, J.H., 1970. Ca-45, Ba-133, and Ra-226 in 6-to 10-year-old 6373 beagle dogs: A 100-day study. In: Radiological Physics Division annual report, Center for 6374 Human Radiobiology, July 1969 through June 1970; Argonne, IL: Argonne National 6375 Laboratory; ANL-7760, Part II, Biology and Medicine, 110-132. 6376 Zitterman, A., Bierschbach, C., Giers, G., Hotzel, D., Stehle, P., 1995. Determination of intestinal 6377 strontium absorption--assessment and validation of routinely manageable test procedures. Z. 6378 Ernahrungswiss. 34, 301-307. 6379

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6380 11. YTTRIUM (Z = 39) 6381 6382 (485) Yttrium is a rare earth element which occurs mainly in oxidation state III. 6383 Lanthanoids are good chemical analogues of yttrium. Yttrium may be encountered in a 6384 variety of chemical and physical forms, including oxides (Y2O3), hydroxides, chlorides, 6385 fluorides, sulphates, nitrates and oxalates. 91 6386 (486) Yttrium-90 and Y are the main fission products which may be encountered in the 90 6387 nuclear industry. Y is used in nuclear medicine for the treatment of various cancers with 6388 labelled drugs. 6389 6390 Table 11-1. Isotopes of yttrium addressed in this report 6391 Isotope Physical half-life Decay mode Y-84m 39.5 m EC, B+ Y-85 2.68 h EC, B+ Y-85m 4.86 h EC, B+ Y-86 14.74 h EC, B+ Y-86m 48 m IT, EC, B+ Y-87 79.8 h EC, B+ Y-87m 13.37 h IT, EC, B+ Y-88 106.65 d EC, B+ Y-90a 64.10 h B- Y-90m 3.19 h IT, B- Y-91 58.51 d B- Y-91m 49.71 m IT Y-92 3.54 h B- Y-93 10.18 h B- Y-94 18.7 m B- Y-95 10.3 m B- 6392 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 6393 are given on accompanying electronic disk. 6394 6395 6396 11.1. Routes of Intake 6397 6398 11.1.1. Inhalation 6399 6400 Absorption Types and parameter values 6401 (487) Information is available from experimental studies of yttrium mainly as chloride or 6402 in fused aluminosilicate particles (FAP). Analysis of the results to estimate absorption 6403 parameter values is facilitated by the close correspondence of fecal excretion to particle 6404 transport from the respiratory tract: absorption of yttrium in the alimentary tract is low, and 6405 systemic yttrium is excreted mainly in urine. 6406 (488) Absorption parameter values and Types, and associated fA values for particulate 6407 forms of yttrium are given in Table 11-2. 6408 6409 Yttrium chloride (YCl3) 6410 (489) Extensive studies have been conducted on the biokinetics of yttrium following 6411 deposition of the chloride in the lungs of dogs, guinea pigs, rats, and mice. Most of the 6412 studies involved small masses of radiolabelled yttrium, and showed a similar pattern. 6413 Initially, most of the excretion was to faeces, indicating that there was little absorption from

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6414 the upper respiratory tract. Nevertheless, subsequent clearance of most of the lung deposit 6415 was rapid with corresponding systemic uptake: mainly deposition in skeleton and excretion in 6416 urine. Similar lung dissolution kinetics were observed in the different species, and the 6417 distribution of yttrium absorbed systemically was similar to that observed after intravenous 6418 injection. 6419 (490) In a detailed low-level study carried out to complement a lifespan study of the 91 91 6420 effects of inhaled YCl3, the biokinetics of Y were followed for 270 days after inhalation of 91 6421 YCl3 (in caesium chloride solution) by dogs (McClellan and Rupprecht, 1967; Muggenburg 91 6422 et al., 1998). On average, about 60% of total-body Y cleared during the first few days after 91 6423 administration. It was inferred that Y deposited in the upper respiratory tract was mainly 6424 cleared by mucociliary transport and subsequent swallowing and fecal excretion. This 6425 suggests that the rapid dissolution rate is low compared to particle transport rates from these 6426 airways. Nevertheless, there was significant deposition in liver and skeleton immediately 6427 after inhalation, with the lung content falling to about 15% of the initial lung deposit (ILD) 6428 by 4 days, and to about 2% ILD by 64 days. Studies of the distribution of activity retained in 6429 the respiratory tract provide evidence for the formation of particulate material. 6430 Autoradiographs were made using tissues from dogs in the life-span study that died in the 6431 first few weeks after exposure (McClellan and Rupprecht, 1967). Within the respiratory tract, 6432 aggregates of radioactivity were observed on bronchial mucosal surfaces and in recesses of 6433 the mucosal lining. Smaller particles were also found in alveolar ducts and alveoli. Some of 6434 the material had been phagocytized, absorbed into the lymphatic system, and could be seen in 91 6435 the lymphatic spaces beneath the bronchial epithelium. Large amounts of Y were found in 91 6436 bronchial cartilage plates, but attributed to systemic Y, with similar deposition in skeletal 6437 cartilage. Muggenburg et al. (1998) reported concentrations in a wide range of tissues at 32 6438 days after inhalation. The concentration in tracheo-bronchial lymph nodes was similar to that 6439 in liver, and higher than in other soft tissues, suggesting some transfer in particulate form. 6440 Modelling conducted by the task group showed a good fit to the data with fr = 0.94, -1 -1 6441 sr = 0.74 d and ss = 0.013 d (consistent with assignment to default Type F). As this is the 6442 most comprehensive and longest duration dataset for YCl3, it probably provides the best 6443 estimates of sr and ss, and these values were used in analysis of some other datasets below. 91 6444 (491) Schiessle et al. (1963) followed the biokinetics of Y for 180 days after inhalation 91 6445 of YCl3 (carrier free) by guinea pigs. There are comprehensive measurements at seven time 6446 points up to 28 days, but few results at later times. Modelling conducted here gave parameter -1 -1 6447 values: fr = 0.81, sr = 1.07 d and ss = 0.016 d (consistent with assignment to default Type F) 6448 in broad agreement with those based on the study by Muggenburg et al. (1998). Schmidtke et 91 6449 al. (1963) followed the biokinetics of Y for 56 days after inhalation by guinea pigs of 91 91 6450 YCl3 with added stable yttrium. Compared to the behaviour with carrier-free YCl3 6451 (Schiessle et al., 1963), lung retention and faecal clearance were somewhat higher, and 6452 skeletal uptake and urinary excretion lower. Schmidtke et al. (1964) carried out 6453 complementary autoradiographic studies on respiratory tract tissues obtained 21 days after 91 6454 inhalation of YCl3 by guinea pigs. Schmidtke (1964) investigated the effect of DTPA on 91 91 6455 the biokinetics of Y for 8 days after inhalation of YCl3 (carrier free) by guinea pigs. 6456 Unusually, the tissue distribution was measured at several time points during the first day. 6457 Modelling conducted here on results from control animals (using a fixed value of -1 6458 ss = 0.013 d , derived above, because of the short duration of measurements in this study) -1 6459 gave parameter values: fr = 0.83 and sr = 1.3 d (consistent with assignment to default Type 6460 F) in good agreement with those based on the study by Schiessle et al. (1963). Treatment 91 6461 with DTPA caused rapid clearance from the lungs and excretion from the body of Y.

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88 6462 (492) Wenzel et al. (1969) followed the biokinetics of Y for 32 days after inhalation by 88 6463 rats of YCl3, either carrier-free with added stable yttrium. Lung retention was higher, and 88 6464 skeletal uptake and urinary excretion lower, in rats exposed to Y with stable yttrium than in 88 6465 those that inhaled carrier-free Y. Faecal clearance was also higher, suggesting that the 6466 additional lung retention was in particulate form, rather than bound. Using fixed values of -1 -1 6467 sr = 0.74 d and ss = 0.013 d , derived above, modelling conducted here gave values of fr = 88 6468 0.94 (consistent with assignment to Type F) for the YCl3 inhaled in carrier-free form; and fr 88 6469 = 0.7 (consistent with assignment to Type M) for the YCl3 inhaled with added stable 6470 yttrium. 88 6471 (493) Bailey et al. (1978) followed the biokinetics of Y for 9 days after intratracheal 88 6472 instillation of YCl3 into rats. By 2 days, about 20% ILD remained in the lungs, 50% ILD 6473 had been excreted in faeces, and 30% was deposited in systemic sites or excreted in urine, 6474 again suggesting little absorption from the upper airways, but considerable absorption from 88 6475 the deep lung. They also developed a systemic compartment model for Y in the rat based on 6476 an intravenous injection study. With only two time points, there are insufficient data to define -1 -1 6477 all three dissolution parameter values. Using fixed values of sr = 0.74 d and ss = 0.013 d , 6478 derived above, modelling conducted here showed a good fit to the data with fr = 0.7 6479 (consistent with assignment to default Type M). 6480 (494) Hirano et al. (1990) followed the lung retention and distribution of yttrium for 162 6481 days after intratracheal instillation into rats of 100 µg of stable yttrium as chloride. The 88 6482 retention half-time of about 170 days is far greater than observed in the studies with YCl3 or 91 6483 YCl3 reviewed here. There was also relatively little systemic uptake, but few details are 6484 given: the authors concluded that the yttrium was retained in the lungs in an insoluble form. 6485 The clearance was considerable slower than would be expected for insoluble particles in rats 6486 (ICRP, 2002), suggesting that there was considerable binding of yttrium to lung structures. 6487 Yttrium was detected in alveolar and interstitial macrophages and in basement membranes, 6488 supporting this inference. However, dose-related inflammatory responses were seen over the 6489 range of masses (10 – 200 µg) administered in complementary short-term experiments, and 6490 so the kinetics may well differ from those pertaining at tracer levels. Marubashi et al. (1998) 6491 reported that 30 days after intratracheal instillation into rats of 50 µg of stable yttrium as 6492 chloride, about 67% ILD remained, again, much slower clearance than observed in the 6493 radiotracer studies. 6494 (495) Gensicke and Nitschke (1964) showed that treatment with hexametaphosphate 91 91 6495 increased the clearance of Y after inhalation of YCl3 by mice. There is insufficient 6496 information in the paper to enable dissolution parameter values to be derived reliably, but the 6497 biokinetics in the controls appears broadly similar to that in the other radiotracer studies 6498 outlined above, with activity in the skeleton exceeding that in the lungs by about a week after 6499 inhalation. 6500 (496) Based on the results of the experiments outlined above, specific absorption -1 -1 6501 parameter values of fr = 0.9, sr = 1 d and ss = 0.01 d (consistent with assignment to default 6502 Type F), and fA = 0.02 (the default value for ingestion of yttrium) are used here for yttrium 6503 chloride. 6504 6505 Yttrium oxide (Y2O3) 91 6506 (497) Newton et al. (1971) measured tissue retention of Y at 8 and 64 days after 91 6507 inhalation of Y2O3 by dogs. At 8 days, the activity in the skeleton was about 30% of that in 6508 the lungs, and at 64 days they were approximately equal. From results of a complementary 6509 gavage experiment it was calculated here that fractional absorption from the alimentary tract -1 6510 fA = 0.0003. Using a fixed value of sr = 0.74 d derived above for yttrium chloride, modelling

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-1 6511 conducted here gave values of fr = 0.45 and ss = 0.006 d , (consistent with assignment to 6512 Type M). Given the relatively sparse information, specific parameter values are not 6513 recommended here for yttrium oxide: instead it is assigned to Type M. 6514 6515 Yttrium phosphate (YPO4) 91 6516 (498) Newton et al. (1971) measured tissue retention of Y at 8 and 64 days after 91 6517 inhalation of YPO4 by dogs. At 8 days, the activity in the skeleton was about 20% of that in 6518 the lungs, and at 64 days 45% of it. [The authors noted that following both inhalation and 91 6519 gavage of YPO4, the ratio of deposition in the skeleton to that in the liver (~3:1) was lower 91 6520 than following inhalation of other forms of Y (~6:1 for chloride, oxide and FAP), but that 6521 this observation needed confirmation.] From results of a complementary gavage experiment 6522 it was calculated here that fractional absorption from the alimentary tract fA = 0.0004. Using a -1 6523 fixed value of sr = 0.74 d derived above for yttrium chloride, modelling conducted here gave -1 6524 values of fr = 0.33 and ss = 0.002 d , (consistent with assignment to Type M). Given the 6525 relatively sparse information, specific parameter values are not recommended here for 6526 yttrium phosphate: instead it is assigned to Type M. 6527 6528 Fused aluminosilicate particles (FAP) 6529 (499) FAP or “fused clay” particles have been extensively used as relatively insoluble 6530 particles in inhalation studies, both of biokinetics and of radiation effects. A natural clay 6531 mineral is labelled by ion exchange, and the labelled clay particles heated to about 1100˚C, to 6532 form aluminosilicate glass microspheres in which the label is incorporated. It has been 6533 demonstrated that when yttrium is incorporated into FAP, only a small fraction is rapidly 6534 absorbed, while the remainder is retained within the particles and absorbed slowly. 6535 (500) In a detailed low-level study carried out to complement a lifespan study of the 91 91 6536 effects of inhaled Y-FAP (Hahn et al., 1994), the biokinetics of Y were followed for 320 91 6537 days after inhalation of Y-FAP by dogs (Hobbs et al., 1971). By 8 days after inhalation, 91 6538 97% of Y remaining in the body was in the lungs, with <1% in the skeleton, but by 256 -1 6539 days the latter had increased to about 10%. Using a fixed value of sr = 0.74 d derived above 6540 for yttrium chloride, and taking the default assumption for fractional absorption from the 6541 alimentary tract (Table 11-2) to be fA = 0.002*fr, modelling conducted here gave values of fr = -1 6542 0.004 and ss = 0.0009 d , (consistent with assignment to Type S). In a similar low-level 90 6543 study carried out to complement a lifespan study of the effects of inhaled Y-FAP (Hahn et 90 90 6544 al., 1983), the biokinetics of Y were followed for 12 days after inhalation of Y-FAP by 6545 dogs (Hobbs et al., 1970; Barnes et al., 1972). The shorter duration reflects the 64-hour half- 90 6546 life of Y. During this period, the activity distribution was similar to seen in the more 91 6547 extensive Y-FAP study. Estimates of the rate of dissolution of Y-FAP, following inhalation 88 –1 6548 of Y-FAP by rats and men were in the range 0.00015 – 0.0005 d (Bailey et al., 1981; 91 6549 1985), indicating assignment to Type S. Rates of dissolution of Y-FAP measured in vitro 6550 varied considerably, depending on particle size and conditions, in the range 0.00001 – –1 6551 0.001 d (Kanapilly and Goh, 1973), and indicate Type M or S behaviour. 6552 6553 Rapid dissolution rate for yttrium –1 6554 (501) Studies with yttrium chloride give values of sr of about 1 d , and this is applied here –1 6555 to all Type F forms of yttrium. Because it is lower than the general default value of 3 d for 6556 Type M and S materials, it is also applied to Type M and S forms of yttrium. 6557 6558 Extent of binding of yttrium to the respiratory tract 91 6559 (502) The results of autoradiographic studies of the distribution of Y after

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91 91 6560 inhalation of YCl3 suggest that the Y retained in the lungs was in particulate form rather 6561 than bound to lung structures. It is therefore assumed that for yttrium the bound state can be 6562 neglected, i.e. fb = 0.0. 6563 6564 Table 11-2. Absorption parameter values for inhaled and ingested yttrium 6565 Absorption parameter Absorption from valuesa the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Specific parameter valuesb Yttrium chloride 0.9 1 0.01 1x10-4

Default parameter valuesc,d Absorptio Assigned forms n Type F 1 1 – 1x10-4 M Oxide, phosphate, all unspecified 0.2 1 0.005 2x10-5 formse S FAP 0.01 1 1x10-4 1x10-6

Ingested material All chemical forms 1x10-4 a 6566 It is assumed that for yttrium the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M and 6567 S forms of yttrium (1 d–1, respectively) are element-specific. 6568 b See text for summary of information on which parameter values are based, and on ranges of parameter 6569 values observed for individual materials. For yttrium chloride specific parameter values are used for 6570 dissolution in the lungs, but the default value of fA. 6571 c Materials (e.g. yttrium-labelled FAP) are listed here where there is sufficient information to assign to a 6572 default absorption Type, but not to give specific parameter values (see text). 6573 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 6574 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 6575 absorption Type and the fA value for ingested soluble forms of yttrium (1x10-4). 6576 e Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 6577 or if the form is known but there is no information available on the absorption of that form from the 6578 respiratory tract. 6579 6580 11.1.2. Ingestion 6581 6582 (503) Yttrium absorption has been poorly studied. Studies performed on dogs and goats 6583 suggested that yttrium absorption from the gastrointestinal tract is very low (Nold et al., 91 6584 1960). One other study performed on rats with Y used to label solid and liquid food showed 6585 that the total recovery of Y in the gastrointestinal tract between 30 min and 12 hours after 6586 ingestion was about 98% (Marcus and Langemann, 1962). 90 6587 (504) Study performed with rats fed daily with Y in drinking water showed that, after a 6588 60 days period of ingestion, the skeleton contained less than 0.01% of the total ingested 6589 activity (Sullivan et al., 1963). This poor absorbability of yttrium has also been noticed in 6590 studies using fowl and has led to designate Y as a non-absorbed reference substance (Sklan et 6591 al., 1975). 6592 (505) Recent studies performed in rats (Damment and Pennick, 2007) and in human 6593 subjects (Pennick et al., 2006) with carbonate can provide a good assessment of 6594 yttrium absorption because of their chemical analogies. Results in rats showed that 0.004% of 6595 the administered dose was recovered in the urine over a period of 7 days (Damment and

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6596 Pennick, 2007), and results in humans showed an absolute bioavailability of lanthanum of 6597 about 0.0013 % (Pennick at al., 2006). -4 6598 (506) In Publication 30 (ICRP, 1980), an absorption value of 1x10 was recommended. 6599 Since no relevant additional data on the gastrointestinal absorption of yttrium is available, an -4 6600 fA value of 1x10 is adopted here for all chemical forms. 6601 6602 11.1.3. Systemic Distribution, Retention and Excretion 6603 6604 11.1.3.1. Summary of the database 6605 6606 Overview 6607 (507) The biokinetics of systemic yttrium varies with the mode of administration and the 6608 administered form and mass, due in part to the tendency of yttrium compounds to form 6609 colloids (Lloyd, 1961; Rosoff et al., 1961; Spencer, 1968). Colloidal yttrium deposits largely 6610 in the liver, spleen, or bone marrow, with the distribution depending on particle size (Dobson 6611 et al., 1948). Yttrium that is absorbed to blood across membranes or intravenously injected in 6612 non-colloidal form initially clears with a half-time of 1 h or less (Ekman and Aberg, 1961; 6613 Kawin, 1963, Schmidtke, 1964) and transfers mainly to bone surfaces, liver, kidneys, and 6614 urinary bladder contents (Hamilton, 1949; Durbin, 1960; Herring et al., 1962; Ando et al., 6615 1989; Muggenburg et al., 1998). A few percent of the absorbed or injected amount clears 6616 more slowly from blood, presumably due mainly to attachment to plasma proteins (Rosoff et 6617 al., 1958; Hirano and Suzuki, 1996). 6618 (508) Yttrium is tenaciously retained by bone, and a substantial portion of that deposited in 6619 soft tissues also shows relatively slow return to blood. After intravenous administration of 88 6620 Y as citrate to human subjects, about one-fifth of the injected amount was excreted within a 6621 few days, primarily in urine, and the remainder was retained with a projected half-time of 6622 years (Etherington et al., 1989a,b). 6623 6624 Data for human subjects 90 6625 (509) Rosoff et al., (1961) and Spencer (1968) studied the rate of excretion of Y in 6626 elderly hospital patients after intravenous injection of different forms of yttrium and the 6627 effects of chelating agents on the excretion rate. Less than 0.5% of the administered amount 90 6628 was excreted in urine during the first 24 hours after administration of YCl3. About 5% of 90 6629 the administered activity was excreted in urine during the first day after administration of Y 90 6630 as nitrilotriacetate ( Y-NTA), a form thought to prevent the formation of yttrium hydroxy 90 6631 colloids. The chelating agents EDTA and DTPA were found to be effective in removing Y 90 6632 from the body if administered in the first day or two after intake of Y. 6633 (510) Retention, distribution, and urinary and fecal excretion of yttrium were studied in 88 6634 two healthy adult male volunteers who received Y as citrate (T1/2 = 107 d) by intravenous 88 6635 injection (Etherington et al., 1989a,b). The behavior of Y as determined by in vivo 6636 measurements and bioassay was similar in the two subjects. An estimated 22% of the 6637 injected amount was excreted in the first few days, with urinary excretion accounting for 94% 6638 and 93% of the excreted amount in Subjects A and B, respectively, over 5 d and 91% in 6639 Subject B over 14 d. The combined retention data for the subjects could be approximated by 6640 a two exponential function to time t (days) after injection: 6641 6642 R(t) = 0.22 exp (-0.693 t / T1) + 0.78 exp (0.693 t / T2) 6643 6644 where the short-term half-time T1 was about 16 hours and the long-term half-time T2 was

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6645 much longer than the measurement period of about one year. Uptake by the liver was 6646 estimated from external measurement as about 12% and 10% for Subjects A and B, 6647 respectively. One-fourth or more of the liver content was lost over the first few days or 6648 weeks, and the remainder was removed more slowly. In Subject B, at least half the initial 6649 deposit was retained in the liver after 6 months. The results of a longitutinal scan on one 6650 subject at 22 days were consistent in magnitude and qualitative shape with the estimated bone 6651 surface area distribution in the body. 6652 6653 Data for laboratory animals 6654 (511) For comparison with findings summarized above for their two human subjects, 88 6655 Etherington and coworkers (1989a,b) determined the tissue distribution of Y in rats 88 6656 intravenously injected with similar Y solutions. The findings for rats were broadly 6657 consistent with the systemic biokinetics estimated for the human subjects, the main difference 6658 being that removal from the liver was faster and the fecal excretion rate was higher in rats. 6659 On average, urinary and fecal excretion accounted for 26.1% and 8.4%, respectively, of 6660 injected activity after 4 days in rats. The contents of liver, kidneys, gastrointestinal tract, and 6661 carcass (including skeleton) accounted for 4.4%, 1.4%, 0.9%, and 58.6%, respectively. 91 6662 (512) In rats receiving YCl3 by parenteral injection, 55-65% of the administered amount 6663 deposited in the skeleton, and little of this was lost over the next 2-3 months (Hamilton, 1949; 6664 Durbin, 1960). At 4 d after administration, the liver contained about 12% of the administered 6665 activity, and excreta (primarily urine) accounted for about 26% (Durbin, 1960). Data of 6666 Ando et al. (1989) indicate that the liver contained a major portion of the systemic activity 90 6667 between 3 hours and 2 days after intravenous injection of YCl3 into rats. 90 6668 (513) Watanabe et al. (2005) studied the effectiveness of CaNa3DTPA in removing Y 90 6669 from the body in rats contaminated with Y chloride via a puncture wound. In control 90 6670 animals the concentration of Y in bone was on average about 10 times that in liver, 6 times 6671 that in kidney, and 60 times that in blood during the first 24 h. At 7 d the concentration in 6672 bone was about 39 times that in liver, 17 times that in kidney, and 1900 times that in blood. 6673 Prompt treatment of the wound with CaNa3DTPA was found to be more effective than 90 6674 systemic treatment in minimizing accumulation of Y in bone. 91 6675 (514) A goat receiving Y by intravenous injection excreted about 20% of the injected 6676 amount in urine and 4% in faeces over the first 10 d (Ekman and Aberg, 1961). The 91 6677 concentration of Y in blood serum declined by a factor of ~8 from a few minutes to 3 h after 6678 injection and a factor of ~2.5 from 3-24 h after injection. About half of the total 10-d urinary 6679 losses occurred on the first day and about one-fourth occurred on the second day. Fecal 6680 losses were about 0.7% on day 1, 2% on day 2, and 0.4% on day 3, and declined 6681 monotonically thereafter. Examination of cartilage from the trachea and ribs indicated that 91 6682 Y may have been bound to chondroitinsulphuric acid. 91 6683 (515) After brief inhalation of YCl3 by guinea pigs, about 28% of the deposited activity 6684 was absorbed to blood over the first 8 days (Schmidtke, 1964). At that time the skeleton, 6685 liver, kidneys, and blood of animals not receiving chelation therapy contained about 65%, 6686 5%, 1%, and 0.15%, respectively, of the absorbed activity. Urinary excretion during the first 6687 8 days accounted for about 22% of the absorbed amount. 91 6688 (516) The biokinetics, dosimetry, and radiological effects of Y have been studied in dogs 91 6689 exposed to different Y aerosols (McClellan and Rupprecht, 1967; Barnes et al., 1972; 6690 Muggenburg et al., 1998). Detailed systemic data were obtained for dogs exposed to 91 91 6691 relatively soluble YCl3 aerosols. A sharp drop in total-body Y occurred during the first 6692 several days after exposure, presumably due to clearance of activity deposited in the upper 6693 respiratory tract by mucociliary transport and subsequent swallowing and fecal excretion.

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6694 After about 3 weeks the rate of decline of the body burden approximated the radiological 91 6695 half-life of Y. Daily losses in urine and faeces were measured in three dogs through 64 6696 days post exposure. On average about 15% of the initial body burden was removed in urine 6697 and about 45-50% in faeces during the first week. Fecal excretion was the dominant route of 6698 excretion during the first four days, but beyond two weeks post injection daily urinary 91 6699 excretion was 1.5-4 times greater than daily fecal excretion. Tissue concentrations of Y 6700 measured in three dogs at 32 d after intake indicated that the skeleton, liver, and kidneys 6701 contained roughly 75%, 15%, and 1%, respectively, of the systemic burden. Autoradiographs 6702 were made using tissue collected at necropsy of dogs dying in the early postexposure period. 6703 In bones, activity was prominent on bone surfaces. The concentration in long bones was 6704 higher near the ends than in the shaft. Activity was generally diffuse in the liver and spleen. 91 6705 Absorbed Y was found in bronchial cartilage. 91 6706 (517) In studies on young dogs receiving Y by intravenous or intraperitoneal injection, 6707 activity depositing in the skeleton was found to concentrate on non-growing, highly calcified 6708 surfaces and resorbing surfaces of bone (Jowsey et al., 1958, Herring et al., 1962). No 6709 deposition was found in osteoid tissue. It was suggested that the mechanism of binding of 6710 yttrium to bone surfaces may be different from that of plutonium or despite the 6711 general similarities in the skeletal behavior of these elements (Herring et al., 1962). 91 90 90 90 6712 (518) Weanling rabbits were injected intravenously with Y, Sr free from Y, or Sr 90 6713 and Y in equilibrium to compare the relative distributions of strontium and yttrium and to 90 90 6714 determined whether Y produced in vivo from decay of Sr behaves differently from 6715 yttrium introduced as a parent radionuclide (Lloyd, 1961). A qualitative similarity in the two 90 90 6716 chemically dissimilar radionuclides Y and Sr was observed in that the tissues containing 90 91 6717 the highest concentration of Sr were also those containing the highest concentration of Y 90 91 6718 (i.e. bone, pituitary, cartilage, and kidney). The distributions of Sr and Y differed 91 6719 quantitatively. For example, kidney, liver, and spleen concentrated Y to a much greater 90 91 6720 extent than Sr. The rate of disappearance of Y from the soft tissues was much lower than 90 91 6721 the rate of disappearance of Sr. At 9 days, the Y concentration in the liver was 150 times 90 90 90 6722 that of Sr. When Sr was injected there was a secondary uptake of Y in the liver, spleen, 90 6723 and kidneys after the initial distribution of Sr. 6724 (519) Stevenson (1975) studied the influence of age and gender on the relative behaviors 90 90 90 6725 of Y and Sr in rats over a period of 32 d following administration of solutions with Sr 90 90 90 6726 and Y in equilibrium. The activity ratio Y : Sr in bone depended to some extent on age 6727 and gender but typically was 1.0-1.6 at 1 d, increased by ~30% over the next 3 d, and then 90 90 6728 declined to near equilibrium levels over the next month. The ratio Y : Sr in the liver rose 6729 from about 10 at 30 min after injection to about 400 by the fourth day. During the same 6730 period the ratios for the kidney and spleen rose from about 3 to about 100-150 and the ratio 6731 for the heart rose from 1.5 to 14-22. The general conclusion was that the yttrium in blood is 6732 initially taken up to a much larger extent than strontium by soft tissues but gradually transfers 90 90 6733 to the skeleton, resulting in a temporary elevation of the ratio Y : Sr in bone. 90 90 6734 (520) By measuring the relative activities of Sr and Y in various tissues of a beagle, 90 90 6735 Arnold et al. (1955) concluded that Y does not separate from Sr in bone volume. Their 90 6736 conclusion was based mainly on the observation that Y did not become more concentrated 90 90 6737 than Sr at sites where migrating Y would have tended to accumulate. 6738 (521) Mueller (1972) studied the relative behavior of strontium and yttrium in mice and 90 90 90 6739 intraperitoneal injection of Sr and Y in radioactive equilibrium or Sr freshly purified 90 90 90 6740 from Y. At 7 d after injection of equilibrium activities, the concentration ratio Y: Sr was 90 6741 about 150 for liver and spleen and near 1 for bone. At 7 d after injection of purified Sr, the 6742 activity ratio was about 3 for liver and spleen and 0.9 for bone.

