Handbuch der experimentellen Pharmakologie Handbook of Experimental Pharmacology

Heffter-Heubner New Series

Herausgegeben von/Edited by

0. Eichler A. Farah H. Herken A. D. Welch Heidelberg Syracuse, N. Y. Berlin New Haven, Conn.

Beirat/Advisory Board

G. Acheson· E.J. Ariens · Z. M. Bacq · F. von Briicke · V. Erspamer U.S. von Euler · W. Feldberg · R. Furchgott ·A. Goldstein· G. B. Koelle 0. Krayer · K. Repke · M. Rocha e Silva · P. Waser · W. Wilbrandt

Vol.XX/1

Springer-Verlag Berlin Heidelberg GmbH 1966 Pharmacology of Fluorides

Part 1

Contributors

E. W. Alther · R. E. Banks · F. Brudevold · ]. W. Clayton jr. H. Goldwhite · J. C. Krantz jr. · R. L. Metcalf F. L. M. Pattison · R. A. Peters · F. G. Rudo · J. L. Shupe F. A. Smith· M.D. Thomas· J.A.Weatherell

Sub-Editor Frank A. Smith

With 155 Figures

Springer-Verlag Berlin Heidelberg GmbH 1966 Ali rights, especially that of translation into foreign languages reservcd. It is also forbidden to reproduce this book, either whole or in pari, by photome<:hanical rneans (photostat, microfilm and/or microcard) or by any other procedure without writ· ten permission !rom Springer-Verlag Berlin Heidelberg GmbH. © by Springer·Verlag Berlin Heidelberg 1966 Originally published by Springer-Verlag Berlin Heidelberg New York 1966 Softeover reprint of the hardcover lst edition 1966

Library of Congress Catalog Card Number AGR 25~99

ISBN 978-3-662-23198-2 ISBN 978-3-662 -25198-0 (eBook) DOI 10.1007/978-3-662-25198-0

The reproduction of general descriptive names, trade names, trade marks, etc. in this publication, even when !here is no special identification mark, is not to be taken as a sign !bat such names, as understood by the Trade Marks and Merchandise Marks Law, may accordingly be freely used by anyone.

Title No. 5729 Preface

One might well ask why another volume dealing with biological aspects of compounds of should be offered to the scientific community, already burdened with a literature too massive to be comfortably ingested. Prior toWorld War II this question simply did not arise: there was not sufficient interest or literature in the field to warrant anything beyond the classical monograph pub• lished by KAJ RoHOLM in 1937 1• RoHOLM's work was directed chiefly toward a better understanding of the effects of fluorides on the general health of workers in the cyrolite industry. However, with the demonstration that water-borne fluoride was a causative agent of both mottled enamel and increased resistance to dental caries, the ground• work was laid in the 1930's and early 1940's for a greatly increased interest in the biological effects of fluorides in human beings. During this time and earlier for that matter, work also had been going steadily ahead in the less spectacular area of effects produced in poultry and livestock when fluorine-containing rock phosphate was incorporated in the ration, and when pasture land was contami• nated with fluorides released during the large-scale conversion of rock phosphate to fertilizer and phosphoric acid. These latter aspects of the problem had led to the development of a respectable literature in plant physiology, dealing with the effects of fluoride on vegetation. Much of the work in this period, especially that dealing with dental health and with chronic experimental poisoning in animals, was reviewed by EICHLER in 1950, in an earlier volume of this Handbuch 2• As a result of research initiated during World War II, the commercial uses of fluorine and fluorides increased rapidly and enormously, and this growth has been sustained in the post-war years. For example, in 1963 the yearly consumption of fluoride was estimated to be 215,000 short tons, of which production of aluminum fluoride, fluorocarbons, uranium and synthetic cyrolite consumed 30, 31, 10 and 12%, respectively. In addition to these industries, a partial list of the processes or industries wherein inorganic fluorides are used includes production of steel, chemical cleaning, as catalysts, electrotinning of steel, as a laundry sour, in acidizing oil wells, beryllium production, electropolishing, as an abrasive and as an electrolyte. After World War II, and as a result of research initiated in those days, great interest arose in the potentialities of organic compounds of fluorine. In the popular press, these were identified with the rodenticide known as 1080, or sodium fluoro• acetate, and with the "nerve gases" such as DFP, or diisopropyl fluorophosphate. Less well appreciated is the fact that organic fluorine compounds, e.g. fluoro• carbons, are used in very considerable amounts in aerosol propellents, hydraulic fluids, in fire extinguishing systems, as refrigerants, and in plastics. 1 ROHOLM, K. (1937): Fluorine intoxication. A clinical-hygienic study with a review of the literature and some experimental investigations. H. K. Lewis and Co., London. 364 p. See also RoHOLM, K. (1938): Handbuch der experimentellen Pharmakologie. Siebenter Band. Fluor und Fluorverbindungen. Springer-Verlag. Berlin p. 1-62. 2 EICHLER, 0. (1950): Chronic poisoning by fluorides, p. 1032-1107, In Handbuch der experinlentellen Pharmakologie. Zehnter Band, Die Pharmakologie anorganischer Anionen. Springer-Verlag, Berlin, Gottingen, Heidelberg. VI Preface

Finally, there is a continuing scientific interest in the development of new pharmacological agents containing fluorine. Fluorine-containing steroids, anes• thetic agents and anti-cancer drugs come immediately to mind. Historically then, interest in the biological effects of fluorides came about initially in relation to water fluoridation programs and atmospheric contamina• tion problems. After World War II interest was augmented by the industrial growth of both inorganic and organic fluorine compounds. One is tempted to suspect at times that the rapidly expanding literature in the field reflects a feeling that fluorine and fluorides have suddenly become more toxic than they used to be. Obviously, such is not the case. What has come about however, is an appreciable increase in the hazard associated with these materials. That is to say, the possibility of encountering the characteristic toxic effects of these materials under the conditions of their use has been increased, because the variety, amounts, and ways of usage have increased so tremendously. This distinction between hazard and toxicity is often lost sight of. It is the increased hazards of fluoride which have led to the burgeoning literature in the field of biological effects of fluorides. This volume is an attempt to evaluate and bring together in one place at least a portion of the extensive and widespread literature dealing with certain of these aspects. A succeeding volume is intended to deal in a similar fashion with other equally important areas.

Rochester, N. Y. 18. April 1965 FRANK A. SMITH Contributors

ERNEST W . .ALTHER, Dr., Cantonal .Agricultural College, Flawil, St. GallenJSchweiz. R. E. BANKS, Professor Dr., Faculty of Technology, University of Manchester, Manche• ster/England. FINN BRUDEVOLD, Dr., Professor Forsyth Dental Infirmary, 140 The Fenway, Boston 15, Massachusetts/USA. J. WESLEY CLAYTON JR., Dr., Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Co., Wilmington, DelawareJUS.A. H. GoLDWHITE, Professor Dr., Faculty of Technology, University of Manchester, Manche• ster/England. Present Address: Department of Chemistry, California State College at Los .Angeles, Los .Angeles, California/USA. JoHN C. KRANTz JR., Professor Dr., Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland/USA. R. L. METCALF, Professor, Dr., Department of Entomology, University of California, Riverside, California/USA. F. L. M. PATTISON, Professor Dr., Department of Chemistry, University of Western Ontario, London, Ontario/Canada. SIR RuDOLPH .A. PETERS, Professor Dr., Department of Biochemistry, Tennis Court Road, Cambridge/England. FRIEDA G. Runo, Professor Dr., Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland/USA. JAMES L. SHUPE, Dr., Formerly Professor of Veterinary Science, Utah State University. Present Address: Research Veterinarian .Animal Disease and Parasite Research Division, U.S . .Agricultural Research Service, Logan, Utah 84321/US.A. FRANK .A. SMITH, Professor Dr., University of Rochester, School of Medicine and Dentistry, Department of Radiation Biology and Biophysics, Rochester 20, New York/US.A. MoYER D. THOMAS, Professor Dr., .Air Pollution Research Center, University of California, Riverside, California/USA. JoHN .A. WEATHERELL, Professor Dr., Biological Research Unit, School of Dentistry, Uni• versity of Leeds, Blundell Street, Leeds !/England. Contents Chapter 1: Fluorine Chemistry By R. E. BANKS and H. GOLDWHITE I. Introduction ...... 1 II. Inorganic fluorine chemistry. 2 A. Elementary fluorine . . . 2 1. Occurrence . . . . . 2 2. Preparation ...... 3 3. Physical properties of fluorine and their effect on its chemistry . 3 a) Isotopes of fluorine 3 b) Covalent radius . . 3 c) Dissociation energy 4 d) Ionization potential 4 e) Entropy . . . . . 4 f) Electronegativity . 4 g) Nuclear magnetic properties 4 4. Chemical properties of fluorine . . . . . 4 5. Valency of fluorine and bonding in fluorine compounds 4 6. The fluoride ion ...... 5 a) Ionic radius...... 5 b) Heat and entropy of hydration ...... 5 7. Standard potential of fluorine-fluoride ion electrode. 5 8. Hydrogen fluoride ...... 6 a) Preparation and handling...... 6 b) Properties of anhydrous hydrogen fluoride 6 c) Aqueous hydrogen fluoride 7 B. Inorganic fluorides . . • ...... 7 1. Some general considerations ...... 7 2. General methods of preparation of inorganic fluorides . 8 a) General methods ...... 8 a) Use of aqueous hydrogen fluoride ...... 8 {1) Use of anhydrous hydrogen fluoride...... 8 y) Use of antimony trifluoride (promoted by antimony pentachloride) 9 !5) Use of elementary fluorine . 9 e) Use of halogen fluorides 9 b) Group I fluorides . 9 c) Group II fluorides . 9 d) Group III fluorides 9 e) Group IV fluorides. 10 a:) Carbon . . . . 10 {1) Silicon...... 10 y) Germanium, tin and lead 11 f) Group V fluorides . . . . . 11 a) Nitrogen...... 11 {1) Phosphorus ...... 12 y) Arsenic, antimony, and bismuth 12 g) Group VI fluorides. . . . . 12 a:) Oxygen ...... 12 {3) Sulphur ...... 13 y) Selenium and tellurium . . . . 14 h) Group VII fluorides (Cl, Br, I) (interhalogen compounds) . 14 i) Fluorides of the transition metals 15 a) Cobalt...... 16 {1) Uranium...... 16 j) Fluorides of the rare gases . . . 17 Contents IX