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6743 6744 11.1.3.2. Biokinetic model for systemic yttrium 6745 6746 (522) The structure of the systemic model for yttrium is shown in Figure 11-1. Transfer 6747 coefficients are listed in Table 11-3. The transfer coefficients describing movement of 6748 yttrium between bone compartments and removal from bone are default values for bone- 6749 surface seekers. Other transfer coefficients in the model are based on deposition fractions 6750 and biological half-times summarized below. Deposition fractions and half-times describing 6751 uptake and retention by the liver and rates of urinary and faecal excretion were selected for 6752 consistency with yttrium injection data for healthy human subjects described earlier. The 6753 remaining deposition fractions and half-times were based on animal data described earlier, 6754 with preference given to data for large animals. 6755 (523) Blood is divided into compartments Blood 1 and Blood 2 representing fast and slow -1 6756 clearance, respectively. Yttrium leaves Blood 1 at the rate 16.6 d corresponding to a 6757 biological half-time of 1 h. Outflow from Blood 1 is divide as follows: 3% moves to Blood 2; 6758 15% to the urinary bladder contents; 1% to the small intestine (SI) contents; 40% to bone 6759 surfaces, equally divided between trabecular and cortical surfaces; 10% to a fast-turnover 6760 liver compartment called Liver 0; 1% to the kidneys; 22% to a fast-turnover soft-tissue 6761 compartment called ST0; and 8% to a slow-turnover soft-tissue compartment called ST1. 6762 Activity is removed from Liver 0 with a biological half-time of 3 d. Activity leaving Liver 0 6763 is divided among Blood 1, SI contents (representing biliary secretion), and a slow-turnover 6764 liver compartment called Liver 1 in the ratio 0.5 : 0.4 : 0.1. Activity is removed from 6765 Blood 2 to Blood 1 with a half-time of 1.5 d; from ST0 to Blood 1with a half-time of 3 d; and 6766 from Liver 1, Kidneys, and ST1 to Blood 1 with a half-time of 1 y. The fate of yttrium 6767 deposited on bone surfaces is described by the generic model for bone-surface-seekers, 6768 except that yttrium biologically removed from bone is assumed to return to blood rather than 6769 to be channeled through bone marrow. Thus, yttrium is removed from cortical or trabecular 6770 bone surfaces at a rate proportional to (1.5 times) the turnover rate of that bone type. The -1 -1 6771 assumed bone turnover rates are 3% y for cortical bone and 18% y for trabecular bone. 6772 One-third of activity removed from bone surfaces is buried in bone volume and two-thirds 6773 transfers to Blood 1. Activity is removed from cortical or trabecular bone volume to Blood 1 6774 at the rate of turnover of that bone type. 6775 (524) Model predictions are compared with the human injection data of Etherington et al. 6776 (1989a,b) in Figures 11-2 to 11-4. In these two subjects, urinary excretion accounted for 93- 6777 94% of the excreted amount over 5 d and 91% over 14 d. Model values are 91% over 5 d and 6778 89% over 14 d.

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6779 6780 Figure 11-1. Structure of the biokinetic model for systemic yttrium. 6781 6782 Table 11-3. Parameter values in the systemic model for yttrium. From To Transfer coefficient (d-1) Blood 1 Blood 2 0.498 Blood 1 Liver 0 1.66 Blood 1 Kidneys 0.166 Blood 1 ST0 3.652 Blood 1 ST1 1.328 Blood 1 Urinary bladder contents 2.49 Blood 1 SI contents 0.166 Blood 1 Trabecular surface 3.32 Blood 1 Cortical surface 3.32 Blood 2 Blood 1 0.462 Liver 0 SI contents 0.0231 Liver 0 Blood 1 0.0924 Liver 0 Liver 1 0.116 Liver 1 Blood 1 0.0019 Kidneys Blood 1 0.0019 ST0 Blood 1 0.231 ST1 Blood 1 0.0019 Trabecular Blood 1 0.000493 surface Trabecular Trabecular volume 0.000247 surface Trabecular Blood 1 0.000493 volume Cortical surface Blood 1 0.0000821 Cortical surface Cortical volume 0.0000411 Cortical volume Blood 1 0.0000821 6783 6784 11.1.3.3. Treatment of radioactive progeny 6785 6786 (525) Chain members addressed in the derivation of dose coefficients for internally 6787 deposited yttrium isotopes include isotopes of yttrium, strontium, zirconium, and niobium.

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6788 An yttrium isotope produced in the body after uptake of an yttrium parent is assumed to have 6789 the same systemic biokinetics as the parent. and niobium produced in 6790 systemic compartments after intake of an yttrium parent are assigned the characteristic 6791 systemic models for zirconium and niobium, respectively, described elsewhere in this report. 6792 The characteristic systemic models for yttrium, zirconium, and niobium all have the same 6793 model structure. A zirconium or niobium atom produced in a given compartment by 6794 radioactive decay is assumed to behave as if it had entered that compartment as a parent 6795 radionuclide. This includes subcompartments of ‘Other soft tissue’. 6796 (526) The model for strontium produced in systemic compartments after intake of an 6797 yttrium parent is an extension of the characteristic model for strontium described elsewhere 6798 in this report. That model is extended by adding individual compartments representing liver 6799 and kidneys, which are represented explicitly in the model for yttrium. Each of these 6800 compartments is assumed to exchange strontium with blood. Parameter values describing 6801 rates of uptake and removal of strontium by liver and kidneys are set for reasonable 85 6802 agreement with postmortem measurements on human subjects injected with Sr during late 6803 stages of various terminal illnesses (Schulert et al., 1959). The transfer coefficients from -1 6804 blood to liver and kidneys are both set at 0.05 d . The transfer coefficient from blood to the 6805 intermediate-term soft-tissue compartment in the characteristic model for strontium is -1 -1 6806 reduced from 1.5 d to 1.4 d to leave the total outflow rate from blood unchanged. The 6807 removal half-times from liver and kidneys to blood are set at 6 d and 2 d, respectively. 6808 Strontium produced by radioactive decay in compartments of the yttrium model that are not 6809 identifiable with compartments of the strontium model is treated as follows. Strontium 6810 produced in either of the two blood compartments of the yttrium model is assumed to transfer -1 6811 to the single blood compartment of the strontium model at the rate 1000 d (half-time of ~1 6812 min). Strontium produced in either of the two liver compartments of the yttrium model is 6813 assumed to transfer to the blood compartment of the strontium model with a half-time of 6 d, 6814 which is the removal half-time of strontium from the liver in the extended strontium model 6815 described above. Strontium produced in either of the two compartments of ‘Other soft tissue’ 6816 in the yttrium model is assumed to transfer to the blood compartment of the strontium model -1 6817 at the rate 2.5 d , which is the shortest removal half-time from the soft-tissue compartments 6818 in the characteristic model for strontium. 6819 6820

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6821 6822 Figure 11-2. Model predictions of total-body retention of intravenously injected yttrium 6823 compared with observations of Etherington et al. (1989a,b) for two human subjects 6824 intravenously injected with 88Y as citrate. 6825

6826 6827 Figure 11-3. Model predictions of liver content of yttrium as a function of time after intravenous 6828 injection, compared with observations of Etherington et al. (1989a,b) for two human subjects 6829 intravenously injected with 88Y as citrate. 6830

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6831 6832 Figure 11-4. Model predictions of urinary excretion of yttrium as a function of time after 6833 intravenous injection, compared with observations of Etherington et al. (1989a,b) for two 6834 human subjects intravenously injected with 88Y as citrate. 6835 6836 11.2. Individual monitoring 6837 90 6838 (527) Monitoring of Y is generally accomplished by measuring its beta emission in 6839 urine, either using liquid scintillation or beta proportional counting. 6840 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 90Y Urine Bioassay Liquid Scintillation 1-5 Bq/L 1 Bq/L Counting 90Y Urine Bioassay Beta proportional 0.4 Bq/L 0.05 Bq counting 6841 6842 References 6843 6844 Ando, A., Ando, I., Hiraki, T., Hisada, K., 1989. Relation between the location of elements in the 6845 periodic table and various organ-uptake rates. Nucl. Med. Biol. 16, 57-80. 6846 Arnold, J.S., Stover, B.J., Van Dilla, M.B., 1955. Failure of Y-90 to escape from skeletally-fixed Sr- 6847 90. Soc. Exp. Biol. Med. 90, 260-263. 6848 Bailey, M.R., Fry, F.A., James, A.C., 1985. Long-term retention of particles in the human respiratory 6849 tract. J. Aerosol Sci., 16, 295–305. 6850 Bailey, M.R., Hodgson, A., Smith, H., Strong, J.C., Savory, A.J., 1981. In vitro and in vivo 6851 dissolution characteristics of monodisperse labelled aluminosilicate glass particles. In: Stöber 6852 W., Hochrainer D., Editors. Aerosols in Science, Medicine and Technology - Physical and 6853 Chemical Properties of Aerosols. Proc. GAeF 8 Conference. Gesellschaft für 6854 Aerosolforschung, pp. 265-70. 6855 Bailey, M.R., Smith, H., Hostford, J.E., 1978. In vivo behaviour of the radionuclides used to label 6856 fused clay particles. NRPB/ R&D2. National Radiological Protection Board Annual Research 6857 and Development Report 1977, pp. 80-83.

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6858 Barnes, J. E., McClellan, R.O., Hobbs, C.H., Kanapilly, G.M., 1972. Toxicity in the dog of inhaled 6859 90Y in fused clay particles: distribution, retention kinetics, and dosimetry. Radiation Research 6860 49, 416-429. 6861 Damment S., Pennick M., 2007. Systemic lanthanum is excreted in the bile of rats. Toxicol. Lett. 171, 6862 69-77. 6863 Dobson, E.L., Gofman, J.W., Jones, H.B., Kelly, L.S., Walker, L.A., 1948. Studies with colloids 6864 containing radioisotopes of yttrium, zirconium, columbium, and lanthanum. J. Lab. Clin. 6865 Med. 34, 305-312. 6866 Durbin, P.W., 1960. Metabolic characteristics within a chemical family. Health Phys. 2, 225-238. 6867 Ekman, L., Aberg, B., 1961. Excretion of niobium-95, yttrium-91, -144 and -147, 6868 in goats. Res. Vet. Sci. Vol. 2. pp.100-105. 6869 Etherington, G., Bailey, M.R., Dorrian, M.D., Hodgson, A., 1989a. A study of the biokinetics of 6870 intravenously administered yttrium-88 in man. Radiation Protection – Theory and Practice. 6871 Paper presented at 4th Int. Symp., Malvern, 445-448. 6872 Etherington, G., Bailey, M.R., Dorrian, M.D., Hodgson, A., 1989b. The biokinetics of intravenously 6873 administered yttrium-88 in man. Radiation Protection Bulletin. No. 105, 16-19. 6874 Gensicke, F., Nitschke, H.W., 1964. Effect of hexametaphosphate aerosols on the metabolism of 6875 inhaled 91Y chloride. Health Phys. 10, 1243-1249. 6876 Hahn, F.F., Griffith, W.C., Hobbs, C.H., Muggenburg, B.A., Boecker, B.B., 1994. Biological effects 6877 of 91Y in relatively insoluble particles inhaled by beagle dogs. Ann. Occup. Hyg. 38, 275-280. 6878 Hahn, F.F., Boecker, B.B., Cuddihy, R.G., Hobbs, C.H., McClellan, R.O., Snipes, M.B., 1983. 6879 Influence of radiation dose patterns on lung tumor incidence in dogs that inhaled beta 6880 emitters: A preliminary report. Radiat. Res. 96, 505-517. 6881 Hamilton, J.G., 1949. The metabolism of the radioactive elements created by . New 6882 England J. Med. 240:863-870, 1949. 6883 Herring, G.M., Vaughan, J., Williamson, M., 1962. Preliminary report on the site of localization and 6884 possible binding agent for yttrium, americium and plutonium in cortical bone. Health Phys. 8, 6885 717-724. 6886 Hirano, S., Kodama, N., Shibata, K., Suzuki, K.T., 1990. Distribution, localization, and pulmonary 6887 effects of yttrium chloride following intratracheal instillation in the rat. Toxicol. Appl. 6888 Pharmacol. 104, 301-311. 6889 Hirano, S., Suzuki, K.T., 1996. Exposure, metabolism, and toxicity of rare earths and related 6890 compounds. Environ. Health Perspect. 104 (Suppl. 1), 85-95. 6891 Hobbs, C.H., Barnes, J.E., Chiffelle, T.L., Jones, R.K., Kanapilly, G.M., Lundgren, D.L., Mauderley, 6892 J.L., McClellan, R.O., Pickrell, J.A., Rypka, E.W., 1970. Toxicity of inhaled 90Y fused clay in 6893 beagle dogs. II. In: Fission Product Inhalation Program Annual Report 1969-1970, LF-43, pp. 6894 146-162. Lovelace Foundation for Medical Education and Research, Albuquerque, New 6895 Mexico. Available from National Technical Information Service, Springfield, Virginia. 6896 Hobbs, C.H., Cuddihy, R.G., Hahn, F.F., Jones, R.K., Kanapilly, G.M., Mauderley, J.L., McClellan, 6897 R.O., Pickrell, J.A., 1971. Toxicity of inhaled 91Y fused clay in beagle dogs. II. In: Fission 6898 Product Inhalation Program Annual Report 1970-1971, LF-44, pp. 151-163. Lovelace 6899 Foundation for Medical Education and Research, Albuquerque, New Mexico. Available from 6900 National Technical Information Service, Springfield, Virginia. 6901 ICRP, 1980. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Part 2. Pergamon 6902 Press, Oxford. Ann. ICRP 4, (3/4). 6903 ICRP, 2002. Guide for the Practical Application of the ICRP Human Respiratory Tract Model.ICRP 6904 Supporting Guidance 3 Annals of the ICRP 32(1-2). 6905 Jowsey, J., Rowland, R.E., Marshall, J.H., 1958. The deposition of the rare earths in bone. Radiat. 6906 Res. 8, 490-501. 6907 Kanapilly, G.M., Goh, C.H.T., 1973. Some factors affecting the in vitro rates of dissolution of 6908 respirable particles of relatively low solubility. Health Phys. 25, 225–237. 6909 Kawin, B., 1963. Effects of zirconium citrate on early femur uptake and urinary excretion of 6910 radioisotopes. Health Phys. 9, 1031-1034.

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6911 Lloyd, E., 1961. The relative distributions of radioactive yttrium and strontium and the secondary 6912 deposition of Y-90 built up from Sr-90. Int. J. Radiat. Biol. 3:457-492. 6913 Lloyd, E., 1961. The relative distributions of radioactive yttrium and strontium and the secondary 6914 deposition of Y-90 built up from Sr-90. Int. J. Radiat. Biol. 3, 457-492. 6915 Marcus, C., Lengemann, F., 1962. Use of radioyttrium to study food movement in the small intestine 6916 of the rat. J. Nutrition 76, 179-182. 6917 Marubashi, K., Hirano, S., Suzuki, K.T., 1998. Effects of intratracheal pretreatment with yttrium 6918 chloride (YCl3) on inflammatory responses of the rat lung following intratracheal instillation 6919 of YCl3. Toxicology Letters 99, 43–51. 91 6920 McClellan, R.O., Rupprecht, F.C., 1967. Toxicity of inhaled YCl3 in beagle dogs. In: Fission 6921 product inhalation program annual report. Lovelace Foundation for Medical Education and 6922 Research, Albuquerque, New Mexico, LF-38, pp. 40-64. 6923 Mueller, W.A., 1972. Y-90 distribution in male mice after injection of Sr-90, and consequences for 6924 dose burden of bone, soft tissue, and gonads. In: Comar, C. L., president, Second international 6925 conference on strontium metabolism. Glasgow and Strontian. 16-19 August 1972, pp. 137- 6926 143. 6927 Muggenburg, B.A., Boecker, B.B., Hubbs, A.F., Hahn, F.F., Snipes, M.B., Diel, J.H., Newton, G.J., 91 6928 Griffith, W.C., 1998. Toxicity of inhaled YCl3 in dogs. Radiat. Res. 150, 212-226. 6929 Newton, G.J., Hobbs, C.H., McClellan, R.O., 1971. The intraorgan distribution in the beagle dog of 6930 91Y inhaled as the oxide, phosphate and in fused clay. In: Fission Product Inhalation Program 6931 Annual Report 1970-1971, LF-44, pp. 76-80. Lovelace Foundation for Medical Education and 6932 Research, Albuquerque, New Mexico. Available from National Technical Information 6933 Service, Springfield, Virginia. 6934 Nold, N., Hayes, R., Comar, C., 1960. Internal radiation dose measurements in live experimental 6935 animals. Health Phys. 4, 86-100. 6936 Pennick, M., Dennis, K., Damment, S., 2006. Absolute bioavailability and disposition of lanthanum in 6937 healthy human subjects administered lanthanum carbonate. J. Clin. Pharmacol. 46, 738-746. 6938 Rosoff, B., Lewin, R., Hart, H.E., Williams, G.L., Laszlo, D., 1958. Interaction of yttrium compounds 6939 with serum and serum constituents in vitro. Arch. Biochem. Biophys. 78, 1-9. 6940 Rosoff, B., Ritter, S., Sullivan, K., Hart, H., Spencer-Laszlo, H., 1961. Effect of chelating agents on 6941 the removal of yttrium and lanthanum from man. Health Phys. 6, 177-182. 6942 Schiessle, W., Schmidtke, I., Philipp, K., Fibich, K., 1963. Inhalationsversuche mit trägerfreiem Y91 6943 Cl3 beim Meerschweinchen. Zentr. Biol. Aerosol Forsch. 11, 12-36. 6944 Schmidtke, I., 1964. Removal of inhaled radioactive yttrium by the use of diethylenetriamine- 6945 pentaacetic acid (DTPA). Health Phys. 10, 1235-1241. 6946 Schmidtke, I., Blattner, L. Schiessle, W., 1964. Über einige autoradiographische Beobachtungen nach 6947 Inhalation von radioactiven Yttrium und Zirkonium. Strahlentherapie, 124, 232-241. 6948 Schmidtke, I., Schiessle, W., Philipp, K., 1963. Über den Einfluss des Trägerzusatzes bei 91 6949 Inhalationsversuchen mit Y Cl3, Strahlentherapie, 122, 123-136. 6950 Schulert, A.R., Peets, E.A., Laszlo, D., Spencer, H., Charles, M., Samachson, J., 1959. Comparative 6951 metabolism of strontium and calcium in man. Int. J. Appl. Radiat. Isotop. 4, 144-153 6952 Sklan, D., Dubrov, D., Eisner, U., Hurwitz, S., 1975. 51Cr-EDTA, 91Y and 141Ce as nonabsorbed 6953 reference substances in the gastrointestinal tract of the chicken. J Nutr 105, 1549-1552. 6954 Spencer, H., 1968. Metabolism and removal of some radioisotopes in man. In: Kornberg, H. A.; 6955 Norwood, W. D., eds., Diagnosis and treatment of deposited radionuclides. Proceeding of a 6956 symposium held in Richland, Washington, 15-17 May, 1967. 6957 Stevenson, A.F.G., 1975. The influence of age and sex on the activity ratio of yttrium-90 to strontium- 6958 90 in the rat skeleton after incorporation of strontium-90. Health Phys. 29, 285-290. 6959 Sullivan, M.F., Marks, S., Thompson, R.C., 1963. Beta irradiation of rat intestine. Long-term studies 6960 after daily yttrium-90 ingestion. Am J Pathol 43, 527-37. 6961 Watanabe, N., Tanada, S., Sasaki, Y., 2005. Effect of calcium trisodium DTPA in rats with puncture 6962 wound contaminated by 90Y chloride. Radiat. Prot. Dosim. 114, 509-513.

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6963 Wenzel, W.J., Thomas, R.G. McClellan, R.O., 1969. Effect of stable yttrium concentration on the 6964 distribution and excretion of inhaled radioyttrium in the rat. Am. Ind. Hyg. Assoc. J. 30, 630- 6965 634. 6966

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6967 12. ZIRCONIUM (Z = 40) 6968 6969 12.1. Chemical Forms in the Workplace 6970 6971 (528) Zirconium is a transition metal which mainly occurs in oxidation state IV. It may be 6972 encountered in industry in a variety of chemical and physical forms, including oxides, 93 95 6973 carbonates, oxalates and zircon (ZrSiO4). Zirconium radionuclides such as Zr and Zr are 6974 likely to be encountered in the nuclear industry in the form of activated Zircalloy fuel 6975 element cladding, and in acidic fission product solutions. Zirconium could also be present in 6976 fragments of irradiated fuel. 6977 6978 Table 12-1. Isotopes of zirconium addressed in this report 6979 Isotope Physical half-life Decay mode Zr-86 16.5 h EC, B+ Zr-87 1.68 h EC, B+ Zr-88 83.4 d EC Zr-89 78.41 h EC, B+ Zr-93 1.53E+6 y B- Zr-95a 64.032 d B- Zr-97 16.744 h B- 6980 a Data for these radionuclides are given in the printed copy of this report. Data for other 6981 radionuclides are given on accompanying electronic disk. 6982 6983 12.2. Routes of Intake 6984 6985 12.2.1. Inhalation 6986 6987 Absorption Types and parameter values 6988 95 6989 (529) In all the studies noted below the zirconium isotope followed was Zr (t½ 64 d), 95 6990 which decays to niobium-95 ( Nb, t½ 35 d). In most studies both radionuclides were 6991 deposited in the respiratory tract, and the combined activity of the two radionuclides 6992 followed. Thus in interpreting the results it has to be assumed that their behaviour was 95 6993 similar. Furthermore, the Nb measured was partly that which deposited, and partly that 95 6994 formed from the in situ decay of Zr. Because of the relatively short half-lives of these 6995 radionuclides few studies are of sufficient duration to distinguish Types M and S behaviour 6996 based on the ICRP Publication 71 criteria of lung retention or total absorption up to 180 d 6997 after intake. 6998 (530) Some information was found on the behaviour of inhaled zirconium in man, mainly 6999 associated with irradiated fuel. Information is available from experimental studies of 7000 zirconium as oxalate, oxide, and irradiated dioxide. 7001 (531) Absorption parameter values and Types, and associated fA values for particulate 7002 forms of zirconium are given in Table 12-2. 7003 7004 Zirconium oxalate 95 7005 (532) Following inhalation by guinea pigs of carrier-free Zr-oxalate, the activity in the 7006 lungs immediately after the 30-minute exposure, and at 1 and 28 days later was about 24%, 7007 10% and 5% of the “recovered dose”. Amounts in the skeleton at these times were 8%, 15%

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95 7008 and 9% respectively. Similar results were obtained using Zr-oxalate with added zirconium 7009 oxychloride (ZrOCl2) (Schmidtke et al., 1964; Schiessle et al., 1964). The large uptake in the –1 7010 skeleton at the first measurement suggests a rapid dissolution rate, sr, of the order of 100 d . 7011 However, about 10% of the activity deposited in the lungs was not cleared rapidly (fr ~0.9). 7012 The decrease in lung content between 4 and 28 days did not give any obvious increase in 7013 activity in the skeleton, and hence no indication of a significant “bound state” from which 7014 clearance is only by absorption. The amount retained in the lungs at 28 d suggests assignment 7015 to Type M, but is very close to the criterion for assignment to Type F. 95 95 7016 (533) Thomas et al. (1971) studied the biokinetics of Zr– Nb following inhalation by 7017 mice of aerosols formed by heating droplets of zirconium oxalate solution to various 7018 temperatures. In vitro dissolution tests were conducted on similar materials by Kanapilly and 7019 Goh (1973) and Kanapilly et al. (1973). Immediately after inhalation of the aerosols formed 7020 at 100˚C and 250˚C (both zirconium oxalate, but mainly droplets and solid particles 7021 respectively) the skeleton contained about 20% of the body content, the lungs 2% and 25% 95 95 7022 respectively. It was noted that the ratio of Nb to Zr in the lungs was lower than in the 95 7023 aerosol, indicating a pronounced differential loss of Nb. Nevertheless, the results suggest 7024 that at the lower temperature most of the material deposited in the lungs was absorbed –1 7025 rapidly: fr ~0.9 and sr of the order of 100 d . For both materials these results indicate Type F 7026 behaviour, as do those of the in vitro dissolution tests. 7027 (534) Since rapid absorption is incomplete, the results are difficult to interpret, all the more 95 7028 so because of the radionuclide mixture present. Furthermore, absorption of Nb from the 7029 lungs following deposition of the oxalate, is also complex (see niobium inhalation section). 7030 Hence specific parameter values are not recommended by the task group for zirconium 7031 oxalate. The information above suggests assignment to Type F, but also that absorption is 7032 slower than for niobium oxalate, for which there is more comprehensive information, which 7033 gives assignment to Type M. Zirconium oxalate is therefore also assigned to Type M. 7034 7035 Zirconium oxide and carbonate 95 95 7036 (535) As noted above, Thomas et al. (1971) studied the biokinetics of Zr– Nb following 7037 inhalation by mice of aerosols formed by heating droplets of zirconium oxalate solution. The 7038 aerosols formed at 600˚C (Zr(CO3)2 and ZrOCO3) and at 1100˚C (ZrO2 and ZrOCO3) gave 7039 very similar results in vivo (with no differential loss of niobium). From 10 to 130 d after 7040 inhalation the lungs contained more than 90% of the sacrifice body burden (SBB) while the 7041 skeleton content increased from 2% SBB at 2 d to 6% SBB at 130 d. These results indicate 7042 Type S behaviour. In vitro tests on similar materials by Kanapilly and Goh (1973) and 7043 Kanapilly et al. (1973) confirmed low dissolution rates, but their duration was too short to 7044 distinguish Type M from Type S. 95 7045 (536) Cuddihy (1978) applied simulation modelling to measurements of Nb following 95 7046 inhalation of similar Nb-labelled zirconium aerosols (formed at 1000˚C) by dogs to obtain 7047 an absorption function (fractional absorption rate): 7048 –0.04t –1 7049 S(t) = 0.00016 e + 0.0001 d at time t (days) after intake, 7050 –1 –1 7051 which can be represented using the HRTM with fr = 0.004, sr = 0.04 d and ss = 0.0001 d , 95 7052 consistent with assignment to Type S. This assumes that the absorption of Nb is a marker 95 7053 for dissolution of the zirconium oxide matrix, and not leaching of the Nb from it. In vivo 7054 measurements following accidental inhalation of what was probably the same material by a 7055 person gave a lung retention half time of about 220 days, indicating Type M or S behaviour 7056 (Waligora, 1971).