III. Organic fluorine chemistry ...... 17 A. Methods for the introduction of fluorine into organic compounds 17 1. Fluorinating agents based on elementary fluorine...... 18 a) Elementary fluorine ...... 18 b) Use of high-valency metallic fluorides in the "metallic fluoride process" 20 c) Halogen fluorides ...... 21 d) Electrochemical fluorination ...... 21 2. Fluorinating agents based on hydrogen fluoride ...... 23 a) Hydrogen fluoride ...... 23 a) Halogen-exchange reactions ...... 23 {J) Reaction of anhydrous hydrogen fluoride with unsaturated compounds 24 y) Reaction with olefin oxides. 24 b) Potassium fluoride . . 25 c) Antimony fluorides . 26 d) Sulphur tetrafluoride. 27 e) Perchloryl fluoride. . 29 f) Tetrafluoroboric acid. 31 g) Other inorganic fluorides 31 B. Synthesis in organic fluorine chemistry 31 1. Polyfluoro-compounds ...... 31 2. Compounds of low fluorine content . 34 C. Properties and reactions of organic fluorine compounds 34 1. Fluorocarbons and their derivatives 35 a) Alkanes . 35 b) Arenes .. 35 c) Hydrides . 36 d) Halides 36 e) Olefins . . 37 f) Carboxylic acids. 39 2. Organic compounds of low fluorine content 40 a) Aliphatic fluorides . . 40 b) Aromatic fluorides. . 43 IV. Analysis of fluorine compounds 44 A. Determination of fluorine . 44 1. Conversion of fluorine into a determinable form 44 2. Determination of fluoride ion 44 B. Physical methods ...... 44 1. Infrared spectroscopy ...... 44 2. Nuclear magnetic resonance spectroscopy 44 3. Mass spectroscopy ...... 45 V. Industrial aspects of fluorine chemistry . 45 Text books on fluorine chemistry 47 References ...... 49 Chapter 2: Metabolism of Inorganic Fluoride By F. A. SMITH I. Introduction 53 II. Absorption . 54 A. Absorption from the gastrointestinal tract 54 1. Absorption in different portions of the gastrointestinal tract . 56 2. Rate of absorption ...... 56 3. Extent of absorption ...... 58 a) Normal dietary fluoride ...... 58 b) Fluoride in food vs. fluoride in water . 60 c) Fluoride in milk vs. fluoride in water. 61 d) Nature of the compound . . 62 4. Alleviators ...... 63 5. Increased retention of fluoride . 64 X Contents