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7057 7058 Zirconium tritide 7059 (537) For details see the hydrogen inhalation section. Measurements of tritium following 7060 intratracheal instillation of zirconium tritide into rats were consistent with assignment to Type 7061 S. 7062 7063 Nuclear weapons fallout 95 95 7064 (538) During the early 1960s, measurements were made of Zr– Nb activities in human 7065 lungs due to fall-out from atmospheric nuclear weapons tests. Most were made post mortem 7066 (Schönfeld et al., 1960; Osborne, 1963; Wrenn et al., 1964; Dutailly et al., 1966), but in vivo 7067 measurements were also made, enabling the variation with time in individual subjects to be 7068 determined (Rundo and Newton, 1962; 1965). Several authors compared their measurements 7069 with those predicted from measured air concentrations, using a single exponential model 7070 (ICRP, 1959). Biological lung retention half-times were estimated to be between about 70 d 7071 (Wrenn et al., 1964) and more than 120 d (Rundo and Newton, 1965). Wrenn et al., (1964) 95 95 7072 noted that little Zr– Nb activity was found in other tissues, and that Wegst et al. (1964) had 95 95 7073 shown that Zr- Nb activity in the lungs was present in particulate form. Overall this 7074 indicates Type M or S behaviour. 7075 7076 Irradiated fuel 7077 (539) Following an accidental release, zirconium could be present in fragments of 7078 irradiated fuel, where the matrix is predominantly uranium oxide. The results of a study on 7079 one person following accidental inhalation of irradiated fuel indicate Type M behaviour of 95 95 7080 the zirconium present (Rundo, 1965). In another, measurements of Zr- Nb made on a 7081 worker for 6 months following an accidental intake, probably of irradiated fuel (UO2), 7082 indicate Type S behaviour (Thind, 1995). 7083 (540) Mirell and Blahd (1989) made whole-body measurements of activity on seven 7084 people from about two weeks to several months after exposure to the initial Chernobyl 7085 reactor accident plume in Kiev, Ukraine. Biological retention half-times were similar for 95 7086 different radionuclides (49 days for Zr-Nb) and different from those expected for systemic 7087 retention, indicating that they were trapped in particles and metabolically inert, and thus 7088 indicating Type M rather than Type F behaviour. 7089 (541) Tissue distribution and retention of several radionuclides were followed for 3 7090 months after intratracheal instillation of irradiated UO2 powder into rats (Lang et al., 1994). 95 7091 For Zr, the total amounts absorbed by 1 and 3 months were estimated to be about 1% and 7092 3% of the initial lung deposit (ILD) respectively, indicating values of fr <0.01 and ss -1 7093 ~0.001 d , and assignment to Type S. 7094 (542) The in vitro dissolution of samples of particles released from the Chernobyl accident 7095 was measured for up to 60 d (Cuddihy et al., 1989). For all radionuclides, including 95 95 7096 Zr- Nb, 10% dissolved in a few hours, and the rest with a half-time of 160 d. Hence fr = –1 –1 7097 0.1, sr ~10 d , and ss = 0.004 d , consistent with assignment to Type M. 7098 7099 Other compounds 95 95 7100 (543) Measurements of Zr– Nb in the lungs of a person for 5 months following an 7101 accidental intake of unspecified material indicate Type M or S behaviour (Cofield, 1963). 7102 7103 Decay products of zirconium formed in the respiratory tract 7104 (544) The general approach to treatment of decay products formed in the respiratory tract 7105 is described in Part 1, Section 3.2.3. In summary, it would be expected that the rate at which a

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7106 particle dissociates is determined by its matrix, and hence the physico-chemical form of the 7107 inhaled material, but that the behaviour of soluble (Type F) material in the respiratory tract 7108 would depend on its elemental form, i.e. that of the . Nevertheless, for 7109 simplicity, in this series of documents it is assumed that decay products formed in the 7110 respiratory tract have the same dissolution parameter values as the parent inhaled. 95 7111 (545) Of particular importance in the case of zirconium is the formation of Nb (t½ 35 d) 95 7112 from Zr (t½ 64 d). Some experimental results were found from which the absorption of 95 95 7113 Nb could be compared directly with that of Zr under the same conditions. However, the 95 95 7114 Nb in the respiratory tract would have been partly administered with the Zr and partly 95 7115 formed in the respiratory tract by decay of the Zr parent. 95 95 7116 (546) Thomas et al. (1971) studied the biokinetics of Zr– Nb following inhalation by 7117 mice of aerosols formed by heating droplets of zirconium oxalate solution to various 7118 temperatures (see above). For the aerosols formed at 100˚C and 250˚C (both zirconium 95 95 7119 oxalate) the ratio of Nb to Zr in the lungs was lower than in the aerosol, indicating a 95 7120 pronounced differential loss of Nb. The aerosols formed at 600˚C (Zr(CO3)2 and ZrOCO3) 7121 and at 1100˚C (ZrO2 and ZrOCO3) showed no differential loss of niobium. 7122 (547) Lang et al. (1994) followed the tissue distribution and retention of several 7123 radionuclides for 3 months after intratracheal instillation of irradiated UO2 powder into rats 95 7124 (see above and niobium inhalation section). For Zr, the estimated total amounts absorbed 95 7125 by 1 and 3 months were ~1% and 3% ILD, whereas for Nb they were ~5% and 9% ILD. 7126 (548) Thus there is evidence that for some, especially soluble, forms of zirconium, the 7127 niobium daughter is absorbed from the lungs more rapidly than the zirconium parent. 7128 However, as there is insufficient information to estimate element-specific rapid dissolution –1 7129 rates for either element, the general default value of 30 d is applied to both, and so their 7130 dissolution parameter values are the same. 7131 7132 Rapid dissolution rate for zirconium 7133 (549) Evidence from the zirconium oxalate studies outlined above suggests a rapid –1 7134 dissolution rate of the order of 100 d , but only of part of the ILD, (fr < 1). There is therefore –1 7135 no justification for choosing a rate different from the general default value of 30 d , which is 7136 applied here to all Type F forms of zirconium. 7137 7138 Extent of binding of zirconium to the respiratory tract 7139 (550) Evidence from the zirconium oxalate studies outlined above suggests that following 7140 the rapid phase of absorption about 10% of the initial lung deposit clears slowly from the 7141 lungs. Clearance of this material does not appear to be mainly by absorption to blood, as 7142 assumed for material in the “bound state”, and therefore does not give evidence for 7143 significant binding of zirconium. Moreover, the results available are difficult to interpret (see 7144 above). It is therefore assumed that for zirconium the bound state can be neglected, i.e. fb = 7145 0.0. 7146 7147

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7148 7149 Table 12-2. Absorption parameter values for inhaled and ingested zirconium 7150 Absorption parameter Absorption from valuesa the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorption Assigned forms Type F — 1 30 – 0.002 M Oxalate; all unspecified 0.2 3 0.005 4x10-4 forms S Carbonate, oxide, tritide 0.01 3 1x10-4 2x10-5

Ingested material All chemical forms 0.002 a 7151 It is assumed that for zirconium the bound state can be neglected i.e. fb = 0. The values of sr for Type F, M 7152 and S forms of zirconium (30, 3 and 3 d–1, respectively) are the general default values. 7153 b Materials (e.g. zirconium oxalate) are listed here where there is sufficient information to assign to a default 7154 absorption Type, but not to give specific parameter values (see text). 7155 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 7156 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the -3 7157 absorption Type and the fA value for ingested soluble forms of zirconium (2x10 ). 7158 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 7159 or if the form is known but there is no information available on the absorption of that form from the 7160 respiratory tract. 7161 7162 12.2.2. Ingestion 7163 7164 (551) Few human data are available on the absorption of zirconium from the 96 7165 gastrointestinal tract. In a study using stable tracer Zr-chloride given to a healthy male -3 7166 volunteer, the absorption of zirconium was estimated to be 2.5∙10 (Veronese et al., 2003a 7167 and b). A broader study was conducted with stable tracers in a total of 14 volunteers, to 7168 which zirconium was administered in the form of oxalate or citrate (Greiter et al., 2011). The -3 7169 fractional absorption was found to be equal to (7.4±1.5)∙10 for oxalate and to -3 7170 (1.10±0.23)∙10 for citrate. 7171 (552) These values are similar to those found with animals. Fletcher (1969) reported -4 -3 95 7172 values ranging from 3.10 to 2.10 for the fractional absorption of Zr in young adult rats 7173 after administration of a number of chemical forms, including the chloride, sulphate and 7174 organic complexes with lactate and oxalate. Similar values were reported by Shiraishi and 7175 Ichikawara (1972) for Zr oxalate in adult rats, de Bartolo et al. (2000) for Zr sulphate in 7176 rabbits and Sirotkin et al. (1970) for Zr chloride in cows. Taylor et al. (1983) obtained values -4 7177 ranging from 1.5 to 8.10 for the fractional absorption of the chemically similar radionuclide 181 7178 Hf in rats and hamsters. 7179 (553) Reference values used previously were 0.002 in ICRP Publication 30 (1979) and 7180 0.01 for intake from members of the public (ICRP, 1989). However, this latter value was 7181 adopted for taking account of the biologically incorporated form of the element present at low 7182 concentration in the diet. On the basis of the recent human and animal data, an fA value of 7183 0.002 is adopted here for all chemical forms. 7184 7185 7186

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7187 12.2.3. Systemic Distribution, Retention and Excretion 7188 7189 12.2.3.1. Summary of the database 7190 7191 Human subjects 89 7192 (554) Mealey (1957) studied the biokinetics of Zr (T1/2 = 78.4 h) following its 7193 intravenous administration as citrate to a comatose subject with brain cancer but with vital 7194 signs, electrolyte levels, and renal function within normal limits. Activity cleared slowly 89 7195 from plasma, apparently due to binding of Zr to plasma proteins. About 10% of the injected 7196 amount (corrected for decay) remained in plasma at 7 d. There was little if any accumulation 89 7197 of Zr in red blood cells. Urinary excretion accounted for 2.5% of the administered amount 89 7198 over the first 24 h and 7.6% over 7 d. Intravenously administered Zr was also measured in 7199 biopsy samples from two patients undergoing neurological surgery. In one of the subjects the 89 89 -1 7200 Zr concentrations in bone (skull) and muscle were 1.2 and 4.8% of injected Zr kg tissue, 89 7201 respectively, at 90 min after administration. In the other subject, concentrations of Zr in -1 7202 bone, muscle, and normal brain tissue were 0.9, 7.6, and 0.8% kg , respectively, at 3 h. High 89 7203 accumulation of Zr in muscle was also indicated by external measurements on other 7204 patients. External measurements on one subject over three successive days indicated a 7205 sustained high concentration of activity in muscle but a substantial decrease in the 7206 concentrations in the skull and brain during this period. 7207 (555) The biokinetics of zirconium was studied in three healthy subjects (one male and 7208 two females in the age range 27-60 y) following oral or intravenous administration of stable 7209 zirconium isotopes (Veronese et al., 2003a,b). Clearance of injected zirconium from plasma 7210 could be characterized by a relatively fast component representing roughly half of the 7211 administered amount, followed by a slower component. The half-time associated with the 7212 faster component was estimated as 3.6 h in two subjects and 0.8 h in the third subject. The 7213 investigators derived a half-time of about 3 d for the slower component after combining their 7214 findings with longer-term measurements of plasma clearance of zirconium reported by 7215 Mealey (1957). 7216 (556) Relatively long-term studies of the biokinetics of orally or intravenously 7217 administered stable zirconium isotopes were later conducted on seven male and six female 7218 subjects in the age range 26-60 y (Greiter et al., 2011). The zirconium isotopes were prepared 7219 either in citrate or oxalate solution. Blood plasma and urine were sampled up to 100 d after 7220 administration. Mean fractional absorption of zirconium was sevenfold higher after oral 7221 intake of zirconium oxalate than after intake of zirconium citrate. The derived urinary 7222 excretion data are difficult to interpret in terms of typical excretion rates due to the high 7223 variability of the measurements and a relatively high detection limit. Approximately 20% and 7224 40% of the urinary measurements were below the detection limit in the injection and oral 7225 tracer studies, respectively. Taken at face value, the data indicate that urinary losses over the 7226 first week averaged about 6% of the intravenously injected amount. The investigators’ 7227 proposed biokinetic model for zirconium with expected transfer coefficients based on results 7228 of the study predicts total urinary losses of about 2% at 7 d and 8% at 100 d after intravenous 7229 injection. 7230 7231 Laboratory animals 7232 (557) Bone was found to be the main systemic repository for zirconium tracers following 7233 their administration by various routes to rats (Durbin, 1960; Fletcher, 1969), guinea pigs 7234 (Schiessle et al., 1961), and mice (Bäckström et al., 1967; Thomas et al., 1971; Abou et al., 7235 2011). Autoradiographic studies on rats (Hamilton, 1947) indicated that skeletal zirconium

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7236 was confined largely to bone surfaces. 95 7237 (558) At 4 d after intramuscular administration of Zr as citrate to rats, the liver, kidneys, 7238 and bone contained approximately 6.6, 4.9, and 35%, respectively, of the administered 7239 activity (Durbin, 1960). About 18% of administered activity had been excreted by that time, 7240 mainly in faeces. Nearly two-thirds of the administered amount remained in the body after 2- 7241 4 mo. 95 95 95 7242 (559) Autoradiographic studies following intravenous administration of Nb or Zr- Nb 7243 to mice indicated qualitatively similar distributions of activity in the two cases (Bäckström et 7244 al., 1967). These distributions were also similar to that observed by the investigators in an 103 7245 earlier study of Ru. All of these radionuclides showed an affinity for connective tissue as 103 95 95 95 7246 well as bone. The affinity for bone increased in the order Ru < Nb < Zr- Nb 7247 (Bäckström et al., 1967). 95 7248 (560) Following intraperitoneal administration of Zr citrate to rats, about 60% of the 7249 injected amount was retained after 1 mo and about 50% was retained after 3 mo (Richmond 7250 et al., 1960). In a similar study on mice conducted by the same investigators (Furchner et al., 95 7251 1964), nearly half of the injected Zr was rapidly lost from the body, and about two-thirds of 7252 the administered amount was lost within a few weeks. Measurements up to 420 d after 7253 injection indicated that the remaining one-third was removed with a biological half-time of 7254 several years. 95 95 7255 (561) Fletcher (1969) studied the behavior of Zr and Nb in rats following oral or 95 95 95 7256 intravenous administration of Zr- Nb or pure Nb as oxalates. Total-body retention of 95 7257 Zr over 80 d was determined by external counting and correction for counts for 95 95 95 7258 simultaneously injected Nb and Nb formed in vivo by radiological decay of Zr. The 95 7259 correction was based on the assumption that Nb formed in vivo behaves as if it had been 7260 injected intravenously at the time of formation. This assumption was consistent with the 95 95 95 7261 measured distributions of Nb and Zr at 80 d. Total-body retention of injected Zr was 7262 greater in males than females at all measurement times. As an average over both sexes, about 95 7263 90% of intravenously administered Zr was retained in the body after 8 d, 80% was retained 95 7264 after 30 d, and 60% was retained after 80 d. The concentration of Zr in tissues following 95 95 7265 administration of a mixture of Zr and Nb was determined using physical decay 7266 measurements or beta scintillation counting of their distinctive beta emissions. At 8 d an 95 7267 estimated 89-92% of total-body Zr was in bone, and the kidneys, spleen, and liver each 7268 contained a few tenths of 1% of the administered amount. 95 95 7269 (562) The relative behaviours of Zr and Nb were studied in mice following inhalation 7270 of these radionuclides at near-equilibrium conditions in aerosols produced at various 95 95 7271 temperatures (Thomas et al., 1971). Comparison of the activity ratios Nb: Zr in the 7272 aerosols, lung, bone, and liver indicated different systemic biokinetics of these radionuclides. 95 95 95 7273 Bone was the main systemic repository for both Zr and Nb, but Zr showed higher 95 7274 accumulation in bone and lower accumulation in liver than Nb. 7275 (563) Shiraishi and Ichikawara (1972) studied the gastrointestinal absorption, retention, 95 95 7276 and distribution of Zr- Nb following a single oral administration to rats of different ages. 7277 Similar rates of loss of absorbed activity were seen for all age groups following an initially 7278 rapid decline in the total-body content presumably representing removal of unabsorbed 7279 activity from the body. At 40 d after administration to adult rats, about 63% of the retained 7280 activity was in bone, 3.8% was in the liver, 20% was in muscle, and 2.9% was in the kidneys. 7281 (564) Razumovskii et al. (1966) studied the effects of various complex-forming agents on 95 95 95 7282 the biokinetics of Zr and Nb in rats. At 3 d after intraperitoneal administration of Zr- 95 7283 Nb oxalate to control animals, the liver, spleen, kidneys, and femur contained about 4.2, 7284 0.56, 1.4, and 0.6% of the administered activity, respectively.

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95 7285 (565) Ando and Ando (1986) examined the early distribution of Zr in soft tissues of 7286 tumor-bearing rats following its intravenous administration as oxalate or nitrate. At 3, 24, 95 7287 and 48 h after administration of either form of Zr the liver contained about 3-4%, the 7288 kidneys contained about 1-1.5%, and skeletal muscle contained about 13-17% of the 7289 administered amount. 89 7290 (566) Abou et al. (2011) investigated the behavior of Zr in mice following its intravenous 7291 administration as oxalate, chloride, phosphate, citrate, or desferrioxamine (DFO). 7292 Concentrations were determined in blood, liver, kidneys, bone, marrow, muscle, heart, lungs, 89 7293 spleen, and gastrointestinal tissues at 4 h, 8 h, and 6 d. After 6 d the total excretion of Zr 7294 amounted to about 20% for the chloride or oxalate but only about 5% for the phosphate. Mice 89 7295 injected with the citrate excreted about 30% after 1 d and 35% after 6 d. Virtually all Zr 89 7296 administered as DFO was excreted the first day. For administration of Zr as phosphate the 7297 highest concentrations were found in the liver and spleen at all times. For administration of 89 7298 Zr as oxalate, chloride, or citrate, the concentration in bone generally was more than twice 7299 that in other tissues at early times and more than 10 times that in other tissues at 6 d. Bone 7300 marrow cells showed little activity compared with calcified tissues. The epiphysis, consisting 7301 mainly of cartilage, contained most of the bone activity. The authors concluded that weakly 7302 bound zirconium is a bone seeker and likely binds to phosphate constituents of mineralized 7303 bone and epiphysis. 95 7304 (567) Results of studies on rats indicate that a substantial portion of Nb formed in vivo 95 95 7305 from decay of systemic Zr is free to redistribute. For example, the distribution of Nb 95 7306 formed in vivo from decay of ingested or intravenously injected Zr it rats was similar to the 95 95 7307 distribution of administered Nb and considerably different from the distribution of Zr 95 95 95 7308 (Fletcher, 1969). Following oral administration of Zr- Nb to suckling rats, the ratio of Zr 95 7309 to Nb was 4-5 in bone and close to 1 in other tissues (Shiraishi and Ichikawa, 1972). 7310 Measurements of activity in blood and tissues of rats following intraperitoneal injection of 95 95 95 7311 Zr- Nb as oxalate indicated preferential accumulation of Zr in bone (Rama Sastry et al., 7312 1964). 7313 7314 12.2.3.2. Biokinetic model for systemic zirconium 7315 7316 (568) The systemic model for zirconium used in this report depicts the following general 7317 behavior of zirconium. Roughly half of zirconium atoms entering blood transfer to tissues 7318 and excretion pathways within a few hours, and the remainder combine with plasma proteins 7319 and are cleared much more slowly from blood. More than 95% of zirconium atoms leaving 7320 blood deposit in tissues and <5% enter excretion pathways, primarily the urinary bladder 7321 contents. Soft tissues initially contain a substantial portion of extravascular zirconium, but 7322 bone eventually contains >90% of the systemic burden due to a relatively high deposition 7323 fraction and much slower turnover than soft tissues. Zirconium atoms that reach blood have a 7324 long residence time in the body due to a low excretion rate and a high level of accumulation 7325 in bone. 7326 (569) The structure of the systemic model for zirconium is shown in Figure 11-1. Transfer 7327 coefficients are listed in Table 12-3. These values were derived from primary parameter 7328 values in the form of deposition fractions and biological half-times. The parameter values 7329 were set to yield blood disappearance curves and urinary excretion rates for zirconium 7330 consistent with those observed in human subjects, a relatively high zirconium content in soft 7331 tissues at early times as observed in human subjects, and a time-dependent systemic 7332 distribution of zirconium suggested by animal studies. The comparative biokinetics of 7333 zirconium and niobium as observed in animal studies has been taken into account. Niobium

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7334 shows qualitatively similar systemic behavior to that of zirconium but a lower rate of transfer 7335 to bone, higher urinary clearance, and apparently greater uptake or retention or both by soft 7336 tissues than zirconium. It was convenient to derive transfer coefficients for zirconium in soft 7337 tissues, in particular, by scaling values developed from more easily interpreted soft-tissue 7338 data for niobium, to which the same model structure (Figure 12-1) is applied in this report. 7339 Except where there are overriding considerations, the assigned deposition fractions and 7340 removal half-times describing uptake and retention of zirconium in soft-tissue compartments 7341 are one-half the values used in the model for niobium. 7342 (570) In the systemic model for zirconium, atoms that are absorbed or injected into blood 7343 initially enter a blood compartment called Blood 1. Zirconium leaves Blood 1 at the rate -1 7344 5 d , corresponding to a removal half-time of about 3.3 h. Outflow from Blood 1 is divided 7345 as follows: 40% goes to a slow-turnover blood pool representing plasma proteins (Blood 2 in 7346 Figure 12-1); 40% goes to a soft-tissue pool with relatively fast turnover (ST0); 15% transfers 7347 to bone surfaces and is equally divided between cortical and trabecular bone; 1.5% goes to 7348 the liver; 0.25% goes to the kidneys; 0.75% transfers to a soft-tissue compartment with 7349 relatively slow turnover (ST1); 2% enters the urinary bladder contents; and 0.5% is secreted 7350 into the small intestine (SI) contents. The deposition fractions for Blood 2 and ST0 are the 7351 same as assumed in the model for niobium; the fraction for bone surfaces is five times greater 7352 than for niobium; the fraction for the urinary bladder contents is about one-fifth the value for 7353 niobium; and values for other repositories are one-half the values applied to niobium. 7354 7355

7356 7357 Figure 12-1. Structure of the biokinetic model for systemic zirconium. 7358 7359 7360

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Table 12-3. Parameter values in the systemic model for zirconium.

From To Transfer coefficient (d-1) Blood 1 Blood 2 2.0 Blood 1 Liver 0 0.075 Blood 1 Kidneys 0.0125 Blood 1 ST0 2.0 Blood 1 ST1 0.0375 Blood 1 Urinary bladder contents 0.1 Blood 1 SI contents 0.025 Blood 1 Trabecular surface 0.375 Blood 1 Cortical surface 0.375 Blood 2 Blood 1 0.462 Liver 0 SI contents 0.116 Liver 0 Blood 1 0.116 Liver 0 Liver 1 0.462 Liver 1 Blood 1 0.01 Kidneys Blood 1 0.01 ST0 Blood 1 0.462 ST1 Blood 1 0.02 Trabecular surface Blood 1 0.000493 Trabecular surface Trabecular volume 0.000247 Trabecular volume Blood 1 0.000493 Cortical surface Blood 1 0.0000821 Cortical surface Cortical volume 0.0000411 Cortical volume Blood 1 0.0000821 7361 7362 (571) Zirconium is assumed to transfer from Blood 2 back to Blood 1 with a half-time of 7363 1.5 d, from ST0 to Blood 1 with a half-time of 1.5 d, from ST1 to Blood 1 with a half-time of 7364 35 d, and from Kidneys to Blood 1 with a half-time of 70 d. The transfer coefficients derived 7365 from these and other half-times given below are rounded values. Zirconium entering the liver 7366 is assigned to a compartment called Liver 0. Zirconium is removed from Liver 0 with a half- 7367 time of 1 d, with two-thirds going to a long-term retention compartment of liver called Liver 7368 1 and the other one-third equally divided between SI contents (representing biliary secretion) 7369 and Blood 1. Zirconium transfers from Liver 1 to blood with a half-time of 70 d. The 7370 removal half-times from Blood 2 and ST0 to Blood 1 were set for consistency with the blood 7371 retention patterns observed in health human subjects. The removal half-times from other soft- 7372 tissue compartments were set to one-half the values for niobium. The fate of zirconium 7373 depositing on bone surface is described by the generic model for bone-surface-seeking 7374 radionuclides, except that zirconium removed from bone is returned directly to blood rather 7375 than channelled through bone marrow. 7376 (572) Model predictions of retention of zirconium in blood are compared in Figure 12-2 7377 with central values for healthy human subjects following intravenous injection with stable 7378 isotopes of zirconium (Veronese et al., 2003b; Greiter, 2008). For the case of intravenous 7379 injection of zirconium, the model predicts cumulative urinary excretion of about 2.3% of the 7380 injected amount over the first 24 h, 5.5% over the first 7 d, and 11% over the first 100 d. 7381 These predictions are reasonably consistent with values observed in human subjects 7382 following intravenous injection of zirconium tracers (Mealey, 1957; Greiter, 2008, 2011).