B. Other routes of entry 65 C. Species differences 65 III. Transport...... 65 IV. Distribution. . . . . 67 A. Volume of distribution 67 B. Organ distribution of absorbed fluoride 68 l. Studies with radioactive fluoride . . 69 2. Studies with nonradioactive fluoride 73 a) Normal fluoride intake . . . 73 b) Chronic ingestion of fluoride 75 C. Distribution of total body fluoride 84 l. Distribution in animals . 84 2. Distribution in man S5 a) Vital organs . . . 92 b) Muscle and skin .. 92 c) Blood ...... 92 d) Extracellular fluid . 92 e) Bone ...... 93 D. Maternal-fetal exchange of fluoride 93 E. Fluoride in milk ...... 102 F. Fluoride in saliva, plaque and calculus 105 G. Skeletal storage of fluoride . . . . . 107 l. Rapidity of skeletal deposition. . . 107 2. Skeletal concentrations of fluoride . lOS 3. Skeletal content vs. intake and duration of exposure Ill 4. Skeletal fluoride and age . . . . ll3 5. Mechanism of skeletal deposition . ll3 6. Enamel deposition ll3 7. Mobilization . . ll4 8. Steady state . . . ll4 9. Cartilage . . . . ll5 10. Prediction of skeletal fluoride ll5 H. Extraskeletal calcification . 116 l. Soft tissues ...... ll6 2. Renal and biliary calculi ll6 V. Excretion...... ll7 A. Urinary excretion. . . . ll7 l. Rapidity of excretion . ll7 2. Urinary excretion as a function of intake liS 3. Physiological factors . . . . ll9 4. Extent of skeletal saturation 120 5. Renal clearance of fluoride 121 B. Fecal excretion . . 122 l. Man ..... 123 2. Animal studies . 124 C. Perspiration . . . 124 VI. Fluoride and disease states l2S A. Diabetes ...... 12S B. Impaired kidney function l2S C. Vitamin deficiencies and vitamin utilization 130 D. Miscellaneous . . 130 VII. Essentiality of fluoride 131 Contents XI

VIII. Fluoride in the treatment of disease 131 A. Demineralizing diseases 131 B. Bone fractures . . . . 131 C. Magnesium deficiency . 131 D. Cancer 131 IX. References 132 Chapter 3: Fluoride and the Skeletal and Dental Tissues By J. A. WEATHERELL I. General metabolism of fluoride 141 II. Uptake of fluoride by bone . . 142 A. Distribution of fluoride in the skeleton 142 B. Influence of growth and mineralisation on the fluoride cotent of bone 142 C. Variations in fluoride content of bone with age and duration of fluoridation 143 D. Influence of the level of fluoride ingestion on concentrations of fluoride in bone 145 E. Removal of fluoride by resorption of bone 146 III. Uptake of fluoride by dental tissues 146 A. Fluoride in enamel 146 B. Fluoride in dentine 148 C. Fluoride in cementum . 150 D. Influence of growth and calcification on the fluoride content of dental tissues 150 E. Influence of the level of fluoride ingestion on the fluoride content of dental tissues...... 151 F. Removal of fluoride from dental tissues 151 IV. Mechanism of fluoride uptake and removal 151 A. Uptake by ionic exchange 151 B. Uptake by deposition . . 153 C. Removal of fluoride . . . 153 D. Influence of growth and mineralisation on the rate of fluoride uptake 154 V. Fluorosis ...... 154 A. Skeletal changes of chronic fluorosis . 154 l. Formation of exostotic bone . . 155 2. Bone resorption ...... 156 B. Dental changes of chronic fluorosis 157 C. Effect of fluoride on calcification . 157 l. Evidence of interference with calcification . . . . . 157 2. Mechanism of fluoride interference with calcification ...... 159 a) Effect of fluoride upon the calcifiability of the organic matrix . . 160 b) Effect of fluoride upon systems associated with calcification 160 c) Effect of fluoride upon apatite crystal formation. 161 VI. Amounts of fluoride associated with fluorosis 162 A. Levels of fluoride ingestion. 162 l. Dental fluorosis ...... 163 2. Skeletal fluorosis ...... 164 B. Urinary level of fluoride as an index of toxicity. 166 C. Concentration of fluoride in fluorotic bone 167 References ...... 169 XII Contents