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7383 7384 7385 Figure 12-2. Comparison of model predictions of blood retention of zirconium with central 7386 values for healthy human subjects following intravenous administration of stable zirconium 7387 isotopes (Veronese et al., 2003b; Greiter, 2008). 7388 7389 12.2.3.3. Treatment of radioactive progeny 7390 7391 (573) Chain members addressed in the derivation of dose coefficients for internally 7392 deposited zirconium isotopes include isotopes of yttrium, strontium, and niobium. The 7393 characteristic systemic models for yttrium, zirconium, and niobium all have the same model 7394 structure. An yttrium or niobium atom produced in a given compartment by radioactive decay 7395 after intake of a zirconium parent is assumed to behave as if it had entered that compartment 7396 as a parent radionuclide. The model for strontium produced in systemic compartments after 7397 intake of a zirconium parent is the same as the model for strontium produced after intake of 7398 an yttrium parent, as described in the section on yttrium. 7399 7400 12.3. Individual monitoring 7401 95 95 7402 (574) Zr is a γ emitter. Monitoring of Zr is in general accomplished through Whole 7403 Body Counting or/and urine bioassays. 7404 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 95Zr Urine Bioassay γ-ray spectrometry 5 Bq/L 0.1 Bq/L 95Zr Lung monitoring γ-ray spectrometry 19Bq* 95Zr Whole Body γ-ray spectrometry 50 Bq 20 Bq Counting 7405 ∗ Lung monitoring of 95Zr is not generally used in routine monitoring of workers. Monte Carlo program 7406 Visual Monte Carlo was used to simulate the photon emission, to calculate the calibration factor for the 7407 geometry and radionuclide, and to calculate the minimum detectable activity (MDA) in the lung. (Hunt et 7408 al., 2012)

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7409 7410 References 7411 7412 Abou, D.S., Ku, T., Smith-Jones, P.M., 2011. In vivo biodistribution and accumulation of 89Zr in 7413 mice. Nucl. Med. Biol. 38, 675:681. 7414 Ando, A., Ando, I., 1986. Distribution of 95Zr and 181Hf in tumor-bearing animals and mechanism for 7415 accumulation in tumor and liver. Nucl. Med. Biol. 13, 21-29. 7416 Bäckström, J., Hammarström, L., Nelson, A., 1967. Distribution of zirconium and niobium in mice. 7417 Autoradiographic study. Acta Radiol. 6, 122-128. 7418 Cofield, R.E., 1963. In vivo gamma spectrometry for inhalations of -237–-233, 7419 cobalt-60, and zirconium-95–niobium-95. Health Phys. 9, 283–292. 7420 Cuddihy, R.G., 1978. Deposition and retention of inhaled niobium in beagle dogs. Health Phys. 34, 7421 167–176. 7422 Cuddihy, R.G., Finch, G.L., Newton, G.J., Hahn, F.F., Mewhinney, J.A., Rothenberg, S.J., Powers, 7423 D.A., 1989. Characteristics of radioactive particles released from the Chernobyl nuclear 7424 reactor. Environ. Sci. Technol. 23, 89–95. 7425 De Bartolo, D., Cantone, M.C., Giussani, A., Garlaschelli, L., Roth, P., Werner, E., 2000. 7426 Determination of biokinetic parameters for ingestion of radionuclides of zirconium in animals 7427 using stable tracers. Radiat. Environ. Biophys. 39, 53-58. 7428 Durbin, P.W., 1960. Metabolic characteristics within a chemical family. Health Phys. 2, 225-238. 7429 Dutailly, L., Martin, J., Robert, J., Burg, C., 1966. Zirconium-95 and niobium-95 in human lungs and 7430 atmospheric dust during 1963. Nature, 212, 702–703. 7431 Fletcher, C.R., 1969. The radiological hazards of zirconium-95 and niobium-95. Health Phys. 16, 209- 7432 220. 7433 Furchner, J.E., Richmond, C.R., Trafton, G.A., 1964. Retention of zirconium-95 after oral and 7434 intraperitoneal administration to mice. In Biological and Medical Research Group 9H-4) of 7435 the Health Division —Annual Report July 1962 through June 1963, pp.53-58, (LAMS-3034) 7436 Los Alamos Scientific Laboratory, Los Alamos. 7437 Greiter, M.B., 2008. Study of the biokinetics of zirconium isotopes in humans and its relevance to 7438 internal dosimetry. Dissertation. Physics Department. München: Technische Universität 7439 München. 7440 Greiter, M.B., Giussani, A., Höllriegl, V., Li, W.B., Oeh, U., 2011. Human biokinetic data and a new 7441 compartmental model of zirconium - A tracer study with enriched stable isotopes. Sci. Total 7442 Environ. 409, 3701-3710. 7443 Hamilton, J.G., 1947. The metabolism of the fission products and the heaviest elements. Radiology 7444 49, 325-343. 7445 ICRP, 1959. Recommendations of the International Commission on Radiological Protection. Report 7446 of Committee 2 on Permissible Dose for Internal Radiation. ICRP Publication 2. Pergamon 7447 Press, London. 7448 ICRP, 1979. Limits on Intakes by Workers, ICRP Publication 30. Pt.1. Ann. ICRP, 2(3/4), 79-80. 7449 ICRP, 1989. Age-dependent doses to Members of the Public from Intake of Radionuclides: Part 1. 7450 ICRP Publication 56, Ann. ICRP, 20(2), 29-31. 7451 Kanapilly, G.M., Goh, C.H.T., 1973. Some factors affecting the in vitro rates of dissolution of 7452 respirable particles of relatively low solubility. Health Phys. 25, 225–237. 7453 Kanapilly, G.M., Raabe, O.G., Goh, C.H.T., Chimenti, R.A., 1973. Measurement of in vitro 7454 dissolution of aerosol particles for comparison to in vivo dissolution in the lower respiratory 7455 tract after inhalation. Health Phys. 24, 497–507. 7456 Lang, S., Kosma, V.M., Kumlin, T., Halinen, A., Salonen, R.O., Servomaa, K., Rytömaa, T., 7457 Ruuskanen, J., 1994. Distribution and short-term effects of intratracheally instilled neutron- 7458 irradiated UO2 particles in the rat. Environ. Res. 15, 119–131. 7459 Mealey, J., 1957. Turnover of carrier-free zirconium-89 in man. Nature 179, 673-674. 7460 Mirell, S.G., Blahd, W.H., 1989. Biological retention of fission products from the Chernobyl plume. 7461 Health Phys. 57 (4), 649-652.

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7462 Osborne, R.V., 1963. Plutonium and other nuclides in ground-level air and human lungs during spring 7463 1962. Nature, 199, 143–146. 7464 Rama Sastry, B.V., Owens, L.K., Ball, C.O.T., 1964. Differences in the distribution of zirconium-95 7465 and niobium-95 in the rat. Nature 201, 410-411. 7466 Razumovskiĭ, N.O., Torchinskaya, O.L., Yashunskiĭ, V.G., 1966. Effect of certain complex-forming 7467 agents on the build-up level of the radioactive isotopes of zirconium, niobium and 7468 in the organism of the rat. In: Distribution and biological effects of radioactive isotopes. 7469 Atomizdat, Moscow. AEC-tr-6944 (Rev.), USAEC; pp. 713-718. 7470 Richmond, C.R., Furchner, J.E., Trafton, G.A., 1960. Metabolism of zirconium-95 and ruthenium-106 7471 in mammals. In: Biological and Medical Research Group (H4) of the Health Division, 7472 semiannual report July through December 1959. Los Alamos Scientific Laboratory (LAMS- 7473 2445). pp. 90-93. 7474 Rundo, J., Newton, D., 1962. Some recent measurements of caesium-137 and zirconium-95 in human 7475 beings. Nature, 195, 851–854. 7476 Rundo, J., Newton, D., 1965. Inhalation and retention of fall-out zirconium-95 by human beings. 7477 Nature, 205, 37–40. 7478 Rundo, J., 1965. A case of accidental inhalation of irradiated uranium. Brit. J. Radiol. 38, 39–50. 7479 Schiessle, W., Schmidtke, I., Philipp, K., Schroff, E., 1964. Inhalationsuntersuchungen mit 7480 radioactivem Calcium (Ca45) beim Meerschweinchen. Z. Aerosolforsch. 11, 373–396. 7481 Schiessle, W., Philipp, K., Jung-Langhorst, U., Schmidtke, I., 1961. Tier-experimentelle inhalation- 7482 suntersuchungen mit radioactivem zirconium. Strahlentherapie 116:566-584. 7483 Schmidtke, I., Schiessle, W., Philipp, K., 1964. Inhalationsversuche mit radioactivem Zirkonium ohne 7484 und mit Trägerzusatz beim Meerschweinchen. Z. Aerosolforsch. 11, 397–419. 7485 Schönfeld, T., Liebscher, K., Karl, F., Friedman, C., 1960. Radioactive fission products in lungs. 7486 Nature, 185, 192–193. 7487 Shiraishi, Y, Ichikawara, R., 1972. Absorption and retention of 144Ce and 95Zr—95Nb in newborn, 7488 juvenile and adult rats. Health Phys, 22, 373-378. 7489 Sirotkin, A., Burov, N., Tyumenev, L.N., Grishin, A.I., 1970. On the behaviour of strontium-90, 7490 137Cs, 144Ce, 106Ru, 125Sb and 95Zr in cattle. Radiobiologiia 10: 629. 7491 Taylor, D.M., Leggett, R.W., 2003. A generic biokinetic model for predicting the behaviour of the 7492 lanthanide elements in the human body. Rad. Prot. Dosim. 105, 193-198. 7493 Taylor, D.M., Lehman, M., Planas-Bohne, F., Seidel, A., 1983. The metabolism of radiohafnium in 7494 rats and hamsters: A possible analog of plutonium for metabolic studies. Radiat. Res. 95, 339- 7495 358. 7496 Taylor, D.M., Seidel, A., Doerfel, H., 1985. The metabolism of radiohafnium in marmosets and 7497 hamsters. Int. J. Nucl. Med. Biol. 12(5) 387-391. 7498 Thind, K.S. 1995. Retention and excretion of 95Zr – 95Nb in humans. Health Phys. 69, 957–960. 7499 Thomas, R.G., Walker, S.A., McClellan, R.O., 1971. Relative hazards of inhaled 95Zr and 95Nb 7500 particles formed under various thermal conditions. Proc. Soc. Exp. Biol. Med. 138, 228-234. 7501 Veronese, I., Cantone, M.C., Giussani, A., Maggioni, T., Birattari, C., Bonardi, M., Groppi, F., 7502 Garlaschelli, L., Werner, E., Roth, P., Höllriegl, V., Louvat ,P., Felgenhauer, N., Zilker, Th., 7503 2003a. Stable tracer investigations in humans for assessing the biokinetics of ruthenium and 7504 zirconium radionuclides. Radiat. Prot. Dosim. 105, 209-212. 7505 Veronese, I., Giussani, A., Cantone, M.C., Maggioni, T., Birattari, C., Groppi, F., Werner, E., Roth, 7506 P., Höllriegl, V., 2003b. A re-evaluation of the biokinetics of zirconium in humans. Appl. 7507 Radiat. Isot. 58:431-439. 7508 Waligora, S.J., 1971. Pulmonary retention of zirconium oxide (95Nb) in man and beagle dogs. Health 7509 Phys. 20, 89-91. 7510 Wegst, A.V., Pelletier, C.A., Whipple, G.H., 1964. Detection and quantitation of fallout particles in a 7511 human lung. Science, 143, 957–959. 7512 Wrenn, M.E., Mowafy, R., Laurer, G.R., 1964. 95Zr–95Nb in human lungs from fallout. Health Phys. 7513 10, 1051-1058. 7514 7515

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7516 13. NIOBIUM (Z = 41) 7517 7518 13.1. Chemical Forms in the Workplace 7519 7520 (575) Niobium is a transition metal which occurs mainly in oxidation states III and V. It 7521 may be encountered in industry in a variety of chemical and physical forms, including oxides 7522 and oxalates. Minerals that contain niobium often contain and thorium. 7523 (576) Niobium-95 is a high yield fission product, which may be associated with irradiated 95 7524 fuel or corrosion products. Niobium-95 also arises as the decay product of Zr, another high 7525 yield fission product, which also occurs as a neutron activation product derived from 7526 zirconium based fuel cladding. It could also be present in fragments of irradiated fuel. 7527 7528 Table 13-1. addressed in this report 7529 Isotope Physical half-life Decay mode Nb-88 14.5 m EC, B+ Nb-89 2.03 h EC, B+ Nb-89m 66 m EC, B+ Nb-90 14.60 h EC, B+ Nb-91 680 y EC, B+ Nb-91m 60.86 d IT, EC, B+ Nb-92 3.47E+7 y EC Nb-92m 10.15 d EC, B+ Nb-93m 16.13 y IT Nb-94 2.03E+4 y B- Nb-95a 34.991 d B- Nb-95m 3.61 d IT, B- Nb-96 23.35 h B- Nb-97 72.1 m B- Nb-98m 51.3 m B- 7530 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 7531 are given on accompanying electronic disk. 7532 7533 13.2. Routes of Intake 7534 7535 13.2.1. Inhalation 7536 7537 Absorption Types and parameter values 7538 (577) Cuddihy (1978) reviewed information on the lung clearance of inhaled niobium 7539 compounds. He noted that the chemistry of niobium is complex, since it can exist in any 7540 oxidation state between I and V. It does not form simple soluble compounds in aqueous 7541 solution but tends to hydrolyse and form hydrophilic colloids. Niobium oxalate complexes 7542 are stable in acids up to pH 5.5. Niobium oxides, the most common being Nb2O5, are 7543 sparingly soluble in mineral acids and almost inert in solutions of approximately neutral pH, 7544 as are most biological fluids. 95 7545 (578) In all the studies noted below the niobium isotope followed was Nb (t½ 35 d), the 95 7546 decay product of Zr (t½ 64 d). In most studies both radionuclides were deposited in the 95 7547 respiratory tract, and thus the Nb followed was partly that which deposited, and partly that 95 7548 formed from the in situ decay of Zr. In most studies the combined activity of the two 7549 radionuclides was measured, and thus in interpreting the results it has to be assumed that their

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7550 behaviour is similar. Furthermore, in only a few studies was the inhaled material a pure 7551 niobium compound. Because of the relatively short half-lives of these radionuclides, few 7552 studies are of sufficient duration to distinguish Types M and S behaviour based on the ICRP 7553 Publication 71 criteria of lung retention or total absorption up to 180 d after intake. 7554 (579) Some information was found on the behaviour of inhaled niobium in man, mainly 7555 associated with irradiated fuel. Information is available from experimental studies of 7556 niobium as oxalate, oxide, and irradiated uranium dioxide. 7557 (580) Absorption parameter values and Types, and associated fA values for particulate 7558 forms of niobium are given in Table 13-2. 7559 7560 Niobium oxalate 7561 (581) The oxalate has been studied extensively as a form that is relatively soluble in 7562 biological fluids (see above). In probably the most detailed study (Cuddihy, 1978) retention 95 7563 was followed in 27 dogs up to 128 days after inhalation of Nb-labelled zirconium oxalate 7564 by dogs. Cuddihy applied simulation modelling to obtain a time-dependent absorption 7565 function (fractional absorption rate): 7566 –2t –0.1t –1 7567 S(t) = 1.7 e + 0.05 e + 0.004 d at time t (days) after intake, 7568 7569 which shows three phases of absorption. Particle transport was represented by a fractional 7570 mechanical clearance rate: 7571 –0.046t 7572 M(t) = 0.004 e + 0.001 7573 7574 (582) The same function was used to model particle transport of relatively insoluble 7575 niobium oxide administered to dogs in the same study (see below). This suggests that 7576 “binding” to lung tissues was not a significant factor in the time-dependent absorption. The 7577 absorption can be broadly approximated using the HRTM dissolution model with fr = 0.6, sr = –1 –1 7578 1 d and ss = 0.007 d , consistent with assignment to Type M. A good fit is obtained by –1 –1 –1 7579 using three dissolution compartments: 0.57 at 2.5 d , 0.17 at 0.13 d and 0.26 at 0.0041 d . 7580 [An intake of material with these characteristics could be simulated with software that 7581 implements the HRTM by assuming an intake of two materials: 57% with fr = 1 and sr = 2.5 –1 –1 –1 7582 d ; and 43% with fr = (0.17/0.43), sr = 0.13 d and ss = 0.0041 d .] 7583 (583) In other studies with dogs, rats and mice, the observed behaviour was broadly 7584 similar, but variable, indicating assignment to Type F in some and Type M in others. At 30 d 95 7585 after inhalation of Nb oxalate by 3 dogs, the lungs contained about 15% of the initial lung 7586 deposit (ILD), indicating assignment to Type M (Kanapilly et al., 1969). After inhalation of 95 7587 Nb oxalate by rats in one study (Moskalev et al., 1964), ~85% ILD was absorbed within a –1 7588 day (fr ~0.85 and sr >10 d ), and the rest with a half-time of about 10 d, indicating 7589 assignment to Type F. In another study (Thomas et al., 1967) ~30% ILD was absorbed –1 7590 within a day (fr ~0.3 and sr >10 d ), and relatively little thereafter, indicating assignment to 7591 Type M. 95 95 7592 (584) Thomas et al. (1971) studied the biokinetics of Zr– Nb following inhalation by 7593 mice of aerosols formed by heating droplets of zirconium oxalate solution to various 7594 temperatures. In vitro dissolution tests were conducted on similar materials by Kanapilly and 7595 Goh (1973) and Kanapilly et al. (1973). Immediately after inhalation of the aerosols formed 7596 at 100˚C and 250˚C (both zirconium oxalate, but mainly droplets and solid particles 7597 respectively) the skeleton contained about 20% of the body content, the lungs 2% and 25% 7598 respectively. This suggests that at the lower temperature most of the material deposited in the

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–1 7599 lungs was absorbed rapidly: fr ~0.9 and sr of the order of 100 d . For both materials niobium 7600 was absorbed faster than zirconium, especially that formed at 100˚C. These results indicate 7601 Type F behaviour, as do those of the in vitro dissolution tests. 7602 (585) Although specific parameter values for niobium oxalate based on in vivo data are 7603 available, they are not adopted by the task group, because inhalation exposure to it is 7604 unlikely, and because a wide range of absorption was reported from different studies. 7605 Instead, niobium oxalate is assigned to Type M. 7606 7607 Zirconium oxide and carbonate 95 95 7608 (586) As noted above, Thomas et al. (1971) studied the biokinetics of Zr– Nb following 7609 inhalation by mice of aerosols formed by heating droplets of zirconium oxalate solution. The 7610 aerosols formed at 600˚C (Zr(CO3)2 and ZrOCO3) and at 1100˚C (ZrO2 and ZrOCO3) gave 7611 very similar results in vivo, with no differential loss of niobium. From 10 to 130 d after 7612 inhalation the lungs contained more than 90% of the sacrifice body burden (SBB) while the 7613 skeleton content increased from 2% SBB at 2 d to 6% SBB at 130 d. These results indicate 7614 Type S behaviour. In vitro tests on similar materials by Kanapilly and Goh (1973) and 7615 Kanapilly et al. (1973) confirmed low dissolution rates, but their duration was too short to 7616 distinguish Type M from Type S. 95 7617 (587) Cuddihy (1978) applied simulation modelling to measurements of Nb following 95 7618 inhalation of similar Nb-labelled zirconium aerosols (formed at 1000˚C) by dogs to obtain 7619 an absorption function (fractional absorption rate): 7620 –0.04t –1 7621 S(t) = 0.00016 e + 0.0001 d at time t (days) after intake, 7622 –1 –1 7623 which can be represented using the HRTM with fr = 0.004, sr = 0.04 d and ss = 0.0001 d , 7624 consistent with assignment to Type S. In vivo measurements following accidental inhalation 7625 of what was probably the same material by a person gave a lung retention half time of about 7626 220 days, indicating Type M or S behaviour (Waligora, 1971). 7627 (588) Although specific parameter values for niobium oxide based on in vivo data are 7628 available, they are not adopted here, because inhalation exposure to it is so unlikely. Instead, 7629 niobium oxide is assigned to Type S. 7630 7631 Nuclear weapons fallout 95 95 7632 (589) During the early 1960s, measurements were made of Zr– Nb activities in human 7633 lungs due to fall-out from atmospheric nuclear weapons tests. Most were made post mortem 7634 (Schönfeld et al., 1960; Osborne, 1963; Wrenn et al., 1964; Dutailly et al., 1966), but in vivo 7635 measurements were also made, enabling the variation with time in individual subjects to be 7636 determined (Rundo and Newton, 1962; 1965). Several authors compared their measurements 7637 with those predicted from measured air concentrations, using a single exponential model 7638 (ICRP, 1959). Biological lung retention half-times were estimated to be between about 70 d 7639 (Wrenn et al., 1964) and more than 120 d (Rundo and Newton, 1965). Wrenn et al., (1964) 95 95 7640 noted that little Zr– Nb activity was found in other tissues, and that Wegst et al. (1964) had 95 95 7641 shown that Zr- Nb activity in the lungs was present in particulate form. Overall this 7642 indicates Type M or S behaviour. 7643 7644 Irradiated fuel 7645 (590) Following an accidental release, niobium could be present in fragments of irradiated 7646 fuel, where the matrix is predominantly uranium oxide. The results of a study on one person 95 95 7647 following accidental inhalation of irradiated fuel indicate Type M behaviour of the Zr– Nb

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95 95 7648 present (Rundo, 1965). In another, measurements of Zr– Nb made on a worker for 6 7649 months following an accidental intake, probably of irradiated fuel (UO2), indicate Type S 7650 behaviour (Thind, 1995). 7651 (591) Mirell and Blahd (1989) made whole-body measurements of activity on seven 7652 people from about two weeks to several months after exposure to the initial Chernobyl 7653 reactor accident plume in Kiev, Ukraine. Biological retention half-times were similar for 95 7654 different radionuclides (49 days for Zr-Nb) and different from those expected for systemic 7655 retention, indicating that they were trapped in particles and metabolically inert, and thus 7656 indicating Type M rather than Type F behaviour. 7657 (592) Tissue distribution and retention of several radionuclides were followed for 3 7658 months after intratracheal instillation of irradiated UO2 powder into rats (Lang et al., 1994). 95 7659 For Nb, the total amounts absorbed by 1 and 3 months were estimated to be about 5% and -1 7660 9% of the initial lung deposit respectively, indicating values of fr <0.05 and ss ~0.002 d , and 7661 assignment to Type M. 7662 (593) The in vitro dissolution of samples of particles released from the Chernobyl accident 7663 was measured for up to 60 d (Cuddihy et al., 1989). For all radionuclides, including 95 95 7664 Zr- Nb, 10% dissolved in a few hours, and the rest with a half-time of 160 d. Hence fr = –1 –1 7665 0.1, sr ~10 d , and ss = 0.004 d , consistent with assignment to Type M. 7666 7667 Other compounds 95 95 7668 (594) Measurements of Zr– Nb in the lungs of a person for 5 months following an 7669 accidental intake of unspecified material indicate Type M or S behaviour (Cofield, 1963). 7670 7671 Rapid dissolution rate for niobium 7672 (595) As noted above, the oxalate has been studied extensively as a form of niobium that is 7673 relatively soluble in biological fluids. The results show rather complex behaviour, with more 7674 than one phase of absorption, perhaps reflecting the complex chemistry of niobium. Where 7675 measurements have been made soon after administration, there is evidence of very rapid –1 7676 uptake, (sr ~ 100 d ) but only of part of the initial lung deposit, (fr < 1). There is therefore no –1 7677 justification for choosing a rate different from the general default value of 30 d , which is 7678 applied here to all Type F forms of niobium. 7679 7680 Extent of binding of niobium to the respiratory tract 7681 (596) As described above, the oxalate has been studied extensively as a form of niobium 7682 that is relatively soluble in biological fluids. The results show more than one phase of 95 7683 absorption. However, Cuddihy (1978) applied simulation modelling to the results of Nb 7684 measurements following inhalation by dogs of niobium oxalate and relatively insoluble 7685 niobium oxide. The same function was used to model particle transport of both materials, 7686 which suggests that “binding” to lung tissues was not a significant factor in the time- 7687 dependent absorption of the oxalate, because it is assumed in the HRTM that material in the 7688 bound state is not cleared by particle transport, only by absorption to blood. It is therefore 7689 assumed that for niobium the bound state can be neglected, i.e. fb = 0.0. 7690 7691

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7692 7693 Table 13-2. Absorption parameter values for inhaled and ingested niobium 7694 Absorption parameter valuesa Absorption from the alimentary –1 –1 c Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorption Assigned forms Type F 1 30 0.01 M Oxalate, all unspecified 0.2 3 0.005 0.002 formsd S Carbonate, oxide 0.01 3 1x10-4 1x10-4

Ingested materials All forms 0.01 a 7695 It is assumed that for niobium that the bound state can be neglected, i.e. fb = 0.0. The values of sr for Type F, 7696 M and S forms of niobium (30, 3 and 3 d–1, respectively) are the general default values. 7697 b Materials (e.g. niobium oxalate) are listed here where there is sufficient information to assign to a default 7698 absorption Type, but not to give specific parameter values (see text). 7699 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 7700 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 7701 absorption Type and the fA value for ingested soluble forms of niobium (0.01). 7702 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 7703 or if the form is known but there is no information available on the absorption of that form from the 7704 respiratory tract. 7705 7706 13.2.2. Ingestion 7707 7708 (597) Information on the concentration of stable niobium in human diet and urine has been 7709 published by Schroeder and Balassa (1965) but these values were considered to be 7710 insufficient for estimating the absorption of niobium from the human gastrointestinal tract 7711 (ICRP, 1989). 7712 (598) Data on the absorption of niobium are available from a number of animal studies. A 7713 first set of values have been determined by Fletcher (1969), who quoted a range of fractional -4 -3 95 7714 absorption from 4.10 to 2.10 for Nb administered to rats in various chemical forms. 95 7715 (599) Further studies have been then performed on Nb given as oxalate. They shown that 95 -3 7716 fractional absorption of Nb given to rats varied from about 10 (Mraz and Eisele, 1977) to -2 7717 2 to 5x10 (Thomas et al., 1971). These values may vary according to the species as shown 95 7718 by Furchner and Drake (1971), who measured whole body retention of Nb given as oxalte, -2 -3 -3 7719 and estimated levels of absorption of about 2x10 in mice and dogs, 8x10 in rats and 9x10 7720 in monkeys. However, these values may overestimate the true absorption because the 95 7721 retention of Nb rapidly fell to less than detection limits. 7722 (600) Fasting is known to increase the uptake by the gut. Harrison et al. (1990) measured -3 95 7723 absorption of 8x10 for Nb administered as the citrate to normally fed guinea pigs and -2 7724 1.4x10 for animals fasted 24h before and 2h after administration. Paquet et al. (1998) 7725 investigated the fractional absorption of niobium given to fed rats and obtained values of -2 -2 -2 7726 1.25x10 , 0.37x10 and 0.24x10 for the citrate, oxalate and chloride forms, respectively.

7727 (601) In Publication 30 (ICRP, 1979), an absorption value of 0.01 was recommended. This 7728 value was adopted in Publication 56 (ICRP, 1989) for dietary intakes and is also adopted here 7729 as a default value for all chemical forms (fA = 0.01). 7730

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7731 13.2.3. Systemic Distribution, Retention and Excretion 7732 7733 13.2.3.1. Summary of the database 7734 7735 (602) There is little information on the systemic behavior of niobium in humans. Data for 7736 laboratory animals indicate broadly similar systemic biokinetics of niobium for different 7737 animal species, different routes of exposure, and different chemical forms of niobium taken 7738 into the body. Typically, 50% or more of niobium entering blood transfers to tissues and 7739 excretion pathways within a few hours, and the remainder clears much more slowly due to 7740 binding with plasma proteins. Excretion is mainly in urine. Niobium distributes somewhat 7741 uniformly throughout the body but is retained much longer in bone than in other tissues, so 7742 that bone eventually contains a large portion of the total-body content. Niobium depositing in 7743 bone appears to be retained largely on bone surfaces. Total-body retention generally has 7744 been described as a sum of two retention components of roughly equal size. The short-term 7745 component typically has a biological half-time of a few days, and the long-term component 7746 has a half-time of a few months. Reported biokinetic studies have not been sufficiently long 7747 to characterize longer-term components of retention such as may be present in bone. 7748 (603) Hamilton and coworkers (Hamilton, 1948; Durbin et al., 1957; Durbin, 1960) 95 7749 studied the biokinetics of Nb in rats following intramuscular injection of relatively soluble 7750 niobium compounds. A substantial portion of the absorbed activity apparently combined with 7751 plasma proteins and was slowly removed from blood to tissues and excretion pathways. 7752 Activity distributed throughout the body and was removed more slowly from bone, kidney, 7753 and lymphatic tissue than from other repositories. Activity was excreted mainly in urine over 7754 the first 2 wk, but the faecal to urinary excretion ratio increased over time. At 4 d after 95 7755 administration of Nb as citrate, the mean contents of bone, liver, kidneys, and blood were 7756 16%, 8.4%, 2.9%, and 7.7% of the administered activity, respectively, and approximately 7757 39% of the administered amount had been excreted by that time. Autoradiographic studies 95 7758 indicated that skeletal Nb was located largely on bone surfaces. 90 95 7759 (604) The distributions of Nb and Nb were studied in rats over a 4-d period following 7760 their intravenous administration in a solution of oxalic acid (Matthews and Gartside, 1965). 131 7761 Comparison with blood retention of I-labeled plasma proteins suggested that a substantial 7762 portion of the injected activity combined with plasma proteins. Retention in blood was about 7763 30% of the injected amount at 1 d, 16% at 2 d, 11% at 3 d, and 5% at 4 d after correction for 7764 radiological decay. Total-body retention fell to about 65% at 4 d. Bone contained roughly 7765 one-fourth of the injected amount at the end of the study, based on extrapolation of data for 7766 the femur. The liver content was in the range 4.0-5.4% from 1.2 h to 4 d after injection. 7767 Activity in most tissues decreased with time, but activity in the kidneys increased from about 7768 2% after 1.2 h to about 4% at 3-4 d. 95 7769 (605) Semenov et al. (1966) investigated the distribution of Nb in rats following its 7770 intravenous or subcutaneous administration as the oxalate. Similar behavior was seen for the 7771 two modes of exposure. Niobium in blood combined with plasma proteins, primarily 7772 albumin. Little activity was accumulated by red blood cells. Following intravenous injection 7773 the blood contained about 17% of the administered activity at 1 d, 2.9% at 4 d, and 0.12% at 7774 64 d; the liver contained about 5-7% during the first day, 9% at 2-8 d, and 2% at 64 d; the 7775 kidneys contained about 1-2% during the first day and 2-3% during days 2-64; and the 7776 muscles contained 13-24% during the first 8 days, 9% at 16-32 d, and 4% at 64 d. The 7777 concentration in bone increased steadily for several days after injection and then remained at 7778 about the same level for the remainder of the 64-d study. The concentration in bone was 7779 higher than that in most other tissues at 32 and 64 d after injection. About 23% of the

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7780 administered amount was excreted in urine and about 10% was excreted in faeces over the 7781 first 20 d after intravenous injection. A substantial portion of activity entering the 7782 gastrointestinal contents appeared to arise from secretions other than liver bile. 7783 (606) Razumovskii et al. (1966) studied the effects of various complex-forming agents on 95 95 95 7784 the biokinetics of Zr and Nb in rats. At 3 d after intraperitoneal administration of Nb 7785 oxalate to control animals, the liver, spleen, kidneys, and femur contained about 3.1, 0.62, 7786 0.89, and 0.23% of the administered activity, respectively. 95 7787 (607) Autoradiographic studies on mice demonstrated high concentrations of Nb in bone 7788 and connective tissue during the first four days after its intravenous administration as oxalate 7789 (Bäckström et al., 1967). The distribution of activity was similar to that observed after 95 95 7790 intravenous administration of Zr- Nb, but bone appeared to accumulate a smaller portion 95 7791 of the administered activity following injection of pure Nb. 95 7792 (608) Fletcher (1969) studied the behavior of Nb in rats following its administration as 7793 oxalate. Roughly 30% of intravenously administered activity deposited in the skeleton, 18% 7794 in muscle, 2.5% in liver, and 2.5% in kidneys. Total-body retention declined more slowly in 7795 males than in females. Retention was about 70% of the injected amount at 8 d, 50% at 40 d, 7796 and 40% at 80 d as an average for males and females. 95 7797 (609) Furchner and Drake (1971) studied retention and excretion of Nb after oral and 7798 intravenous administration as oxalate to mice, rats, monkeys, and dogs and after 7799 intraperitoneal administration as oxalate to mice and rats. The duration of individual studies 7800 ranged from 4 d to 192 d. Little difference in retention was seen following intravenous and 95 7801 intraperitoneal administration. Whole-body retention of intravenously injected Nb was 7802 described as a sum of three exponential terms for mice and rats and a sum of two exponential 7803 terms for monkeys and dogs. The cumulative urinary to faecal excretion ratio over the first 3 7804 d was about 9 for mice, 3 for rats and dogs, and 6 for monkeys. Estimated long-term 7805 biological half-times were about 100 d for monkeys, 150 d for dogs, 180 d for rats, and 460 d 7806 for mice. The long-term half-time represented about half of the administered amount in 7807 monkeys, dogs, and rats and about one-fourth of the administered amount in mice. Rats 95 7808 receiving Nb by intraperitoneal injection were sacrificed at 1, 4, 7, 14, 23, 35, and 45 d for 7809 tissue distribution studies. The percentage of total-body activity in bone in these animals 7810 increased from about 16% at 1 d to about 27% at 23 d and remained near 27% thereafter. 7811 The muscle, pelt, and liver contained about 33-37%, 17-21%, and 4-5%, respectively, of 7812 total-body activity over the entire observation period. The kidney content increased from 7813 about 1.5% of total-body activity at 1 d to more than 3% after 35 d. 7814 (610) Niobium-95 oxalate was administered orally or intravenously to sheep and swine 6- 7815 18 h after birth or 3 wk after weaning (Mraz and Eisele, 1977). At 3 d after intravenous 7816 administration the mean skeletal content was about 67% of the injected amount in newborn 7817 sheep compared with 43% in weaned sheep, and 66% in newborn swine compared with 51% 7818 in weaned swine. The means contents in the liver, kidneys, and muscle at 3 d varied little if 7819 any with age. The liver contained 1.7% of the injected amount in newborn and weaned sheep 7820 and 3.4-3.5% in newborn and weaned swine; the kidneys contained 0.7-1.1% in newborns 7821 and weanlings of both species; and muscle contained 6.4-7.3% in newborns and weanlings of 7822 both species. 95 7823 (611) Cuddihy (1978) measured the distribution, retention, and excretion of Nb in beagle 7824 dogs following its inhalation as oxalate or oxide aerosols and used the results to model the 7825 respiratory, gastrointestinal, and systemic biokinetics of the inhaled activity. Frequent whole- 7826 body measurements were made, and urine and faecal samples were collected daily throughout 7827 the study. Dogs were sacrificed for tissue distribution studies at 1 h and 2, 4, 8, 16, 32, 64, 7828 and 128 d. An estimated 60% of the initial lung burden was absorbed into the systemic

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7829 circulation after inhalation of the oxalate aerosols, compared with <1% after inhalation of the 95 7830 oxide. Daily urinary excretion of Nb was 2-3 times greater than daily faecal excretion 7831 following early rapid clearance of activity from the upper respiratory tract. As predicted by 7832 Cuddihy’s model, total-body retention of was 44% at 8 d and 28% at 128 d following acute 7833 input of stable niobium to blood. The predicted bone contents at these two times were about 7834 14% and 16%; the liver contents were 9% and 8%; contents of other soft tissues were 17% 7835 and 6%; cumulative urinary losses were 45% and 60%; and cumulative faecal losses were 5% 7836 and 10%. 95 7837 (612) Following intravenous administration of Nb as oxalate to pregnant rats, there was a 7838 slow decrease in the activity concentrations in blood and liver during the first day and a 7839 simultaneous increase in kidneys and bone (Schneidereit et al., 1985). Whole-body retention 7840 over the first 20 d after injection into dams was described as a sum of two exponential terms 7841 with biological half-times of 1.3 d (~30%) and 46 d (~70%). Only a small portion of the 7842 injected activity was transferred to the fetus. 95 7843 (613) The effects of various chelating agents on retention and elimination of Nb were 7844 tested in mice following its intraperitoneal administration as oxalate (Gachalyi et al., 1987). 95 7845 Total-body retention of Nb in control animals was described as a sum of two exponential 7846 terms with mean biological half-times of 1.1 d (~50%) and 54 d (~50%). The mean 7847 concentrations in liver, kidneys, and bone of control animals were, respectively, 3.9, 0.50, -1 -1 7848 and 2.0% g at 4 d and 2.7, 0.54, and 2.4% g at 14 d. Desferrioxamine (DFOA) was shown 95 7849 to be an effective chelating agent for Nb, particularly when combined with 7850 diethylenetriaminepentaacetic acid (DTPA). 95 7851 (614) Harrison et al. (1990) measured retention of Nb following its oral or intraperitoneal 7852 administration in a citrate solution to adult and newborn guinea pigs. Whole-body retention 7853 following intraperitoneal injection was slightly lower in newborns than in adults, with about 7854 50% of the injected activity excreted by newborns during the first day compared with about 7855 40% in adults. The remaining activity cleared with a half-time of about 30 d in both age 7856 groups as estimated from measurements through day 7. Urinary excretion accounted for 7857 more than 90% of total losses in adults over the 7-d observation period. 95 7858 (615) The distribution of Nb formed in vivo from decay of ingested or intravenously 95 95 7859 injected Zr in rats was similar to the distribution of administered Nb and considerably 95 95 7860 different from the distribution of Zr (Fletcher, 1969). Following oral administration of Zr- 95 95 95 7861 Nb to suckling rats, the ratio of Zr to Nb was 4-5 in bone and ~1 in other tissues 7862 (Shiraishi and Ichikawa, 1972). Measurements of activity in blood and tissues of rats 95 95 7863 following intraperitoneal injection of Zr- Nb as oxalate indicated preferential accumulation 95 7864 of Zr in bone (Rama Sastry et al., 1964). 7865 7866 13.2.3.2. Biokinetic model for systemic niobium 7867 7868 (616) The structure of the systemic model for niobium is shown in Figure 13-1. Transfer 7869 coefficients are listed in Table 13-3. These transfer coefficients are rounded values derived 7870 from the deposition fractions and removal half-times summarized below. 7871 (617) The transfer coefficients were set in part for reasonable consistency with predictions 7872 of the systemic model of Cuddihy (1978) of the contents of total body (Figure 13-2), bone, 7873 liver, and total soft tissues over the first few months after acute input of niobium to blood. 7874 The Cuddihy model was used as a guide for modeling the early behavior of niobium because 7875 it was based on detailed measurements of the fate of absorbed niobium in beagle dogs, which 7876 have proven to be a useful laboratory model for the behavior of bone seekers; and its 7877 predictions are reasonably representative of biokinetic data for niobium from other animal

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7878 studies. The present blood retention model was designed for reasonable consistency with 7879 observed blood clearance of the related element zirconium in human subjects over the first 7880 few days after intravenous injection (Veronese et al., 2003; Greiter, 2008) as well as the 7881 blood clearance curve predicted by the Cuddihy model for niobium. Parameter values for the 7882 kidneys, which are not addressed explicitly in the Cuddihy model, were set for reasonable 95 7883 agreement with collective data on the kidney contents of Nb over the first few months after 7884 intravenous or intraperitoneal administration to rats (Semenov et al., 1966; Fletcher, 1969; 7885 Furchner and Drake, 1971). The fate of niobium depositing on bone surface is described by 7886 the generic bone model for bone-surface-seeking radionuclides used in this report, except that 7887 niobium removed from bone is assumed to return to Blood 1 rather than to be channeled 7888 through bone marrow. 7889 (618) In the present model, niobium initially entering the systemic circulation is assigned -1 7890 to a compartment called Blood 1. Niobium leaves Blood 1 at the rate 8 d , corresponding to 7891 a removal half-time of about 2 h. Outflow from Blood 1 is divided as follows: 40% transfers 7892 to a slow-turnover blood compartment called Blood 2, representing plasma proteins; 3% 7893 transfers to Liver; 0.5% transfers to Kidneys; 3% transfers to bone surfaces and is equally 7894 divided between Cortical surface and Trabecular surface; 40% transfers to ST0, a soft-tissue 7895 compartment with relatively fast turnover; 1.5% transfers to ST1, a soft-tissue compartment 7896 with relatively slow turnover; 11% transfers to Urinary bladder contents; and 1.0% transfers 7897 to Small intestine (SI) contents. Activity transfers from Blood 2 back to Blood 1 with a half- 7898 time of 0.5 d, from ST0 to Blood 1 with a half-time of 0.5 d, from ST1 to Blood 1 with a half- 7899 time of 70 d, and from Kidneys to Blood 1 with a half-time of 140 d. Niobium entering Liver 7900 is assigned to a compartment called Liver 0. Niobium is removed from Liver 0 with a half- 7901 time of 2 d, with two-thirds going to a long-term retention compartment of liver called Liver 7902 1 and the other one-third equally divided between Blood 1 and SI contents (representing 7903 biliary secretion). Relative transfer rates from Blood 1 and Liver 0 into SI contents are set so 7904 that biliary secretion accounts for one-third and other endogenous secretions (represented as 7905 transfer from Blood 1 to SI contents) account for two-thirds of total faecal excretion. 7906 Niobium transfers from Liver 1 to blood with a half-time of 140 d. As indicated earlier, 7907 parameter values describing the fate of niobium depositing on bone surface are generic values 7908 applied in this report to bone-surface-seeking radionuclides. 7909

7910 7911 Figure 13-1. Structure of the biokinetic model for systemic niobium. 7912

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7913 Table 13-3. Parameter values in the systemic model for niobium.

From To Transfer coefficient (d-1) Blood 1 Blood 2 3.2 Blood 1 Liver 0 0.24 Blood 1 Kidneys 0.04 Blood 1 ST0 3.2 Blood 1 ST1 0.12 Blood 1 Urinary bladder contents 0.88 Blood 1 SI contents 0.08 Blood 1 Trabecular surface 0.12 Blood 1 Cortical surface 0.12 Blood 2 Blood 1 1.39 Liver 0 SI contents 0.0578 Liver 0 Blood 1 0.0578 Liver 0 Liver 1 0.231 Liver 1 Blood 1 0.005 Kidneys Blood 1 0.005 ST0 Blood 1 1.39 ST1 Blood 1 0.01 Trabecular surface Blood 1 0.000493 Trabecular surface Trabecular volume 0.000247 Trabecular volume Blood 1 0.000493 Cortical surface Blood 1 0.0000821 Cortical surface Cortical volume 0.0000411 Cortical volume Blood 1 0.0000821 7914

7915 7916 Figure 13-2. Total-body retention of niobium after acute uptake to blood. Values indicated by 7917 closed circles are based on a model developed by Cuddihy (1978) as a fit to inhalation data for dogs. 7918 Values indicated by other symbols are based on curve fits to observations of Furchner and Drake 7919 (1971) for intravenously injected 95Nb. 7920

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7921 7922 13.2.3.3. Treatment of radioactive progeny 7923 7924 (619) Chain members addressed in the derivation of dose coefficients for internally 7925 deposited niobium isotopes include isotopes of yttrium, zirconium, and niobium. The 7926 characteristic systemic models for yttrium, zirconium, and niobium all have the same 7927 structure. An atom of any of these elements produced in a compartment by radioactive decay 7928 after intake of a niobium parent is assumed to behave as if it had entered that compartment as 7929 a parent radionuclide. 7930 7931 13.3. Individual monitoring 7932 95 7933 (620) Monitoring of Nb is in general accomplished through Whole Body Counting 7934 or/and urine bioassays. 7935 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 95Nb Urine Bioassay γ-ray spectrometry 4 Bq/L 0.5 Bq/L 95Nb Lung γ-ray spectrometry 10 Bq* measurement 95Nb Whole Body γ-ray spectrometry 40 Bq 12 Bq Counting 7936 ∗ Lung monitoring of 95Nb is not generally used in routine monitoring of workers. Monte Carlo program 7937 Visual Monte Carlo was used to simulate the photon emission, to calculate the calibration factor for the 7938 geometry and radionuclide, and to calculate the minimum detectable activity (MDA) in the lung. (Hunt et 7939 al., 2012) 7940 7941 References 7942 7943 Bäckström, J., Hammarström, L., Nelson, A., 1967. Distribution of zirconium and niobium in mice. 7944 Autoradiographic study. Acta Radiol. 6, 122-128. 7945 Cofield, R.E., 1963. In vivo gamma spectrometry for inhalations of neptunium-237–protactinium-233, 7946 cobalt-60, and zirconium-95–niobium-95. Health Phys. 9, 283–292. 7947 Cuddihy, R.G., 1978. Deposition and retention of inhaled niobium in beagle dogs. Health Phys. 7948 34:167-176. 7949 Cuddihy, R.G., Finch, G.L., Newton, G.J., Hahn, F.F., Mewhinney, J.A., Rothenberg, S.J., Powers, 7950 D.A., 1989. Characteristics of radioactive particles released from the Chernobyl nuclear 7951 reactor. Environ. Sci. Technol. 23, 89–95. 7952 Durbin, P.W., 1960. Metabolic characteristics within a chemical family. Health Phys. 2, 225-238. 7953 Durbin, P.W., Scott, K.G., Hamilton, J.G., 1957. The distribution of radioisotopes of some heavy 7954 metals in the rat. Univ. California Pub. Pharmacol. 3, 1-34. 7955 Dutailly, L., Martin, J., Robert, J., Burg, C., 1966. Zirconium-95 and niobium-95 in human lungs and 7956 atmospheric dust during 1963. Nature, 212, 702–703. 7957 Fletcher, C.R., 1969. The radiological hazards of zirconium-95 and niobium-95. Health Phys. 16, 209- 7958 220. 7959 Furchner, J.E., Drake, G.A., 1971. Comparative metabolism of radionuclides in mammals – IV. 7960 Retention of 95Nb in the mouse, rat, monkey and dog. Health Phys. 21, 173-180. 7961 Gachalyi, A., Namenyi, J., Szegedi, I., Varga, L.P., 1987. Influence of mixed-ligand complexes on 7962 retention and distribution of radioniobium in mice. Radiat. Res. 112, 312-317. 7963 Greiter, M.B., 2008. Study of the biokinetics of zirconium isotopes in humans and its relevance to 7964 internal dosimetry. Dissertation. Physics Department. München: Technische Universität

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7965 München. 7966 Hamilton, J.G., 1948. The metabolic properties of the fission products and actinide elements. Revs. 7967 Modern Phys. 20, 718-728. 7968 Harrison, J.D., Haines, J.W., Popplewell, D.S., 1990. The gastrointestinal absorption and retention of 7969 niobium in adult and newborn guinea pigs. Int. J. Radiat. Biol. 58, 177-186. 7970 ICRP, 1959. Recommendations of the International Commission on Radiological Protection. Report 7971 of Committee 2 on Permissible Dose for Internal Radiation. ICRP Publication 2. Pergamon 7972 Press, London. 7973 ICRP, 1979. Limits on Intakes by Workers, ICRP Publication 30 Part 1. Annals of the ICRP, 2(3/4). 7974 ICRP, 1989. Age-dependent doses to Members of the Public from Intake of Radionuclides: Part 1. 7975 ICRP Publication 56, Annals of the ICRP, 20(2). 7976 Kanapilly, G.M., Goh, C.H.T., 1973. Some factors affecting the in vitro rates of dissolution of 7977 respirable particles of relatively low solubility. Health Phys, 25, 225–237. 7978 Kanapilly, G.M., Cuddihy, R.G., Pillow, W.W., 1969. Some studies on the behavior of intravenously 7979 injected and inhaled 95Nb(V) oxalate in the beagle dog. Fission Product Inhalation Program 7980 Annual Report 1968–1969. LF–41, pp. 121–129. Lovelace Foundation for Medical Education 7981 and Research, Albuquerque New Mexico. Available from National Technical Information 7982 Service, Springfield, Virginia. 7983 Kanapilly, G.M., Raabe, O.G., Goh, C.H.T., Chimenti, R.A., 1973. Measurement of in vitro 7984 dissolution of aerosol particles for comparison to in vivo dissolution in the lower respiratory 7985 tract after inhalation. Health Phys. 24, 497–507. 7986 Lang, S., Kosma, V. M., Kumlin, T., Halinen, A., Salonen, R. O., Servomaa, K., Rytömaa, T. and 7987 Ruuskanen, J. (1994) Distribution and short-term effects of intratracheally instilled neutron- 7988 irradiated UO2 particles in the rat. Environ. Res. 15, 119–131. 7989 Matthews, C.M.E., Gartside, J.M., 1965. Tumour uptake and distribution of niobium isotopes in rats. 7990 British J. Cancer 19, 551-559. 7991 Mirell, S.G., Blahd, W.H., 1989. Biological retention of fission products from the Chernobyl plume. 7992 Health Phys. 57 (4), 649-652. 7993 Moskalev, Y.I., Buldakov, L.A., Burykina, L.N., Strel’tsova, B.N., Semenov, D.I., 1964. The 7994 distribution and biological effect of radioisotopes entering the organism through inhalation 7995 and intratracheally. In: Radiological Health and Safety in Mining and Milling of Nuclear 7996 Materials. Vol 1. pp. 237–252. International Atomic Enery Agency, Vienna. 7997 Mraz, F.R., Eisele, G.R., 1977. Gastrointestinal absorption, tissue distribution, and excretion of 95Nb 7998 in newborn and weanling swine and sheep. Radiat. Res. 72, 33-536. 7999 Mraz, F.R., Eisele, G.R., 1977. Gastrointestinal absorption of 95Nb by rats of different ages. Radiat. 8000 Res. 69, 591-593. 8001 Osborne, R.V., 1963. Plutonium and other nuclides in ground-level air and human lungs during spring 8002 1962. Nature, 199, 143–146. 8003 Paquet, F., Houpert, P., Verry, M., Grillon, G., Harrison, J.D., Métivier, H., 1998. The gastrointestinal 8004 absorption of 63Ni and 95Nb in adult and neonatal rats: effect of the chemical form 8005 administered. Radiat. Prot. Dos. 79, 191-195. 8006 Rama Sastry, B.V., Owens, L.K., Ball, C.O.T., 1964. Differences in the distribution of zirconium-95 8007 and niobium-95 in the rat. Nature 201, 410-411. 8008 Razumovskiĭ, N.O., Torchinskaya, O.L., Yashunskiĭ, V.G., 1966. Effect of certain complex-forming 8009 agents on the build-up level of the radioactive isotopes of zirconium, niobium and ruthenium 8010 in the organism of the rat. In: Distribution and biological effects of radioactive isotopes. 8011 Atomizdat, Moscow. AEC-tr-6944 (Rev.), USAEC; pp. 713-718. 8012 Rundo, J., Newton, D., 1962. Some recent measurements of caesium-137 and zirconium-95 in human 8013 beings. Nature, 195, 851–854. 8014 Rundo, J., Newton, D., 1965. Inhalation and retention of fall-out zirconium-95 by human beings. 8015 Nature, 205, 37–40. 8016 Rundo, J., 1965 A case of accidental inhalation of irradiated uranium. Brit. J. Radiol. 38, 39–50. 8017 Schneidereit, M., Senekowitsch, R., Kriegel, H., 1985. Transfer and distribution of niobium-95 in

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8018 adult and newborn rats after injection during pregnancy. Radiat. Environ. Biophys. 24, 125- 8019 130. 8020 Schönfeld, T., Liebscher, K., Karl, F., Friedman, C., 1960. Radioactive fission products in lungs. 8021 Nature, 185, 192–193. 8022 Schroeder, H.A., Balassa, J.J., 1965. Abnormal trace elements in man: niobium. J. Cron. Dis. 18, 229- 8023 241. 8024 Semenov, D.I., Balashova, G.N., Borisova, N.N., 1966. Behavior of niobium in the animal organism. 8025 Tr. Inst. Biol. Akad. Nauk SSSR, Ural. Fil. 46, pp. 5-16. Translated in AEC-tr-7169, pp. 3-14 8026 (1970). 8027 Shiraishi, Y., Ichikawa, R., 1972. Absorption and retention of 144Ce and 95Zr-95Nb in newborn, 8028 juvenile and adult rats. Health Phys. 22, 373-378. 8029 Thind, K.S., 1995. Retention and excretion of 95Zr – 95Nb in humans. Health Phys. 69, 957–960. 8030 Thomas, R.G., Thomas, R.L., Scott, J.K., 1967. Distribution and excretion of niobium following 8031 inhalation exposure of rats. Am. Ind. Hyg. Assn. J. 28, 1–7. 8032 Thomas, R.G., Walker, S.A., McClellan, R.O., 1971. Relative hazards for 95Zr and 95Nb particles 8033 formed under various thermal conditions. Proc. Soc. Exp. Biol. Med. 138, 228–234. 8034 Veronese, I., Giussani, A., Cantone, M.C., Maggioni, T., Birattari, C., Groppi, F., Werner, E., Roth, 8035 P., Höllriegl, V., 2003. A re-evaluation of the biokinetics of zirconium in humans. Appl. 8036 Radiat. Isot. 58, 431-439. 8037 Waligora, S.J., 1971. Pulmonary retention of zirconium oxide (95Nb) in man and beagle dogs. Health 8038 Phys. 20, 89–91. 8039 Wegst, A.V., Pelletier, C.A., Whipple, G.H., 1964. Detection and quantitation of fallout particles in a 8040 human lung. Science, 143, 957–959. 8041 Wrenn, M.E., Mowafy, R., Laurer, G R., 1964. 95Zr–95Nb in human lungs from fallout. Health Phys. 8042 10, 1051–1058. 8043

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8044 14. MOLYBDENUM (Z = 42) 8045 8046 14.1. Chemicals Forms in the Workplace 8047 8048 (621) Molybdenum is a transition metal which mainly occurs in oxidation states IV and 8049 VI. It is an essential element for plants, animals and humans, present in two groups of 8050 enzymes, the nitrogenases and the molybdopterins. Molybdenum may be encountered in 8051 industry in a variety of chemical and physical forms, including oxides, halides, sulphides, 99 8052 nitrates and ammonium molybdate. In the nuclear industry, Mo is a fission product and 99 8053 could be encountered in fragments of irradiated fuel. Large activities of Mo are used in 99m 8054 Tc generators in nuclear medicine. 8055 8056 Table 14-1. addressed in this report 8057 Isotope Physical half-life Decay mode Mo-90 5.56 h EC, B+ Mo-91 15.49 m EC, B+ Mo-93 4.0E+3 y EC Mo-93m 6.85 h IT, EC Mo-99a 65.94 h B- Mo-101 14.61 m B- Mo-102 11.3 m B- 8058 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides 8059 are given on accompanying electronic disk. 8060 8061 14.2. Routes of Intake 8062 8063 14.2.1. Inhalation 8064 8065 Absorption Types and parameter values 8066 (622) Little information is available on the behaviour of inhaled molybdenum in man 8067 following accidental intakes, or from experimental studies in animals. 8068 (623) Absorption parameter values and Types, and associated fA values for particulate 8069 forms of molybdenum are given in Table 14-2. 8070 8071 Ammonium molybdate 99 8072 (624) Cuddihy et al. (1969) measured the tissue distribution of Mo in three dogs at 8 8073 days after inhalation of a solution of ammonium molybdate. About 2% of the sacrifice body 8074 burden (SBB) was in the lungs, compared to 79% SBB in systemic organs (liver, skeleton, 8075 muscle and kidney), showing that most of the Mo deposited in the lungs had been absorbed, 8076 and giving assignment to Type F. 8077 8078 Molybdenum chloride 99 8079 (625) Cuddihy et al. (1969) measured the tissue distribution of Mo in three dogs at 8 8080 days after the inhalation of molybdenum chloride (MoCl4) with 2.5 µm AMAD. About 6% 8081 SBB was in the lungs, compared to 68% SBB in systemic organs, giving assignment to Type 8082 F. 8083 8084 Molybdenum oxide