Chapter 4: The Role of Fluorides in Tooth Chemistry and in the Prevention of Dental Caries By F. BRUDEVOLD I. Introduction ...... 173 II. Development of controlled water fluoridation 173 III. Water fluoridation and dental caries . 174 A. Fluoride exposure throughout life. . . . 174 B. Prenatal fluoride exposure ...... 176 C. Pre-eruptive compared to post-eruptive fluoride exposure 177 D. Fluoridation and dental caries in adults ...... 179 IV. Fluoride supplementation by vehicles other than communal water . 179 A. Fluoride pills and lozenges . 181 B. Fluoridation of kitchen salt 184 C. Fluoridation of milk . . . 185 V. Topical treatment with fluoride 186 VI. Fluoride dentifrices . . . . . 192 VII. Mechanism of action of fluoride in inhibiting caries. 193 A. Introduction ...... 193 B. The mineral phase of enamel and dentin. . . . 194 C. The chemistry of fluoride and tooth mineral as related to water fluoridation 195 D. Fluoride in enamel and dentin ...... 196 1. Distribution of fluoride in enamel ...... 197 2. Distribution of fluoride in crown dentin ...... 199 E. Changes in composition of bone and tooth mineral associated with fluoride deposition . . 201 1. Magnesium 201 2. Carbonate...... 202 3. Citrate ...... 202 VIII. The chemistry of topically applied fluoride 203 A. Fluoride uptake by tooth mineral . 204 1. Effect of concentration . . 204 2. Period of fluoride exposure 205 3. Effect of pH. . . . . 206 4. Cation effect ...... 207 5. Effect of temperature . . . 207 6. Electrophoresis . . . . . 208 7. Topical application mechanism of fluoride uptake 208 B. Loss of fluoride from tooth mineral 211 IX. Inhibition of bacterial acid production 212 X. Solubility . . . . . 214 XI. Remineralization . 218 XII. Concluding remarks 219 References ...... 220 Chapter 6: The Effects of Fluoride on Plants By M. D. THOMAS and E. W. ALTHER I. Industrial sources of fluorine 231 II. Field observations in Europe 233 III. Early fumigation studies . . 234 Contents XIII

IV. Determination of fluorine in vegetation. . 235 A. Willard and Winter method . . . . . 235 l. Sample preparation and combustion 235 2. Steam distillation and fluoride estimation 235 3. Statistical evaluation ...... 235 B. Modifications of Willard-Winter method . 236 C. Rapid semi-quantitative methods . . . . 237 l. Lipase method ...... 237 2. Silico-fluoride- Silica-molybdate methods 237 3. Oxygen combustion-diffusion method . 238 V. Determination of fluoride in the atmosphere. 239 A. Field methods . . . 239 B. Automatic methods . . . 239 C. Lime paper method . . . 240 VI. Fluorine in minerals and soils 240 VII. Fluorine in normal plants . . 241 A. Is fluorine an essential element ? 241 B. Effect of fluorine on water relations in plants. 243 C. Effect of fluorine on germination . . 244 VIII. Local studies of fluoride effects . . . . 246 A. Pot and field experiments in France . 246 B. Tennessee studies ...... 247 l. Lysimeter experiments . . . . 247 2. Phosphate-fluoride relationships 247 C. New Jersey studies ...... 249 l. Effect of fluoride concentration in nutrient solution. 250 2. Effect of a major nutrient upon uptake of fluoride . 252

D. Boyce Thompson studies with radioactive fluorine, F 18 • 254 E. Stanford Research Institute fumigation studies . 255 F. Fluorides in Florida...... 256 G. Fluorine studies in Western United States . 256 l. Citrus and grapes in Southern California 257 a) Fluoride from the nutrient solution . 257 b) Fluoride sprays on citrus ...... 258 c) Fumigation of seven citrus varieties . . 258 d) Fumigation of large bearing orange trees 259 e) Effects on wine grapes . . . . . 261 2. Gladiolus and pine in the Northwest . 262 a) Gladiolus...... 262 b) Ponderosa pine blight at Mead .. 264 c) Injury to gladiolus at Mead. . . . 264 3. Fumigation studies with higher plants 265 a) New techniques ...... 265 b) Uptake of fluoride and injury . . . 266 c) Surface absorption...... 267 d) Protection by lime sprays 267 e) Color sensitivity of gladiolus ...... 268 f) Time-concentration fumigation with hydrogen fluoride 268 g) Effects on polysaccharides ...... 269 h) Effects on growth ...... 270 i) Histological studies of fluoride injury 271 4. Soft suture of peaches ...... 274 a) Occurrence ...... 274 b) Experimental studies 274 c) Calcium metabolism in peach 276 XIV Contents