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99 8085 (626) Cuddihy et al. (1969) measured the tissue distribution of Mo in three dogs at 8 8086 days after the inhalation of molybdenum oxide (MoO3) with 1.5 µm AMAD. About 46% 8087 SBB was in the lungs, compared to 39% SBB in systemic organs, giving assignment to Type 8088 M. 8089 8090 Other compounds 99 99m 8091 (627) Measurements of Mo and Tc whole body retention and excretion in urine were 8092 made from 1.3 days up to about 10 days after intake of an aerosol released during handling of 99 99 99m 8093 a Mo source ( Mo alkaline solution) by workers at a company manufacturing Tc 8094 generators for use in nuclear medicine (Alvarez et al., 1994; Navarro et al., 1995). Navarro et 8095 al. showed good agreement between ICRP Publication 30 model predictions (lung Class D) 8096 and measured whole body retention and urinary excretion for two workers representative of 8097 Group 1 (workers who were in the facility where the accident happened, and exposed directly 8098 to the source aerosol) and Group 2 (workers who were in a nearby laboratory and were 8099 contaminated by the aerosols dispersed through the air-conditioning system.) A critical 8100 analysis of the data (Giussani et al., 2004) showed different biokinetic behaviours between 8101 workers in Group 1 and Group 2. This seems to suggest that the aerosol composition was 2 8102 different in the two environments. Analysis of the data for several workers conducted here 8103 confirmed good agreement assuming absorption Type F, and less good for Type M (with a 8104 correspondingly lower value of fA). However, with the first measurement made more than 1 8105 day after intake and a large contribution to systemic uptake from absorption in the alimentary 8106 tract, it was not possible to estimate a specific value for sr from the data. 8107 8108 Rapid dissolution rate for molybdenum 8109 (628) There is insufficient experimental information to estimate the rapid dissolution rate 8110 for molybdenum. There is therefore no justification for choosing a rate different from the –1 8111 general default value of 30 d , which is applied here to all Type F forms of molybdenum. 8112 8113 Extent of binding of molybdenum to the respiratory tract 8114 (629) Cuddihy et al. (1969) observed that at 8 days after inhalation of ammonium 99 8115 molybdate or molybdenum chloride by dogs, the amounts of Mo associated with the nasal 8116 turbinates were similar to those in the lungs. This suggests that there could be some binding 8117 of molybdenum. However, the experimental information is insufficient to estimate the extent 8118 of any bound state, and it is assumed by default that fb = 0. 8119

2 Data kindly provided by Dr M. A. Lopez, CIEMAT.

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8120 8121 Table 14-2. Absorption parameter values for inhaled and ingested molybdenum 8122 Absorption parameter Absorption from valuesa the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Default parameter valuesb,c Absorption Assigned forms Type F Chloride and ammonium 1 30 – 0.9 molybdate M Oxide and all unspecified 0.2 3 0.005 0.2 formsd S — 0.01 3 0.0001 0.009

Ingested materials Sulphide 0.05 All other forms 0.9 a 8123 It is assumed that for molybdenum the bound state can be neglected i.e. fb = 0. The values of sr for Type F, 8124 M and S forms of molybdenum (30, 3 and 3 d–1, respectively) are the general default values. 8125 b Materials (e.g. molybdenum chloride) are listed here where there is sufficient information to assign to a 8126 default absorption Type, but not to give specific parameter values (see text). 8127 c For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 8128 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 8129 absorption Type and the fA value for ingested soluble forms of molybdenum (0.9). 8130 d Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 8131 or if the form is known but there is no information available on the absorption of that form from the 8132 respiratory tract. 8133 8134 14.2.2. Ingestion 8135 8136 (630) Human investigations with stable isotope have shown that fractional absorption of 8137 molybdenum in inorganic form (chloride and ammonium-molibdate) is greater than 0.85 8138 (Turnlund et al. 1995a, 1995b, Giussani et al., 1998a, 2006). These studies also showed that 8139 intestinal absorption of molybdenum is usually complete within the first 4 hours after 8140 administration (less than two hours if administered in liquid form), indicating that the 8141 absorption is only from the upper part of the alimentary tract (Giussani et al., 2006). 8142 (631) A large number of studies have been conducted in ruminants in order to investigate 8143 the metabolism of molybdenum after ingestion and the potentially lethally effects of an 8144 imbalance between the contents of molybdenum, copper and sulphur in the diet (Huising and 8145 Matrone, 1976; Price et al., 1988). Those effects were due to interactions of those elements in 8146 the rumen of the animals (production of thiomolybdates) and they were not observed in non- 8147 ruminants, except when thiomolybdates were directly administered to them (Mills et al., 8148 1978; Mills, 1985; Chen et al., 1988); therefore, data from studies with ruminants will not be 8149 further considered here. Molybdenum is readily absorbed by non-ruminants when ingested as 8150 salts of molybdic acid, such as MoO3 or CaMoO4 (Mills and Davis, 1987). In contrast, the 8151 highly insoluble compound molybdenum disulphide is only poorly absorbed (Underwood, 8152 1971). The absorption of Mo is considered to be dependent on its concentration in diet, the 8153 amounts of Cu and S present, and the age of the animals (Comar et al., 1949; Nederbragt, 8154 1983). 8155 (632) In Publication 30 (ICRP, 1979), the recommended absorption values were 0.05 for 8156 the sulphide and 0.8 for all other compounds of the element. The value of 1 was adopted in

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8157 Publication 67 (ICRP, 1993) for dietary intakes. The fA values proposed in this report are 8158 0.05 for sulphide and 0.9 for all other compounds. 8159 8160 14.2.3. Biokinetics of systemic molybdenum 8161 8162 14.2.3.1. Summary of the database 8163 8164 Human subjects 8165 (633) In recent years the biokinetics of molybdenum in healthy volunteers was 8166 investigated in a series of studies using stable isotopes as tracers. 8167 (634) A study referred to here as the “GSF study” was conducted by the Institute of 8168 Radiation Protection of GSF (now Helmholtz Zentrum München) in Munich, Germany, in 8169 collaboration with the Department of Physics of the State University of Milano, Italy 8170 (Cantone et al., 1995; Giussani et al., 1998, 2006, 2007; Tavola, 2004; Werner et al., 2000). 8171 Intestinal absorption, plasma clearance and urinary excretion of molybdenum were studied in 8172 a series of investigations on healthy volunteers (6 males and 11 females, age ranging from 27 8173 to 63 y) by simultaneous oral and intravenous administration of two independent tracers. 8174 Repeated studies on the same subjects were conducted to investigate whether and how the 8175 amount and form of administration affect the biokinetic profiles. 8176 (635) The clearance of molybdenum from blood plasma was rapid in all subjects and could 8177 be described with a bi-exponential function with mean characteristic half-times of 30 min 8178 (median: 29 min, range 4-70 min) and 6.6 h (median: 4.4 h, range 2.6-30 h). The mean transit 8179 time in plasma was calculated to be approximately 150 min, and the average mass of the 8180 distribution compartment was evaluated to be in the range 7-19 kg, indicating that 8181 molybdenum was at least partially homogeneously distributed between blood plasma and 8182 interstitial fluids. 8183 (636) The urinary excretion in the first day after intake ranged between 30% and 80% of 8184 the intake, depending on the total mass of molybdenum present in the circulation: the higher 8185 the content of circulating molybdenum, the higher the fraction excreted. The excretion 8186 process was rapid; most of the molybdenum was excreted in the first eight to twelve hours 8187 after administration. It was also shown that administration of elevated dietary molybdenum 8188 mobilized molybdenum stored in the body and increased its excretion rate. No significant 8189 dependence of the results on age or sex was observed. 8190 (637) Another large study referred to here as the “USDA study” was conducted at the 8191 metabolic research unit of the Western Human Nutrition Research Center of the US 8192 Department of Agriculture (USDA) , Presidio of San Francisco (Turnlund and Keyes, 2004, 8193 Turnlund et al., 1995a, 1995b). In the first set of investigations four healthy male subjects 8194 were kept on a low molybdenum diet for 24 days and the metabolic fate of infused 8195 molybdenum in plasma was followed. In the second series of investigations four healthy male 8196 subjects were kept on a low molybdenum diet for 102 days (depletion regime, daily intake 22 8197 µg Mo), followed by an 18-day repletion period (daily intake approx. 500 µg Mo). A further 8198 investigation was structured in five dietary regimes, each with duration of 24 days (dietary -1 8199 intake in each of the five periods: 22, 72, 121, 467 and 1490 µg Mo∙d , respectively). In all 8200 dietary regimes except the depletion regime, the basic diet (containing on average 22 µg -1 8201 Mo∙d ) was supplemented with molybdenum taken from a liquid formula, and the behaviour 97 8202 of systemic molybdenum was studied by injection of the stable isotope Mo. 8203 (638) Analyses of the blood plasma samples showed a correlation between daily intake 8204 and the plasma level of molybdenum. It was also observed that the intravenous administration 97 8205 of even low amounts of tracer (33 µg of Mo) affected the metabolism of endogenous

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8206 molybdenum. Initial clearance from plasma was slightly faster than in the GSF studies; the 8207 published data could be described with a bi-exponential function with half times of 8 and 40 8208 minutes. 8209 (639) Molybdenum turnover as reflected by urinary excretion was faster with higher 8210 dietary molybdenum intakes, similarly to what was observed in the GSF studies. The 8211 percentage of oral tracer excreted in the urine over 6 days increased from 18% during the 8212 depletion period to 82% at the higher dietary regime. Similarly, the percentage excretion of 8213 the infused tracer increased from 33% to 87%. Faecal excretion of systemic molybdenum was 8214 negligible, as less than 2% of the infused tracer was excreted over 6 days. The faecal to 8215 urinary excretion ratio ranged from 1:20 to 1:62, depending on the total mass of circulating 8216 Mo. 99 8217 (640) Rosoff and Spencer (1964) injected Mo (as ammonium molybdate) into four 8218 seriously ill human patients and observed fast elimination from blood plasma (less than 4% of 8219 the tracer was present one hour after injection), similar to the pattern observed by Turnlund 8220 and Keyes (2004). Ten percent of the injected amount was eliminated in urine after 24 hours, 8221 and 25% was eliminated in urine after 6 days. 99 8222 (641) In studies conducted in the 1960's using Mo (molybdate) as a liver scanning agent 99 8223 (Sorensen and Archambault, 1963; 1964; Henning et al., 1965), the level of Mo in blood 8224 after 6 hours was about 1/300 to 1/600 of the original level. In these studies, the whole body 8225 retention half-time was reported to be of the order of 20-40 days; however, the estimates were 99 8226 highly uncertain due to the short half-life of Mo (2.75 d). Elimination in the urine amounted 8227 to 8 % after 6 hours, 20 % after 24 hours, and 30 to 60 % after 2 weeks. 8228 (642) Recently reported concentrations of stable molybdenum in human organs and tissues 8229 generally are lower than values reported in older studies, suggesting that improvements in the 8230 measuring techniques have led to greater precision and to the elimination of contaminating 8231 factors. Most reported values for the molybdenum concentration in whole blood fall between -1 -1 -1 8232 0.4 μg∙L and 1.2 μg∙L , and around 0.6 μg∙L for blood plasma (Iyengar, 1978, Versieck et 8233 al., 1988, Vanhoe et al., 1989, 1994, Schramel and Wendler, 1995, Rodushkin et al., 1999, 8234 Heitland and Köster, 2006, Yoshida et al., 2006). Blood concentrations appear to be enhanced 8235 in people living in regions with higher daily intakes or suffering from particular diseases. 8236 (643) Autopsy determinations of molybdenum in human organs and tissues (Tipton and 8237 Cook, 1963, Tipton et al., 1965, Schroeder et al., 1970, Sumino et al., 1975, Iyengar et al., 8238 1978, Coughtrey and Thorne, 1983, Versieck, 1983, Zeisler et al., 1988, Yoo et al., 2002) 8239 consistently demonstrate highest concentrations in the liver and kidneys and show that the 8240 liver is the most important storage site for molybdenum in the body. Reported concentrations -1 8241 in liver peak around 1 µg∙g . Based on the reference organ masses given in ICRP (2002), 8242 these values correspond to 1.8 mg Mo in the liver of males (range 0.9-2.7) and 1.4 mg Mo in -1 8243 the liver of females (range 0.7-2.1). Values for kidneys peak around 0.3 µg∙g , corresponding 8244 to 90 µg (range 60-120) in the kidneys of males and 80 µg (range 55-110) in the kidneys of 8245 females (ratio liver:kidneys = 20:1). The preference of molybdenum for liver is confirmed by 99 8246 the findings of the studies with Mo in nuclear medicine, with reported uptake by the liver to 8247 be as high as 80% of the administered activity (Sorensen and Archambault, 1963; Henning et 8248 al., 1965; Colombetti et al., 1974; Shearer et al., 1988). 8249 (644) In previous ICRP reports bone was reported "… to be a major store of 8250 molybdenum", based on data presented by Coughtrey and Thorne (1983) and recalculated on 8251 the basis of measurements of Mo concentration in bone ashes made by Nusbaum et al. 8252 (1965). These values, however, have not been confirmed by any other study (Schroeder et al. 8253 1970, Sumino et al. 1975, Yoo et al., 2002). Furthermore, none of the several studies 99 8254 concerning the distribution of Mo administered to patients either as an agent for liver

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99m 8255 scanning or accidentally as an impurity in radiopharmaceuticals labelled with Tc did report 8256 evidence of accumulation of molybdenum in skeletal tissues (Sorensen and Archambault, 8257 1963, 1964, Henning et al., 1965, Colombetti 1974, Shearer 1988). 8258 8259 Laboratory animals 8260 (645) In dogs, molybdenum translocated from the lung following inhalation of various 8261 compounds of the element was deposited mainly in liver, skeleton, muscle and kidney, with 99 8262 liver and kidney containing the highest concentrations (Cuddihy et al., 1969). When Mo 8263 was intravenously administered as ammonium molybdate to mice, the liver showed the 8264 highest uptake with retention of about 26% of the administered activity at 1 h and about 21% 99 8265 at 1 d. The Mo content of the kidney was relatively high, accounting for about 3.8% of the 8266 administered activity at 1 h and 3.9% at 1 d (Rosoff and Spencer, 1973). When molybdenum 8267 was administered to rats as ammonium molybdate, 74% was excreted within 3 h (Ando et al., 8268 1989), and the tissue distribution was similar to that reported for mice. 8269 (646) The marked differences between the ruminants and non-ruminants were clearly 8270 shown in the study by Bell et al. (1964) comparing absorption and excretion of molybdenum 8271 in swine and cattle. Swine showed fast clearance from blood plasma, fast absorption from the 8272 gastro-intestinal tract, and rapid excretion in the urine (50-80 % within 24 hours after 8273 administration, depending on the total amount of circulating molybdenum). The results for 8274 swine are consistent with those observed in the human stable tracer investigations. 8275 8276 14.2.3.2. Biokinetic model for systemic molybdenum 8277 8278 (647) In ICRP Publication 30 (1979), on the basis of human data, the whole-body 8279 retention R(t) of molybdenum in humans was described by the following equation: 8280 -0.693t/1 -0.693t/50 8281 R(t)= 0.1 e + 0.9 e 8282 8283 (648) For molybdenum translocated to organs or tissues, fractions of 0.1 and 0.9 were 8284 assumed to be retained with half-times of 1 and 50 days, respectively. 8285 (649) In ICRP Publication 67 (1993), for molybdenum entering the transfer compartment, 8286 10% was assumed to be deposited in the skeleton and to be retained with a biological half- 8287 time of 10 000 days. The remaining activity was distributed to liver (25%), kidneys (5%) and 8288 all other tissues (60%). A urinary to faecal excretion ratio of 8:1 was assumed for 8289 molybdenum that has entered the transfer compartment. 8290 (650) In this publication, a recycling model for molybdenum biokinetics is presented. The 8291 definition of the model structure and the procedure for the determination of the model 8292 parameters were presented elsewhere (Giussani, 2008) and are here briefly summarized. 8293 (651) The structure of the model consists of: 8294 8295 • Two compartments to describe the available data of molybdenum in blood plasma; 8296 • Liver; 8297 • Kidneys; 8298 • Urinary bladder; 8299 • Generic tissue pool (other tissue). 8300 8301

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8302 8303 Figure 14-1. The systemic model for molybdenum radionuclides 8304 8305 (652) The presence of a separate compartment for skeleton, as in the previous models, is 8306 no longer believed to be justified by the available data, as discussed above. The skeleton is 8307 therefore pooled together with the rest of the other tissues in the generic common 8308 compartment. 8309 (653) The splitting into two subunits of the compartment associated with the systemic 8310 circulation was made in accordance with the results of the analysis presented in (Giussani et 8311 al., 2007). 8312 (654) The stable isotope studies showed that the absorption and excretion processes 8313 changed for increasing amounts of administered tracers (and consequently of circulating 8314 molybdenum). The values of the characteristic parameters given in Table 14-1 were therefore 8315 determined by fitting the model predictions to a subset of the available data corresponding to 8316 the investigations with molybdenum administration lower than or in the same order of the 8317 average daily intake. No allowance was made for age- or sex-dependent parameters, as no 8318 indication of such a dependence was evident from the review of data presented in the 8319 previous sections. 8320

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Table 14-3. Parameter values in the systemic model for molybdenum.

From To Transfer coefficient (d-1) Blood 1 Blood 2 12.5 Blood 1 Liver 14.2 Blood 1 Urinary bladder contents 6.5 Blood 2 Urinary path 1.7 Blood 2 Other kidney tissue 0.115 Blood 2 Other tissue 1.73 Liver Right Colon Contents 0.0048 Liver Blood 2 0.0122 Other kidney tissue Blood 2 0.0474 Other tissue Blood 2 0.0323 Urinary path Urinary bladder contents 1.40 8321 8322 (655) The Blood 1 compartment receives material from outside (alimentary tract, 8323 respiratory tract, wounds), and distributes it to urinary excretion (direct pathway, 19.5%), 8324 liver (42.8%) and to Blood 2 (37.7%) with a half-life of 30 min. The second Blood 8325 compartment transports material into kidneys (3.2%), into a generic compartment taken to 8326 represent all other tissues (48.8%) and into the urine through the renal urinary path (48.0%), 8327 with a half-life of 280 min. The total mass of compartments associated to the extracellular 8328 fluids (Blood 1+Blood 2) amounts to 12 kg. 8329 (656) The retention half-times of molybdenum in the kidneys and in the other tissues are 8330 equal to 14.6 d and 21.5 d, respectively; from these compartments molybdenum is transported 8331 back to Blood 2. 8332 (657) The retention half-time in liver is equal to nearly 41 d; 28% is excreted into the 8333 faeces, 72% is transported back to the extracellular fluids (Blood 2). The characteristic half- 8334 time for transfer from the urinary pathway into the bladder contents is equal to 0.5 d. 8335 (658) In the following figures the model predictions are compared with the corresponding 8336 human data from the stable tracer studies. 8337

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8338 8339 Figure 14-2. Concentration in plasma of injected molybdenum tracer. Data are from 15 8340 investigations in 6 volunteers (GSF study).

8341 8342 Figure 14-3. Cumulative urinary excretion of the intravenous tracer. Dots: data from the GSF 8343 study (one volunteer, error bars: experimental uncertainties) Triangles: data from the USDA study, 8344 depletion conditions (8 volunteers, mean ± SE). 8345

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8346 8347 Figure 14-4. Cumulative faecal excretion of the intravenous trac. Dots: data from the USDA 8348 study, depletion conditions (8 volunteers, mean er. ± SE). 8349 8350 14.2.3.3. Treatment of radioactive progeny 8351 8352 (659) The radioactive progeny considered in the calculations of dose coefficients for 8353 molybdenum isotopes are isotopes of niobium or technetium. The models for niobium and 8354 technetium as progeny of systemic molydenium are modifications of the models applied in 8355 this series of reports to niobium and technetium, respectively, as parent radionuclides. 99m 8356 (660) External measurements on normal human subjects indicated that Tc produced in 99 99 8357 the liver by decay of Mo following intravenous administration of Mo as sodium or 8358 ammonium molybdate was retained in the liver for an extended period (Sorensen and 99m 8359 Archambault, 1963). By contrast, Tc depositing in the liver after administration as a parent 8360 radionuclide was largely removed with a half-time of a few hours (Sorensen and 8361 Archambault, 1963). On the basis of these findings, technetium produced in the liver by 8362 decay of a molybdenum parent is assigned here to the long-term retention compartment of 8363 liver in the characteristic model for technetium described elsewhere in this report. The 8364 removal half-time from that compartment to blood is ~22 d. For modeling convenience, the 8365 compartment of the molybdenum model called Blood 1 is identified with the central blood 8366 compartment of the technetium model. Technetium produced in the compartment Blood 2 of 8367 the molybdenum model is assumed to transfer to the central blood compartment of the -1 8368 technetium model at the rate 1000 d (half time of 1 min). Technetium produced in any other 8369 compartment of the molybdenum model is assumed to transfer to the central blood -1 8370 compartment of the technetium model at the rate 1.39 d , the highest rate of transfer to blood 8371 from an “other tissue” compartment of the technetium model. After reaching the central 8372 blood compartment, technetium is assumed to follow its characteristic model. 8373 (661) No information was found on the behavior of niobium produced in vivo following 8374 intake of a molybdenum parent. For modeling convenience, the compartment of the 8375 molybdenum model called Blood 1 is identified with the central blood compartment of the 8376 characteristic model for niobium. It is assumed that niobium produced in the compartment 8377 Blood 2 of the molybdenum model transfers to the central blood compartment of the niobium -1 8378 model at the rate 1000 d . Niobium produced in a tissue compartment of the molybdenum

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8379 model is assumed to transfer to the central blood compartment of the characteristic model for -1 8380 niobium at the rate 0.433 d , the highest rate of transfer to blood from an “other tissue” 8381 compartment of the niobium model. After reaching the central blood compartment, niobium 8382 is assumed to follow its characteristic systemic model. 8383 8384 14.3. Individual monitoring 8385 99 8386 (662) Monitoring of Mo is in general accomplished through Whole Body Counting 8387 or/and urine bioassays. 8388 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 99Mo Urine Bioassay γ-ray spectrometry 2 Bq/L 0.01 Bq/L 99Mo Lung γ-ray spectrometry 4 Bq measurement 99Mo Whole Body γ-ray spectrometry 400 Bq 24 Bq Counting 8389 8390 References 8391 8392 Alvarez, A., Navarro, N., Salvador, S., 1994. Urinary excretion measurements after accidental 8393 inhalation of 99mTc and 99Mo. Radiat. Prot. Dosim., 51, 59–61. 8394 Ando, A., Ando, I., Hiraki, T., Hisada, K., 1989. Relation between the location of elements in the 8395 periodic table and various organ-uptakes rates. Nucl. Med. Biol. 16, 57-80. 8396 Bell, M.C., Diggs, B.G., Lowrey, R.S., Wright, P.L., 1964. Comparison of Mo99 metabolism in swine 8397 and cattle as affected by stable molybdenum. J. Nutr. 84, 367-372. 8398 Cantone, M.C., de Bartolo, D., Gambarini, G., Giussani, A., Ottolenghi, A., Pirola, L., Hansen, Ch., 8399 Roth, P., Werner, E., 1995. Proton activation analysis of stable isotopes for a molybdenum 8400 biokinetics study in humans. Med. Phys. 22, 1293-1298. 8401 Chen, J.J., Yang, M.T., Yang, S.P., 1988. Interrelationships between molybdenum and copper in 8402 female rats. in Hurley, L.S., Keen, C.L., Lönnerdal, B. and Rucker, R.B.: Trace elements in 8403 man and animals 6 Plenum Press New York, 321-322. 8404 Colombetti, L.G., Hušak, V., Dvořak, V., 1974. Study of the purity of 99mTc sublimed from fission 8405 99Mo and the radiation dose from the impurities. Int. J. Appl. Radiat. Isotop. 25, 35-41. 8406 Comar, C.L., Singer, L., Davis, G.K., 1949. Molybdenum metabolism and interrelationships with 8407 copper and phosphorus. J. Biol. Chem. 180, 913-922. 8408 Coughtrey, P.J., Thorne, M.C., 1983. Radionuclide distribution and transport in terrestrial and aquatic 8409 ecosystems, Vol 2, A.A. Balkema, Rotterdam, 351-375. 8410 Cuddihy, R.G., Boecker, B.B., Kanapilly, G.M., 1969. Tissue distribution of 99Mo in the beagle dog 8411 after inhalation of aerosols of various chemical forms. Fission Product Inhalation Program 8412 Annual Report 1968–1969, LF-41, pp. 117–120. Lovelace Foundation for Medical Education 8413 and Research, Albuquerque, New Mexico. Available from National Technical Information 8414 Service, Springfield, Virginia. 8415 Giussani, A., Roth, P., Werner, E., Greim, H., Cantone, M.C., De Bartolo, D., 1998. A biokinetic 8416 model for molybdenum radionuclides: new experimental results. Radiat. Prot. Dosim. 79 (1- 8417 4), 367-370. 8418 Giussani, A., Cantone, M.C., Tavola, F., Veronese, I., Lopez, M.A., Navarro, T., 2004. Validation of 8419 the revised model for the biokinetics of molybdenum with data from a real accidental case. 8420 11th International Congress of the International Radiation Protection Association IRPA-11, 8421 Madrid, Spain.

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8422 Giussani, A., Arogunjo, A.M., Cantone, M.C., Tavola, F., Veronese, I., 2006. Rates of intestinal 8423 absorption of molybdenum in humans. Appl. Radiat. Isot. 64, 639-644. 8424 Giussani, A., Cantone, M.C., Höllriegl, V., Oeh, U., Tavola, F., Veronese, I., 2007. Modelling urinary 8425 excretion of molybdenum after oral and intravenous administration of stable tracers. Radiat. 8426 Prot. Dosim. 127, 136-139. 8427 Giussani, A., 2008. A recycling model for the biokinetics of molybdenum radionuclides. Sci. Tot. 8428 Environ. 404, 44-55. 8429 Heitland, P., Köster, H.D., 2006. Biomonitoring of 37 trace elements in blood samples from inhabitants 8430 of northern Germany by ICP-MS. J. Trace Elem. Med. Biol. 20, 253-262. 8431 Henning, K., Woller, P., Strietzel, M., Wagner, G., 1965. 99Mo-markiertes Natriummolybdat – 8432 Herstellung und Eigenschaften sowie Verhalten im menschlichen Körper. J. Nuklear Medizin 5, 8433 88-96. 8434 Huising, J., Matrone, G., 1976. Interactions of molybdenum in animal nutrition. in Chappell, W.R. and 8435 Kellogg Petersen, K.: Molybdenum in the environment (Vol. I), Dekker, New York, 125-148. 8436 ICRP, 1979. Limits on Intakes of Radionuclides for Workers. ICRP Publication 30, Pt.1. Pergamon 8437 Press, Oxford. Ann. ICRP 2, (3/4). 8438 ICRP, 1993. Age-dependent doses to members of the public from intake of radionuclides : Part 2. 8439 Ingestion dose coefficients. ICRP Publication 67. Ann. ICRP. 23(3/4), 45-47. 8440 ICRP, 2002. Basic anatomical and physiological data for use in radiological protection: reference 8441 values. ICRP Publication 89, Ann. ICRP, 32(3-4). 8442 Iyengar, G.V., Kollmer, W.E., Bowen, H.J.M., 1978. The elemental composition of human tissues and 8443 body fluids. Verlag Chemie, Weinheim, New York. 8444 Mills, C.F., Bremner, I., El-Gallad, T.T., Dalgarno, A.C., Young, B.W., 1978. Mechanisms of the 8445 molybdenum/sulphur antagonism of copper utilisation by ruminants. in Kirchgessner, M. 8446 Trace element metabolism in man and animals. 3 Technische Universität München, Freising- 8447 Weihenstephan, 150-158. 8448 Mills, C.F., 1985. Dietary interactions involving the trace elements. Ann. Rev. Nutr. 5 (1985), 173- 8449 193. 8450 Mills C., Davis, G., 1987. Molybdenum. In Trace elements in human and animal nutrition 5th ed. San 8451 Diego: Academic Press. 8452 Navarro, T., Alvarez, A., Lopez, M.A., Navarro, N., 1995. Assessment of accidental intakes of 8453 99mTc/99Mo. in Proceedings of the International Conference on Harmonization in radiation 8454 protection: from theory to practical applications. Taormina, p. 339-346. 8455 Nedebragt, H., 1983. The influence of molybdenum on the copper metabolism of the rat at different 8456 Cu levels of the diet. Br. J. Nutr. 43, 329. 8457 Nusbaum, R.E., Butt, E.M., Gilmour, T.C., Didio, S.L., 1965. Relation of air pollutants to trace metals 8458 in bone. Arch. Environ. Health 10, 227-232 8459 Price, J., Will, A.M., Paschaleris, G., Chesters, J.K., 1988. Demonstration of ruminal synthesis of 8460 thiomolybdates and their subsequent absorption in sheep. in Hurley, L.S., Keen, C.L., 8461 Lönnerdal, B. and Rucker, R.B.: Trace elements in man and animals 6 Plenum Press New 8462 York, 589-590. 8463 Rodushkin, I., Ödman, F., Branth, S., 1999. Multielement analysis of whole blood by high resolution 8464 inductively coupled plasma mass spectrometry, Fres. J. Anal. Chem. 364, 338-346 8465 Rosoff, B., Spencer, H., 1964. Fate of molybdenum-99 in man. Nature, 202, 410-411. 8466 Rosoff, B., Spencer, H., 1973. The distribution and excretion of molybdenum-99 in mice. Health 8467 Phys. 25, 173-175. 8468 Schramel, P., Wendler, I., 1995. Molybdenum determination in human serum (plasma) by ICP-MS 8469 coupled to a graphite furnace. Fres. J. Anal. Chem. 351, 567-570. 8470 Schroeder, H.A., Balassa, J.J., Tipton, I.H., 1970. Essential trace metals in man: molybdenum. 8471 J.Chron. Dis. 23, 481-499. 8472 Shearer, D.R., Pezzullo, J.C., Moore, M.M., Coleman, P., Frater, S.I., 1988. Radiation dose from 8473 radiopharmaceuticals contaminated with molybdenum-99. J. Nucl. Med. 29, 695-700.

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8474 Sorensen, L.B., Archambault, M., 1963. Visualization of the liver by scanning with Mo-99 8475 (molybdate) as tracer. J. Lab. Clin. Med. 62, 30-340. 8476 Sorensen, L.B., Archambault, M., 1964. Preliminary physiological studies of molybdenum (Mo-99) in 8477 liver scanning. Radiology 82, 318-319. 8478 Sumino, K., Hayakawa, K., Shibata, T., Kitamura, S., 1975. Heavy metal in normal Japanese tissues. 8479 Arch. Environ. Health 30, 487-494. 8480 Tavola F., 2004. Sviluppo e validazione di un modello biocinetico per l'incorporazione di radionuclide 8481 di molibdeno, Diploma Thesis (in italian), Università degli Studi di Milano. 8482 Tipton, I.H., Cook, M.J., 1963. Trace elements in human tissue. Part II. Adult subjects from the 8483 United States, Health Phys. 9, 103-145 8484 Tipton, I.H., Schroeder, H.A., Perry, H.M. Jr., Cook, M.J., 1965. Trace elements in human tissue. Part 8485 III. Subjects from Africa, the Near and Far East and Europe, Health Phys. 11, 403-451 8486 Turnlund, J.R., Keyes, W.R., Pfeiffer, G.L., Chiang, G., 1995a. Molybdenum absorption, excretion 8487 and retention studied with stable isotopes in young men during depletion and repletion. Am. J. 8488 Clin. Nutr. 61, 1102-1109. 8489 Turnlund, J.R., Keyes, W.R., Pfeiffer, G.L., 1995b. Molybdenum absorption, excretion, and retention 8490 studied with stable isotopes in young men at five intakes of dietary molybdenum. Am. J. Clin. 8491 Nutr. 62, 790-796 8492 Turnlund, J.R,, Keyes, W.R., 2004. Plasma molybdenum reflects dietary molybdenum intake. J. Nutr. 8493 Biochem. 15, 90-95. 8494 Underwood, E.J., 1971. Trace Elements in Human and Animal Nutrition. 3rd Edition Academic Press, 8495 London. 8496 Vanhoe, H., Vandecasteele, C., Versieck, J., Ache, H.J., 1989. Determination of iron, cobalt, copper, 8497 zinc, rubidium, molybdenum and cesium in human serum by inductively coupled plasma 8498 mass spectrometry. Anal. Chem. 61, 1851-1857 8499 Vanhoe, H., Dams, R., Versieck, J., 1994. Use of inductively plasma mass spectrometry for the 8500 determination of ultra-trace elements in human serum. J. Anal. Atom. Spectr. 9, 23-31. 8501 Versieck, J., 1983. Molybdän. in Zumkley, H. and Bertram, H.P.: Spurenelemente, Georg Thieme 8502 Verlag Stuttgart, 152-165 8503 Versieck, J., Vanballenberghe, L., De Kesel, A., Hoste, J., Wallaeys, B., Vandenhaute, J., Baeck, N., 8504 Steyaert, H., Byrne, A.R., Sunderman, F.W. , Jr 1988. Certification of a second generation 8505 biological reference material (freeze-dried human serum) for trace element determinations. 8506 Anal. Chim. Acta 204, 63-75 8507 Werner, E., Roth, P., Heinrichs, U., Giussani, A., Cantone, M. C., Zilker, Th., Felgenhauer, N., 8508 Greim, H., 2000. Internal biokinetic behaviour of molybdenum in humans studied with stable 8509 isotopes as tracers. Isotop. Environ. Health Stud. 36 (2), 123-132. 8510 Yoshida, M., Ôta, S., Fukunaga, K., Nishiyama, T., 2006. Serum molybdenum concentration in 8511 healthy Japanese adults determined by inductively coupled plasma-mass spectrometry. J. 8512 Trace Elem. Med. Biol. 20, 19-23 8513 Yoo, Y.C., Lee, S.K., Yang, J.Y., In, S.W., Kim, K.W., Chung, K.H., Chung, M.G., Choung, S.Y., 8514 2002. Organ distribution of heavy metals in autopsy material from normal Korean. J. Health 8515 Sci. 48, 186-194. 8516 Zeisler, R., Greenberg, R.R., Stone, S.F., 1988. Radiochemical and instrumental neutron activation 8517 analysis procedures for the determination of low level trace elements in human livers, J. 8518 Radioanal. Nucl. Chem. 124, 47-63. 8519 8520 8521

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8522 15. TECHNETIUM (Z = 43) 8523 8524 15.1. Chemical Forms in the Workplace 8525 8526 (663) Technetium is a transition metal, which occurs mainly in oxidation states IV, VI and - 8527 VII. Technetate or pertechnetate (TcO4 ) is the most common technetium ion in solution. 8528 Technetium may be encountered in industry in a variety of chemical and physical forms, such 8529 as oxides (TcO2, Tc2O7), sulphides, halides and nitrates. Technetium is an artificial element 99m 8530 obtained either from uranium fission or after bombarding molybdenum with neutrons. Tc 8531 is frequently used in nuclear medicine for a wide variety of diagnostic tests as a label for 8532 different pharmaceuticals. 8533 8534 Table 15-1. addressed in this report 8535 Isotope Physical half-life Decay mode Tc-93 2.75 h EC, B+ Tc-93m 43.5 m IT, EC, B+ Tc-94 293 m EC, B+ Tc-94m 52.0 m EC, B+ Tc-95 20 h EC Tc-95m 61 d EC, B+, IT Tc-96 4.28 d EC Tc-96m 51.5 m IT, EC, B+ Tc-97 2.6E+6 y EC Tc-97m 90.1 d IT Tc-98 4.2E+6 y B- Tc-99a 2.111E+5 y B- Tc-99ma 6.015 h IT, B- Tc-101 14.2 m B- Tc-104 18.3 m B- 8536 a Data for these radionuclides are given in the printed copy of this report. Data for other radionuclides are 8537 given on accompanying electronic disk. 8538 8539 15.2. Routes of Intake 8540 8541 15.2.1. Inhalation 8542 8543 Absorption Types and parameter values 8544 (664) Most of the experimental information available on the behaviour of technetium 8545 following deposition in the respiratory tract relates to pertechnetate, or materials labelled with 99m 8546 Tc, especially DTPA. Some information is also available from accidental human intakes. 8547 (665) Absorption parameter values and Types, and associated fA values for particulate 8548 forms of technetium are given in Table 15-2. 8549 8550 Pertechnetate 99m 8551 (666) The absorption of Tc from the lungs following its administration as pertechnetate - 8552 (TcO4 , molecular mass 163 Da) is very rapid. Barrowcliffe et al. (1986) measured retention 8553 halftimes of about 10 minutes after intratracheal instillation into rats. Man et al. (1989) 8554 measured retention halftimes of 3-4 minutes after inhalation by dogs, several times faster than 99m 8555 for Tc-DTPA (see below) inhaled by the same dogs. Following inhalation of sodium

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99m 8556 Tc-labelled pertechnetate by healthy volunteers, Yeates et al. (1973) and Chopra et al. 99m 8557 (1979) measured half-times of absorption of Tc from lungs to blood of about 10 minutes, 8558 with less than 2% of the initial lung deposit retained after 2 hours. Chopra et al. (1979) 8559 obtained similar results in patients with systemic sclerosis. Rinderknecht et al. (1980) 99m 8560 measured retention halftimes in healthy volunteers averaging 13 minutes for inhaled Tc- 99m 8561 labelled pertechnetate, significantly faster than for Tc-DTPA (average 44 minutes), with 8562 faster clearance in patients with interstitial lung disease and slower clearance in patients with 8563 pulmonary alveolar proteinosis. Human studies on ingested pertechnetate (Section 14.2.2) -1 8564 suggest fA ~0.8. Specific absorption parameter values of fr = 1, sr = 100 d (consistent with 8565 assignment to default Type F) and fA =0.8 are used here for pertechnetate. 8566 (667) Based on the results of the experiments outlined above, specific absorption -1 8567 parameter values for pertechnetate were estimated here to be: fr = 1 and sr = 100 d 8568 (consistent with assignment to default Type F). However, although specific parameter values 8569 for pertechnetate based on in vivo data are available, they are not adopted separately here. 8570 The data are used as the basis for the default rapid dissolution rate for technetium. Hence 8571 specific parameter values for pertechnetate would be the same as default Type F technetium 8572 parameter values, and therefore pertechnetate is assigned to Type F instead. 8573 99m 8574 Tc-labelled DTPA (diethylenetriaminepentaacetic acid) 99m 8575 (668) Tc-DTPA has been used extensively, as a convenient, radiolabelled, low 8576 molecular mass (492 Da) solute to study pulmonary epithelial permeability in man. 99m 8577 Following inhalation of Tc-DTPA by healthy non-smokers, lung retention half-times of 99m -1 8578 Tc were reported to be 59 minutes (corresponding to a clearance rate of ~17 d ) by Jones -1 -1 8579 et al. (1980), 72 minutes (14 d ) by Braude et al. (1984), 56 minutes (18 d ) by Nolop et al. -1 8580 (1987a) and 85 minutes (12 d ) by Silveira et al. (2003). “Baseline” clearance rates were -1 -1 -1 -1 8581 reported to be 1.48% min (21 d ) by Nolop et al. (1987b), 0.7% min (10 d ) by Köhn et -1 -1 -1 -1 8582 al. 1990, 0.83% min (12 d ) by Smith et al. (1992) and 0.69% min (10 d ) by Foster and 14 8583 Stetkiewicz (1996). See also the section on C-labelled DTPA (2.2.1). Stather et al. (1983) 14 14 8584 followed the biokinetics of C after administration of C-labelled DTPA to healthy 8585 volunteers by inhalation, intravenous injection, and ingestion (which indicated that about 3% 8586 was absorbed from the alimentary tract). Modelling by the authors gave an estimated rate of –1 99m 8587 absorption from lungs to blood of about 13 d (fr ~1), similar to that obtained for Tc- 8588 DTPA, suggesting that it is characteristic of DTPA rather than technetium. Nolop et al. 99m 113m 8589 (1987a) obtained similar retention half-times for Tc-DTPA (56 minutes) and In-DTPA 99m 8590 (62 minutes), indicating that the results were not affected by dissociation of Tc-DTPA in 99m 99m 8591 the lungs. Thin-layer chromatography of Tc in urine, following inhalation of Tc-DTPA, 99m 8592 suggested that the Tc-DTPA did not dissociate during its movement from lungs to urine 8593 (Köhn et al. 1990). 8594 (669) Jefferies et al. (1984) reported that as premature infants with hyaline-membrane -1 8595 disease recovered, the retention half-time (initially shorter) averaged 56 minutes (18 d ), 99m 8596 similar to that in healthy adults, which suggests no effect of age on absorption of Tc- 8597 DTPA from lungs to blood. 99m 8598 (670) The absorption of Tc-DTPA following deposition in different regions of the 8599 respiratory tract has been investigated. Chopra et al. (1979) measured retention half-times in -1 -1 8600 healthy non-smokers of 35 minutes (29 d ) and 65 minutes (15 d ) for “upper” and “lower” 8601 lung fields measured with a gamma camera. (Both fields were peripheral, i.e. predominantly 99m 8602 alveolar.) Oberdörster et al. (1986) found absorption to be slower in dogs for Tc-DTPA 8603 inhaled with rapid shallow ventilation of large particles to maximise bronchial deposition -1 -1 8604 (1.31% min , 19 d ), than for inhalation with slow deep ventilation of small particles to

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-1 -1 8605 maximise alveolar deposition (2.29% min , 33 d ). Wolff et al. (1988) measured similar -1 99m 8606 rates of clearance (~7 d ) of Tc-DTPA instilled into the nasal passage, trachea, fifth 8607 generation airway, and peripheral airway (approximately tenth generation) of dogs. Bennett 99m 8608 and Ilowite (1989) found clearance of Tc-DTPA by absorption from the bronchial mucosa 8609 to be slower than that from the alveolar region in healthy non-smokers: retention half times -1 -1 8610 were 296 minutes (3.4 d ) and 107 minutes (9.3 d ) respectively. Smith et al. (1992) 99m 8611 reported clearance of Tc-DTPA to be faster following deep inhalation, to enhance alveolar 8612 deposition, than following inhalation with normal tidal breathing. 99m 8613 (671) The absorption of Tc-DTPA from the lungs has been found to be faster in 8614 smokers, and in patients with a wide variety of lung diseases. Because of its potential 8615 diagnostic use for detecting pathological changes in lung epithelial function, it was 8616 extensively studied. However, according to Peterson (1989) in a review, the long list of 8617 conditions that produce similar increases in the clearance rate, including severe lung disease, 8618 smoking, exposure to ozone, and even increased lung volume, make it insufficiently specific 8619 in diagnosis. For example, Jones et al. (1980) found a significantly shorter lung retention 99m -1 8620 half-time of Tc of 20 minutes (50 d ) in asymptomatic smokers than in non-smokers (59 8621 minutes). Similarly Nolop et al. (1987a) measured “baseline” lung retention half-times of 99m -1 -1 8622 Tc of 25 minutes (40 d ) in healthy smokers and 56 minutes (18 d ) in nonsmokers; 8623 hyperinflation increased the clearance rate in both groups. Minty et al. (1981) found a rapid, 8624 but only partial, increase in retention half-time in smokers who abstained from cigarettes for 8625 three weeks -1 8626 (672) Specific absorption parameter values of fr = 1, sr = 10 d (consistent with assignment 99m 8627 to default Type F) and fA =0.03 are used here for Tc-DTPA. 8628 99m 8629 Tc-labelled carbon 99m 8630 (673) An aerosol of ultrafine (<100 nm) Tc-labelled carbon particles (“Technegas”) has 8631 been developed for lung ventilation scans in nuclear medicine. Sodium pertechnetate in saline 8632 is vaporised in a graphite crucible at about 2500°C in an atmosphere, then diluted with 8633 air. The condensation aerosol formed consists of primary particles of about 5-15 nm 8634 diameter, forming agglomerates of about 100 nm diameter. Roth et al. (1997) investigated its 8635 deposition and clearance following inhalation by healthy volunteers. From total urine 8636 collection during 24 hours after inhalation, they assessed that about 9% of the deposited 99m 8637 Tc activity dissolved: mostly in the first 6 hours. 8638 (674) To assess to what extent, and how, inhaled particles from “urban combustion” or 8639 “soot-like” particulate matter pass into the systemic circulation, volunteers inhaled ultrafine 99m 8640 Tc-labelled carbon particles, in most cases produced with a Technegas generator, or a 8641 modified version of it (Nemmar et al., 2002; Wiebert et al., 2006; Mills et al. 2006; Möller et 8642 al., 2008). Brown et al. (2002), however, used a spark generator (arc between carbon 99m 8643 electrodes to which Tc-pertechnetate had been applied). Nemmar et al. (2002) concluded 99m 8644 that inhaled Tc-labelled carbon particles pass rapidly into the systemic circulation, based 8645 on the estimated liver uptake and the results of thin-layer chromatography (TLC) of blood 8646 samples, which indicated that there was one species present corresponding to pertechnetate, 99m 8647 and another which they attributed to Tc-labelled carbon particles. The other studies did not 8648 support this conclusion. All reported that particle accumulation in the liver was not detectable 99m 8649 corresponding to fractions of the Tc-labelled carbon particles deposited in the lungs of 8650 <1.5% for Brown et al. (2002) and <0.5% for Möller et al. (2008). Mills et al. (2006) found 99m 8651 that (also using TLC) the Tc transferred to blood was associated with pertechnetate rather 99m 8652 than with particle-bound Tc.

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8653 (675) With regard to dissolution, Nemmar et al. (2002) observed that activity was detected 8654 in blood at 1 minute, reached a maximum between 10 and 20 minutes, and remained at this 99m 8655 level up to 60 minutes. A considerable fraction of Tc leached from the particles and 99m 8656 distributed as pertechnetate, as indicated by accumulation of Tc in the bladder, thyroid and 8657 salivary glands. For a representative subject, activity in the bladder reached about 25% of the 8658 initial lung activity in 45 minutes. Brown et al. (2000, 2002) measured leaching in vitro 8659 (0.9% saline) to be ~10-15% in 5 minutes and 15-25% in ~24 hours. Mills et al. (2006) noted 8660 that in the presence of even minute amounts of oxygen the Technegas generator produces a 99m 99m 8661 mixture of Tc-labelled particles and soluble oxides of Tc-pertechnetate. Wiebert et al. 99m 8662 (2006) and Möller et al. (2008) made specific efforts to fix the Tc radiolabel firmly to the 8663 carbon particles. Wiebert et al. (2006) reported dissolution in vitro (0.9% saline) to be ~3% in 8664 70 hours, compared to 11% in 24 hours for particles produced by the standard Technegas 8665 method. Möller et al. (2008) reported dissolution in vitro (0.9% saline) to be ~4% in 24 99m 8666 hours. In both studies, urinary excretion of Tc in 24 hours following inhalation by 8667 volunteers was about 1% of activity deposited in the lungs. 99m 99m 8668 (676) These results suggest the fraction of Tc leaching rapidly from Tc-labelled 8669 carbon particles varies from a few percent to tens of percent, depending on the method of 8670 formation. The retention measurements made in the inhalation studies suggest that the 8671 remaining material is relatively insoluble, and more likely to be Type M or S than Type F, 8672 but the short duration of measurements limits the inferences that can be drawn. 8673 8674 Other particulate forms 99m 8675 (677) The use of Tc-labelled materials such as albumin, erythrocytes, ferric oxide, 8676 polystyrene, resin teflon and sulphur colloid, to study mucociliary clearance from the 8677 bronchial tree relies on there being relatively little absorption from the lungs to the body 8678 fluids over the first day or so after deposition (Isawa et al., 1984; Matthys et al., 1983; Albert 8679 et al., 1969; Sutton et al., 1981; Puchelle et al., 1979; Mossberg and Camner, 1980, Man et al. 8680 1989). 8681 8682 Undefined particulate forms 99 99m 8683 (678) The results of measurements of Mo and Tc whole body retention and excretion 8684 in urine made from 1.3 days up to about 10 days after intake of an aerosol released during 99 99 8685 handling of a Mo source ( Mo alkaline solution) by workers at a company manufacturing 99m 8686 Tc generators for use in nuclear medicine (Alvarez et al., 1994; Navarro et al., 1995) are 8687 consistent with assignment to Type F (see section 13.2.1). 8688 8689 Rapid dissolution rate for technetium 8690 (679) Evidence from the pertechetate studies outlined above suggests a rapid dissolution –1 8691 rate of the order of 100 d , which is applied here to all Type F forms of technetium. 8692 8693 Extent of binding of technetium to the respiratory tract 8694 (680) Evidence from the experimental studies outlined above suggests that there is 8695 probably little binding of technetium. It is therefore assumed that for technetium the bound 8696 state can be neglected, i.e. fb = 0.0. 8697

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8698 8699 Table 15-2. Absorption parameter values for inhaled and ingested technetium 8700 Absorption parameter valuesa Absorption from the alimentary –1 –1 Inhaled particulate materials fr sr (d ) ss (d ) tract, fA Specific parameter valuesb Tc-DTPA 1 10 – 0.03

Default parameter valuesc,d Absorption Assigned forms Type F Pertechnetate 1 100 – 0.9 M All unspecified formse 0.2 3 0.005 0.2 S — 0.01 3 0.0001 0.009

Ingested material All forms 0.9 a 8701 It is assumed that for technetium the bound state can be neglected, i.e. fb = 0.0. The values of sr for Type F of 8702 technetium (100d-1) is element specific. The values for types M and S (3 d–1) are the general default values. 8703 b See text for summary of information on which parameter values are based, and on ranges of parameter 8704 values observed for individual materials. 8705 c Materials (e.g. pertechnetate) are generally listed here where there is sufficient information to assign to a 8706 default absorption Type, but not to give specific parameter values (see text). 8707 d For inhaled material deposited in the respiratory tract and subsequent cleared by particle transport to the 8708 alimentary tract, the default fA values for inhaled materials are applied: i.e. the product of fr for the 8709 absorption Type and the fA value for ingested soluble forms of technetium (0.9). 8710 e Default Type M is recommended for use in the absence of specific information, i.e. if the form is unknown, 8711 or if the form is known but there is no information available on the absorption of that form from the 8712 respiratory tract. 8713 8714 15.2.2. Ingestion 8715 99m 8716 (681) Technetium administered as Tc pertechnetate is generally well absorbed by 8717 human subjects. Mean absorption values of about 0.9 and 0.95 were obtained by McAfee et 8718 al. (1964) and Beasley et al. (1966), respectively, whereas the data presented in Andros et al. 8719 (1965) suggest mean absorption fraction of 0.6. 8720 (682) In rats, the fractional absorption seems to range between 0.4 and about 0.9 for 8721 pertechnetate (Gerber et al., 1989; Archimbaud et al., 1992, Berthol et al., 2003) and to be 8722 equal to about 0.5 for Tc chloride (Hamilton, 1948; Sullivan et al., 1977). 8723 (683) In Publication 30 (ICRP, 1980), an absorption value of 0.8 was recommended for all 8724 compounds of technetium. A lower value of 0.5 was adopted in Publication 67 (ICRP, 1993) 8725 for uptake from food. In this report, an fA value of 0.9 is used for all chemical forms in the 8726 workplace. 8727 8728 15.2.3. Systemic Distribution, Retention and Excretion 8729 8730 15.2.3.1. Summary of the database 8731 8732 Overview 8733 (684) Most biokinetic studies of technetium in human subjects and laboratory animals - 8734 have involved its administration as the ion pertechnetate (TcO4 ), the most readily available

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8735 chemical form and the starting point for technetium chemistry. The initial distribution of 8736 pertechnetate is similar to that of inorganic iodide. Pertechnetate and iodide are both 8737 selectively concentrated in the thyroid, salivary glands, and stomach wall. In contrast to 8738 iodide, pertechnetate trapped by the thyroid is not organically bound in the thyroid but is 8739 largely released back to blood over a period of hours. In normal subjects, 1-2% of 8740 intravenously injected pertechnetate is accumulated by the iodide-concentrating mechanism 8741 of the thyroid at 1 hr, which is similar to accumulation of radioiodide in the blocked thyroid. 8742 Thyroid uptake of both iodide and pertechnetate are increased by an order of magnitude in 8743 diffuse toxic goiter. A significant biological difference between the pertechnetate ion and 8744 iodide is their markedly different excretion pattern. Iodide is excreted mainly in urine. After 8745 intravenous administration, about 25-30% of administered pertechnetate is excreted in urine 8746 over the first 24 hr, but thereafter the urinary excretion rate decreases markedly while 8747 cumulative faecal excretion increases to 20% or more of the injected amount at 72 h and may 8748 eventually exceed cumulative urinary excretion. Most of the absorbed or injected 8749 pertechnetate is lost from the body within a few days, but a small percentage is retained for a 8750 period of weeks or longer. During chronic intake, relatively high concentrations are found in 8751 bone, kidneys, liver, skin, hair, and thyroid. 8752 8753 Data for human subjects 8754 (685) Harper, Lathrop, and coworkers (Harper et al., 1962, Andros et al., 1965) found that 99m 8755 intravenously injected TcO4 localized within a few minutes in the thyroid, stomach, and 8756 salivary glands in human subjects and a variety of laboratory animals. Blood clearance could 8757 be described in terms of two approximately equal components with half-times of 8-12 min 8758 and 4-8 h. The first component appeared to represent distribution in the extracellular space. 99 8759 (686) Sorensen and Archambault (1963) developed a liver scanning technique using Mo 99m 8760 molybdate but based on measurement of gamma radiation emitted by its daughter Tc. 8761 Technetium-99m was found to remain in the liver for an extended period after its production 99 99m 8762 by decay of Mo already taken up by liver cells. By contrast, Tc depositing in the liver 8763 after administration as a parent radionuclide was removed with a half-time of a few hours, in 99m 8764 parallel with the decrease in the external counts over the head. About 58% of injected Tc 8765 was recovered in urine and 24% was recovered in faeces over the first 3 days after its 8766 administration as a parent radionuclide. 99m 8767 (687) McAfee et al. (1964) examined the tissue distribution or excretion of Tc (T1/2 = 8768 6.0 h) administered as pertechnetate to 6 healthy male volunteers and 23 patients with 8769 suspected brain tumors. The gastrointestinal absorption and tissue distribution of activity 131 8770 resembled that of I administered as iodide. Absorbed activity was concentrated in the 8771 thyroid, salivary glands, and gastric mucosa. Much of the gastric and salivary secretion was 8772 reabsorbed in the small intestine, but in contrast to iodide a substantial fraction accumulated 8773 in the colon and was excreted in the faeces. An abdominal scan performed 3 h after 8774 intravenous administration revealed high levels of activity within the stomach and duodenal 8775 loop and higher levels in the splenic flexure and descending colon. Following either oral or 8776 intravenous administration the highest count rates were observed over the stomach and next 8777 highest rates over the liver. For both organs the effective (biological plus radiological) 8778 removal half-time initially was about 2 h but increased to 5-7 h after the first hour, which is 99m 8779 approximately the radiological half-life of Tc. This suggests nearly equilibrium conditions 8780 between the rate of secretion into the stomach and removal of the secretion into the small 8781 intestine. Activity in the thyroid peaked at 1-2 h after administration, at which time an 8782 estimated 3-4% of the administered amount (corrected for radioactive decay) was present 8783 within the gland. In contrast to iodide, pertechnetate was not organified by the thyroid but

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8784 returned to blood over a period of hours. At 24 hours the thyroid content was estimated as 8785 0.5% of the administered amount. About 20-25% of intravenously injected activity remained 8786 in blood after 1 h and about 0.8-5% remained after 24 h. Blood plasma and red blood cells 8787 contained on average about 70% and 30%, respectively, of the total blood content at 1 h after 8788 intravenous injection. The rate of urinary excretion of activity closely reflected the plasma 8789 concentration. Following oral administration to 9 subjects, the average urinary excretion was 8790 25% over the first 24 h, 3% over 24-48 h, and 1% over 48-72 h. Following intravenous 8791 administration to 12 subjects, average urinary excretion was 27% at 24 h, 4% over 24-48 h, 8792 and 2% over 48-72 h. Total urinary excretion by individual subjects was in the range 15-50% 8793 over 24 h and 15-58% over 72 h. Total faecal excretion over 72 h was 30-55% after oral 8794 administration and 10-45% after intravenous administration. Recovery of activity from the 8795 colon was incomplete despite administration of laxatives. Total loss in urine plus faeces over 8796 72 h averaged 50% (range, 28-68%) following intravenous administration and 70% (39-88%) 8797 following oral administration. 99m 8798 (688) Andros et al. (1965) studied the biokinetics of Tc over the first 72 h following its 8799 oral or intravenous administration as pertechnetate to 86 patients including 57 euthyroid 8800 subjects. Following intravenous administration the thyroid accumulated up to 2% of the 8801 administered amount at 1 h. The serum contained on average about 0.00045%/ml at 24 h, 8802 indicating that roughly 2% of the dosage was in blood at that time assuming equal 8803 concentrations in plasma and red blood cell water. The concentration ratios saliva : plasma 8804 and gastric juice : plasma averaged 37.5 (range, 11.5-66) and 17.5 (11-28.5), respectively. In 8805 seven subjects, average urinary excretion was 35.7% of the intravenously administered 8806 amount after 24 h, 6.2% at 24-48 h, and 4.8% at 48-72 h, giving a total of 46.7%. Average 8807 faecal excretion in 6 of these subjects was 8.8% after 72 h. In a normal young adult female, 8808 total urinary and faecal excretion at 72 h after intravenous injection accounted for 33.1% and 8809 28.2%, respectively, of the administered amount. The average total-body biological half-time 8810 for all subjects based on all excretion data was 53 h. 95m 96 8811 (689) Beasley et al. (1966) used Tc (T1/2 = 60 d) and Tc (4.3 d) to study the relatively 8812 long-term biokinetics of technetium in 8 normal human volunteers (ages 22-43 y) following 8813 its oral or intravenous administration as pertechnetate. The distribution and total-body 8814 retention of activity were monitored externally, and samples of plasma, urine, faeces, sweat, 8815 tears, and intestinal mucosa were analyzed. By 10 min after intravenous injection the activity 8816 had begun to localize in the bladder. At 2 h activity was found in relatively high 8817 concentrations in the salivary and thyroid glands, stomach, liver, and urinary bladder. The 8818 specific activity of the saliva was high, approaching 95% of dosage per liter of saliva at 2-3 h. 8819 For several days after oral or intravenous administration the saliva contained 10-30 times the 8820 Tc concentration in plasma. Technetium was not concentrated in lacrimal or sweat glands, 8821 but the concentration in nasal secretions was high. There was no indication of localization in 8822 the liver or kidneys at 3 d in a subject who received technetium orally. Biopsies of the 8823 stomach, duodenum, and rectal mucosa were performed on selected subjects at 2, 7, and 19 d. 8824 No appreciable activity was observed in the rectal mucosa, but concentrations in stomach and 8825 duodenum were 40-100 times plasma concentrations at comparable times. On average, about 8826 28% of the injected activity was excreted in urine and about 2-3% was excreted in faeces 8827 during the first 24 h. Thereafter the urinary excretion rate declined rapidly, and faecal 8828 excretion soon became the dominant excretion pathway. Cumulative urinary and faecal 8829 excetion averaged about 35% and 55%, respectively, of the injected amount after 8 d. 8830 Biological retention R (%) in the total body could be described as a sum of three exponential 8831 terms, R(t)=76.7exp(-0.693t/1.6)+19exp(-0.693t/3.7)+4.3exp(-0.693t/22), where t is in days. 99m 8832 (690) Harden and coworkers (1967, 1968, 1969) investigated the uptake of Tc

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8833 pertechnetate by the stomach wall and salivary glands and its secretion in saliva and gastric 8834 juice following its intravenous administration to human subjects. In 10 subjects with no 8835 evidence of diseases of the alimentary tract the mean uptake by the stomach at 20 min was 8836 3.0 +/- 0.4% of the administered activity, and uptake at 1 h was in the range 2.4-11.4%. 99m 8837 (Harden et al., 1967). In seven male volunteers the average concentration ratio Tc in 99m 8838 saliva : Tc in plasma at 40-70 min after administration was 27.3. The average 99m 99m 8839 concentration ratio Tc in gastric juice : Tc in plasma over that time was 11.0. 99m 132 8840 Clearance of TcO4 was about half that of I in both saliva and gastric juice. 99m 8841 (691) Atkins and Richards (1968) studied thyroidal uptake of Tc pertechnetate in 143 99m 8842 patients who were hospitalized for reasons other than thyroid disease. Uptake of Tc and 131 99m 8843 I by the thyroid were positively correlated. Uptake of Tc in 120 euthyroid subjects 8844 averaged about 2% and exceeded 5% in only one subject. Fifteen hyperthryoid subjects had 99m 8845 Tc uptake in the range 3.5-28.5%. 99m 8846 (692) Mean thyroid uptake of intravenously injected TcO4 in 18 normal volunteers was 8847 estimated as 1.6 +/- 0.7% (SD) (Goolden et al., 1971). Uptake in 20 patients with 8848 thyrotoxicosis ranged from 0.8% to 22%. 99m 8849 (693) Thyroid uptake of Tc pertechnetate was measured 20 min after administration of 8850 a tracer dose in seven normal controls and 52 patients with thyroid disease (McGill et al., 8851 1971). The mean uptake was 0·96 ± 0·17% in normal subjects, 2·87 ± 0·39% in patients with 8852 non-toxic goiter, 16·7 ± 1·9% in thyrotoxic patients, and 1·94±0·27% in hypothyroid 8853 patients. 8854 (694) One hundred patients with clinically suspected Meckel's diverticulum were studied 8855 with pertechnetate scintigraphy of the abdomen (Berquist et al., 1976). The investigators 8856 noted that intestinal radioactivity seen in a scan could be either in the gut wall or in the 8857 lumen. They found no technetium in the mucosa of the small or large intestine at 30 min 8858 after administration and only small amounts at later times. 99m 8859 (695) Hays (1973) studied the biokinetics of TcO4 after its administration to 15 normal 8860 subjects by oral, subcutaneous, or intravenous routes. Absorption from the gut was highly 99m 8861 variable. As observed earlier by Andros et al. (1965) and Beasley et al. (1966), TcO4 8862 showed substantial pooling in the gut and subsequent faecal excretion after all modes of 8863 intake. This is in contrast to radioiodide, which shows substantial pooling in the stomach due 8864 to secretion by the salivary glands and gastric mucosa but is nearly completely reabsorbed to 8865 blood after passing into the small intestine. 99m 8866 (696) Hays and Berman (1977) investigated the biokinetics of Tc pertechnetate during 8867 the first 8 h of its continuous intravenous infusion into normal volunteers. A group of 9 8868 subjects was studied during hours 0-4, and another group of 10 subjects was studied during 8869 hours 4-8. One gram of sodium iodide was administered intravenously to the second group at 8870 6.5 h. Plasma, salivary, and urinary activities were assayed, and external measurements were 8871 made over the neck, thigh, and right upper abdomen. The investigators found that 8872 pertechnetate was initially distributed much like iodide and that the administration of iodide 8873 markedly reduced transport of pertechnetate into the thyroid, saliva, stomach, and small 8874 intestine. In contrast to the systemic behavior of iodide, the large intestine appeared to play 8875 an important role in the retention and excretion of pertechnetate. The investigators developed 8876 biokinetic model for pertechnetate from the results of their study, analogy with iodide 8877 biokinetics, and data from previous biokinetic studies of pertechnetate. The model depicts 8878 three main subsystems that determine the fate of systemic pertechnetate: the thyroid trap; 8879 technetium distributed throughout the body, represented by plasma and two extravascular 8880 compartments; and four compartments within the gastrointestinal tract representing the 8881 salivary glands, stomach plus upper small intestine, and two lower intestinal pools. One of

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8882 the latter compartments is identified with the bowel wall on the basis of external 8883 measurements. 8884 8885 Data for laboratory animals 8886 (697) Following intravenous administration of technetium isotopes to rats, 73% of the 8887 administered activity was recovered in urine and 15% in faeces after 24 h (Durbin et al., 8888 1957, Durbin, 1960). At 24 h the gastrointestinal tract, bone, liver, and thyroid contained 8889 9.0%, 0.4%, 0.7%, and <0.1%, respectively, of the administered amount. At 8 d after 8890 intravenous administration of technetium isotopes to rats the only tissues containing 8891 measureable amounts of activity were the skin, kidney and liver (Hamilton, 1948). 99m 8892 (698) Following intravenous administration of Tc as pertechenate to mice, the organ 8893 with the highest accumulation was the stomach, which contained 10% of the administered 8894 amount (corrected for radioactive decay) at 1-3 h and 14% at 6 h (McAfee et al., 1964). From 8895 1 to 6 h the small intestine content increased from 2 to 6% and the large intestine content 8896 from 2 to 9% of administered technetium. 99m 8897 (699) Matthews and Mallard (1965) studied the distribution and tumor uptake of Tc 8898 pertechenate in the first few hours after its intravenous administration to rats and compared 8899 its behavior with that of other tracers. The distribution was found to be broadly similar to 131 8900 that of I administered as iodide. Pertechnetate equilibrated rapidly with the extracellular 131 8901 spaces of several organs. Some observed differences from I as iodide were that the liver 99m 131 99m 8902 accumulated 3 times as much Tc as I, the kidneys accumulated 2-5 times as much Tc 131 99m 131 8903 as I, and the Tc content of the intestines continued to rise for 4.25 h while that of I 99m 8904 reached a peak relatively quickly and then began to decline. The content of Tc in the liver 8905 decreased from 8.7% of the administered amount at 0.57 h to 4.2% at 4.25 h. At 3-4 h after 99m 8906 injection the concentration of Tc in the liver was about 2.5 times that in bone and 7 times 8907 that in muscle. 99m 99m 8908 (700) Yeh and Kriss (1967) compared the biokinetics of Tc pertechnetate and a Tc 8909 citrate complex in mice over the first 24 h after intravenous administration. The 8910 pertechnetate showed high concentration in the salivary glands, stomach, thyroid, and colon. 8911 The liver content decreased from 8.5% of the administered amount at 0.5 h to 2.8% at 24 h. 8912 The kidney content was 1.8% at 0.5 h and below the detection limit at 24 h. Total-body 8913 retention was 70% at 0.5 h and 16.5% at 24 h. The citrate complex showed a much higher 8914 urinary excretion rate than pertechenate and in contrast to pertechnetate was not localized in 8915 the salivary glands, stomach, or thyroid. The liver content was roughly 2.5% of the 8916 administered amount from 0.5 to 2 h and declined to 1.5% at 24 h. The kidney content 8917 decreased from 2.3% at 0.5 h to 0.8% at 24 h. Total-body retention was 20% at 0.5 h and 7% 8918 at 24 h. 8919 (701) McRae et al. (1974) studied the effects of stannous tin on the distribution of 8920 pertechnetate in rats. The following distribution was determined at 1 h after intravenous 99m 8921 administration of TcO4 to control animals: liver, 4.3% of administered activity; kidneys, 8922 1.0%; stomach, 17.1%; intestines, 7.2%; skeleton, 7.3%; muscle, 11.3%, and skin, 27.2%. 95m 8923 (702) Coffee et al. (1984) studied the biokinetics of intravenously injected TcO4 or 99m 99 8924 TcO4 administered to rats with and without a TcO4 carrier. Retention in all organs was 95m 8925 reduced substantially by administration of the carrier. Total-body retention of TcO4 was 8926 about 9% at 7 d and >1% at 6 mo when administered with no carrier, 5% at 7 d and 0.6% at 6 99 8927 mo when administered with 2.4 mg TcO4/kg, and ~2.1% at 7 d and <0.2% at 6 mo when 99 8928 administered with 24 mg TcO4/kg. The relative concentrations in tissues at 24 h after 99m 8929 injection of TcO4 with no carrier were liver, 0.15; kidneys, 0.82; stomach, 0.40; large 8930 intestine, 0.05; and skin, 0.11.

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99 8931 (703) Maize containing bound Tc was introduced acutely into the rumen of sheep 99 8932 (Kirchmann et al., 1986). The Tc concentration in the kidneys over the period 1-28 d after 8933 administration was an order of magnitude greater than that in the liver and three orders of 99 8934 magnitude greater than that in muscle. The biological half-times for Tc in kidneys, liver, 8935 and muscle based on measurements at 7 and 28 d after administration were about 6 d, 9 d, 8936 and 9 d, respectively. 99 8937 (704) The biokinetics of Tc was studied in sheep following its introduction into the 8938 rumen as pertechnetate or biologically bound to algae (Bruwaene et al., 1986). Tissue 8939 concentrations and urinary and faecal excretion rates were determined up to 3 mo after 99 8940 administration. The biokinetics of Tc administered in algae appeared to be broadly similar 99 8941 to that for Tc administered as pertechnate except for possible differences in uptake and 99 8942 retention by the thyroid, but variability in the data for Tc administered in algae hampered 99 8943 precise characterization of its biokinetics. Gastrointestinal absorption of Tc was low. 99 8944 Urinary excretion amounted to about 1% of the dosage. Highest concentrations of Tc were 8945 found in thyroid tissue, followed by liver and kidney. Relatively high concentrations were 8946 also found in the skin and wool. Two components of total-body retention were observed 99 8947 following administration of Tc either as pertechnetate or algae. Two components of 8948 retention were also evident for the liver, kidneys, and thyroid following administration of 99 8949 Tc as pertechnetate. Following administration as pertechnetate, the size (coefficient) of the 8950 first component of retention was about 35 times that of the second component for the total- 8951 body, 6 times that of the second component for the kidneys, and 2 times that of the second 8952 component for the thyroid; the size of the second component was not determined for the liver. 8953 The estimated biological half-time of the long-term components for the total-body and 8954 individual tissues were in the range 20-50 d. 99 8955 (705) Holm and Rioseco (1987) investigated the transfer of Tc from lichens to reindeer 8956 in a region of central Sweden. Activity was measured in reindeer tissues during the period 8957 1963-1981. Activity concentrations in the liver and kidneys typically were much higher than 8958 those in muscle. The mean activity concentration in bone expressed on a wet weight basis 8959 was about 2.5 times that in liver and 10 times that in muscle. Compact and trabecular bone 99 8960 showed similar concentrations of Tc. 95m 8961 (706) Gerber et al. (1989) compared the biokinetics of Tc in rats (a monogastric animal) 8962 and sheep (a polygastric animal) following its intravenous injection or ingestion as TcO4 or 8963 biologically incorporated in maize. The pattern of absorption and excretion and, to some 8964 extent, the organ distribution and retention depended on the animal species and the form of 8965 administered activity. Pertechnetate given orally was better absorbed by rats than by sheep. 8966 Absorption of activity bound to maize was roughly equal to that of TcO4 in sheep but much 8967 less than that of TcO4 in rats. Endogenous excretion of injected activity by rats was primarily 8968 in urine and by sheep was primarily in faeces. The highest tissue concentration at 3 and 7 d 8969 following intravenous administration to sheep and all modes of administration to rats was 99m 8970 found in the thyroid, followed by the kidneys. Following ingestion of either form of Tc by 8971 sheep, the kidneys showed the highest tissue concentration. Bone, skin, muscle, and liver 8972 contributed significantly to the total-body burden. Biological half-times for tissues of sheep 8973 were estimated from tissue concentrations up to 90 d and characterized for each tissue as a 8974 sum of two exponential terms. The half-time of the first component of retention was about 5 8975 d for all tissues. The half-time of the second component was about 20 d for kidneys, 40 d for 8976 liver, and 50 d or longer for bone, muscle, and skin. 95m 8977 (707) Jones (1989) studied the intestinal absorption and systemic biokinetics of Tc 8978 following its administration to female goats and swine. At 200 h after administration the 8979 highest tissue concentration in both species was found in the thyroid, followed by kidneys

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8980 and then liver. In swine the total content of the liver was roughly three times the content of 8981 the kidneys or thyroid. 8982 (708) Ennis et al. (1989) studied the transfer of technetium isotopes to milk and tissues of 99 8983 lactating goats. At 35-40 d after oral administration of Tc pertechnetate, the concentration 99 8984 of Tc in tissues and fluids decreased in the order thyroid > hair > kidney > mammary gland 99 8985 > liver > lower large intestine > muscle > blood > milk. The concentration of Tc in the 8986 thyroid was roughly 20 times that in the kidneys, 100 times that in the liver, and 1000 times 8987 that in muscle. 125 99m 8988 (709) Zuckier et al. (2004) compared the time-dependent distributions of I, Tc, and 188 99m 8989 Re in mice after their intravenous injection as iodide, pertechnetate ( TcO4), and 188 8990 perrhenate ( ReO4), respectively. The early distributions of these three radionuclides were 8991 remarkably similar. Activity concentrations of all three in salivary glands and stomach were 8992 several times higher than the blood concentration, remained elevated over the initial 2 h, and 8993 subsequently declined. A broadly similar pattern of accumulation and decline of 8994 pertechnetate and perrhenate was observed in the thyroid. By contrast, the concentration of 125 8995 I in the thyroid continued to increase through the 19-h time point, presumably due to 99m 8996 organification of the iodide. At 20 min, the concentration of Tc decreased in the order 8997 stomach > salivary glands > thyroid > liver > kidney > spleen > muscle. This order was 8998 maintained at 2 h except that the concentration in the thyroid had become slightly greater 8999 than that in the salivary glands by this time. 9000 (710) Valenca et al. (2005) investigated the effects of cigarette smoke on the initial 99m 9001 distribution of intravenously injected Tc pertechnetate in mice. The following 99m 9002 concentrations (% injected Tc/g) were determined in control animals at 1 h: stomach, 5.7; 9003 red blood cells, 3.6; lung, 1.7; thyroid, 1.1; kidney, 0.89; spleen, 0.36; bone, 0.26; and testis, 9004 0.25. 9005 9006 15.2.3.2. Biokinetic model for systemic technetium 9007 9008 (711) The structure of the systemic model for technetium used in this report is shown in 9009 Figure 15-1. Transfer coefficients are listed in Table 15-3. 9010 (712) The model structure is a modification of the generic structure for bone-volume- 9011 seeking radionuclides. Although technetium is not regarded as a bone seeker, that structure 9012 provides a convenient starting place for modeling its systemic kinetics. Compartments 9013 representing the thyroid, salivary glands, stomach wall, and right colon wall are added to the 9014 model because they have been identified in human or animal studies as important repositories 9015 for pertechnetate. The bone, kidneys, liver, thyroid, and other soft tissues are each divided 9016 into multiple compartments representing different phases of retention and, in the case of 9017 bone, also different types of tissue. 9018 (713) Blood is treated as a well-mixed pool. The total outflow rate from blood is assumed -1 9019 to be 25 d (half-time of 40 min). This initially understates the clearance rate of 9020 intravenously administered pertechnetate in human subjects but reproduces observed blood 9021 clearance reasonably well after 1-2 h. Outflow from blood is divided as follows: 9% goes to 9022 a fast turnover thyroid compartment (Thyroid 1), 25% to the stomach wall; 15% to the 9023 salivary glands, 7.5% to the urinary bladder contents, 15% to a fast-turnover liver 9024 compartment (Liver 1), 2.5% to a fast-turnover kidney compartment (Urinary path), 0.25% to 9025 a slow-turnover kidney compartment (Other kidney), 13% to the colon wall, 2% to cortical 9026 bone surface, 0.5% to trabecular bone surface, 0.5% to a soft-tissue compartment with 9027 relatively slow turnover (ST2), and the remaining 9.75% to a soft-tissue compartment with 9028 relatively fast turnover.

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9029

9030 9031 9032 Figure 15-1. Structure of the biokinetic model for systemic technetium used in this 9033 report. 9034 9035 (714) It is assumed that 99% of activity entering Thyroid 1 returns to Blood and 1% enters 9036 Thyroid 2, representing relatively long-term retention in the thyroid. The transfer coefficient -1 9037 from Thyroid 1 to Blood is 36 d , based on analogy with iodide (see the section on iodine). -1 9038 Activity transfers from Thyroid 2 to Blood at the rate 0.032 d , corresponding to a half-time 9039 of 22 d. The 22-d half-time for this and other compartments in the model is based on the 9040 long-term component of retention of total-body technetium determined in the human study by 9041 Beasley et al. (1966). -1 9042 (715) Activity transfers from the salivary glands to the oral cavity at the rate 36 d , based 9043 on the estimate of Hays and Berman (1977) on healthy human subjects. The same value is 9044 applied here to transfer from the stomach wall to the stomach contents. The model of Hays 9045 and Berman does not include a separate compartment representing stomach wall, but the -1 9046 value 36 d assumed here is reasonably consistent with the time course of movement of 9047 pertechnetate from plasma to a rapid turnover tissue compartment to stomach contents in -1 9048 their model. This transfer coefficient is also reasonably consistent with the value 50 d 9049 applied to transfer from stomach wall and salivary glands to gastrointestinal contents in the 9050 model for iodide used in this report. The subsequent behavior of technetium entering the oral 9051 cavity or stomach content is described by default transfer coefficients of the Human 9052 Alimentary Tract Model and a reference gastrointestinal absorption fraction of 0.9 for 9053 technetium. 9054

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Table 15-3. Parameter values in the systemic model for technetium.

Transfer coefficient From To (d-1) Blood Thyroid 1 2.16 Blood ST1 2.34 Blood ST2 0.12 Blood Urinary bladder content 1.8 Blood Salivary glands 3.6 Blood Stomach wall 6.0 Blood Kidneys 1 0.6 Blood Kidneys 2 0.06 Blood Liver 1 3.6 Blood Right colon wall 3.12 Blood Trabecular bone surface 0.12 Blood Cortical bone surface 0.48 Thyroid 1 Blood 36 Thyroid 1 Thyroid 2 0.364 Thyroid 2 Blood 0.032 ST1 Blood 0.433 ST2 Blood 0.032 Salivary gland Oral cavity 36 Stomach wall Stomach content 36 Kidneys 1 Urinary bladder content 8.32 Kidneys 2 Blood 0.032 Liver 1 Blood 8.234 Liver 1 Liver 2 0.0832 Liver 2 Blood 0.032 Right colon wall Right colon content 0.693 Trabecular bone surface Blood 0.429 Trabecular bone surface Trabecular bone volume 0.00433 Cortical bone surface Blood 0.429 Cortical bone surface Cortical bone volume 0.00433 Trabecular bone volume Blood 0.000493 Cortical bone volume Blood 0.0000821 9055 9056 (716) Activity is removed from Liver 1 with a half-time of 2 h, with 99% returning to 9057 Blood and 1% moving to Liver 2, which represents relatively long-term retention in the liver. 9058 The removal half-time from Liver 2 to Blood is 22 d. Activity is removed from the kidney 9059 compartment called Urinary path to Urinary bladder contents with a half-time of 2 h. 9060 Activity is removed from the kidney compartment with relatively long-term retention (Other 9061 kidney tissue) to Blood with a half-time of 22 d. Activity is transferred from other soft tissue 9062 compartments ST1 and ST2 to blood with half-times of 1.6 d and 22 d, respectively; 1.6 d 9063 and 22 d are the fitted short-term and long-term half-times of removal from the body 9064 determined in the human study by Beasley et al. (1966) described earlier. Activity is lost 9065 from the right colon wall to the right colon contents with a half-time of 1 d. This is shorter 9066 than the half-time of 2.4 d estimated by Hays and Berman (1977), but this shorter half-time 9067 provides a better fit to the mean faecal excretion curve for technetium based on the human 9068 subjects of Beasley et al. (1966). 9069 (717) The model for bone depicts a low rate of uptake of technetium by bone but a sizable 9070 portion of the total-body content in bone during chronic intake. Activity is removed from

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9071 bone surface with a half-time of 1.6 d, with 99% returning to blood and 1% entering the 9072 associated bone volume compartment. Activity is removed from bone volume at the 9073 reference rate of bone turnover for the given bone type. 9074 (718) Model predictions of total-body retention of technetium as a function of time after its 9075 acute input to blood are compared in Figure 15-2 with a curve fit to observed values for 9076 human subjects (Beasley et al., 1966). Predictions of cumulative urinary and faecal excretion 9077 of technetium after its acute input to blood are compared in Figure 15-3 with mean values 9078 derived from results from the same study. The data for urine (circles) are based on 9079 measurements tabulated by Beasley et al. for a 25-day observation period. The data for faeces 9080 (plus signs) for days 1-8 are based on a graphical representation of cumulative faecal 9081 excretion over the first 8 d following intake. Data for faeces for later days were calculated as 9082 100% minus estimated mean total-body retention (%) minus estimated mean cumulative 9083 urinary excretion (%). 9084 9085 15.2.3.3. Treatment of radioactive progeny 9086 9087 (719) All of the chain members addressed in this report in the derivation of dose 9088 coefficients for internally deposited isotopes of technetium are also isotopes of technetium. 9089 These chain members are assigned the biokinetic model for technetium as a parent 9090 radionuclide, starting at the time of production of the progeny in the body. 9091

9092 9093 Figure 15-2. Model predictions of total-body retention of technetium following its acute input 9094 into blood, compared with a curve fit to observations for human subjects (Beasley et al., 1966). 9095 9096 9097

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9098 9099 9100 Figure 15-3. Model predictions of cumulative urinary and faecal excretion of technetium 9101 following its acute input into blood, compared with central estimates based on observations for 9102 human subjects (Beasley et al., 1966). 9103 9104 15.3. Individual monitoring 9105 99 9106 Tc 99 9107 (720) Tc is beta emitter. Monitoring of is done through urine bioassay techniques. 9108 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 99Tc Urine Bioassay Liquid Scintillation 1-5 Bq/L 1 Bq/L Counting 99Tc Urine Bioassay Beta proportional 4 Bq 0.04 Bq/L counting 9109 99m 9110 Tc 99m 9111 (721) Monitoring of Tc is in general accomplished through Whole Body Counting. In 99m 9112 addition Tc may be detected through urine bioassay. If needed lung monitoring may be 9113 performed. 9114 Isotope Monitoring Method of Typical Achievable Technique Measurement Detection detection limit Limit 99mTc Urine Bioassay γ-ray spectrometry 5-10 Bq/L 0.01 Bq/L 99mTc Whole Body γ-ray spectrometry 90 Bq 25-30 Bq Counting 9115

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