IX. Relative susceptibility of plant species to fluoride 276 X. Chemical and enzymatic effects of fluorides in plants . 279 A. Inorganic fluorine compounds 279 B. Organic fluorine compouuds . 280 C. Enzyme inhibition by fluoride 281 1. Enolase ...... 281 2. Cellular oxidation . . . . 282 3. Metabolism of fructose diphosphate and glycerol . 283 D. Fluoride effects on carotinoids and chlorophyll . . 284 E. Growth and respiration of plants and plant parts . 285 1. Growth ...... 285 2. Growth and respiration . . . . 287 3. Respiration ...... 288 4. Utilization of labelled glucose . 290 5. Ion absorption and respiration. 291 F. Carbon dioxide exchange of intact higher plants 292 1. Respiration . . 292 2. Photosynthesis. 294 References ...... 299 Chapter 6: The Effects of Fluorides on Livestock, with Particular Reference to Cattle By J. L. SHUPE and E. W. ALTHER I. Introduction ...... 307 A. Relevant past European history 307 B. Relevant past American history 309 II. Experimental work with species other than cattle 309 A. Sheep. 309 B. Swine .. 310 C. Horses . 311 D. Turkeys. 313 ill. The toxicity of fluorine compounds 313 IV. Response of cattle to ingested fluoride 315 A. General considerations. 315 B. Mineralizing matrix. 315 1. Teeth ...... 316 2. Bones .... . 320 a) Radiology . . 327 b) Histopathology 329 c) Joint appearance, lameness, stiffness . 335 d) Alkaline bone phosphatase 338 C. Urine analysis . . . 338 D. Other effects ..... 339 1. General condition . 339 2. Hair, coat and skin. 341 3. Hoofs ...... 341 4. Soft tissues . . . . . 341 5. Kidney and liver fuuction . 342 6. Reproduction . . 342 7. Blood ...... 343 8. Placental transfer . . . . 343 9. Milk production ...... 343 10. Feed digestion and metabolism 345 Contents XV

11. .... 346 E. Data correlation . . 346 F. Diagnosing fluorosis. 347 1. Clinical . 347 2. Acute ...... 347 3. Chronic .... . 348 a) Sequential development of chronic fluorosis . 348 b) Urine ...... 348 c) Teeth ...... 349 d) Bone ...... 349 e) Lameness and stiffness . 349 f) Other diagnostic aids 349 G. Methods of alleviating toxicity of fluorine 350 H. Conclusion . 350 References . . . . . 351

Chapter 7: Fluorine-Containing Insecticides By R. L. METCALF I. Introduction . . . 355 II. Elemental fluorine . 355 III. Inorganic fluorine insecticides . 355 A. Fluorides . . . . 355 B. Fluoroaluminates . 356 C. Fluorosilicates . . 357 1. Mode of action of fluorides, fluoroaluminates, and fluorosilicates 358 D. SuHuryl fluoride ...... 359 1. Mode of action of suHuryl fluoride 360 IV. Organic fluorine insecticides ...... 361 A. Fluoroalcohols and derivatives . . . 361 1. Fluoroethanol, its esters, and acetals . 361 2. Carbamates of fluoroethanol . . . . . 361 3. Mode of action of fluoroalcohols and derivatives 362 B. , fluoroacetamide, and derivatives 362 1. Insecticidal activity of fluoroacetic acid and derivatives . 363 2. Mode of action of fluoroacetic acid and derivatives 364 C. Phosphorofluoridates ...... 365 1. Mode of action of phosphorofluoridates 367 D. Fluorinated diphenylethanes . . . 370 1. DFDT or fluoro-DDT. . . . . 370 a) Insecticical action of DFDT 371 2. Analogues of DFDT . . . . . 372 3. Diphenyl trifluoroethanes . . . 373 4. o-Fluoro-DDT and resistance to DDT and DFDT 374 5. Fluorocarbinols as DDT synergists . . . 375 6. Fluorocarbinols as oviposition inhibitors 376 7. Fluorinated acaricides 377 a) Fluorocarbinols . . 377 b) Fluorobenside. . . 378 c) Fluorotedion . . . 378 E. Fluorinated cyclohexanes 378 F. Fluorinated cyclodienes . 379 XVI Contents

G. Fluorinated carbamates 379 H. Sulfonyl fluorides . . . 380 I. Fluorosulfonates . . . 381 J. Miscellaneous organofluorine compounds described as insecticides . 381 V. Summary 381 References ...... 382

Chapter 8: Monofluoro Aliphatic Compounds By F. L. M. PATTISON and R. A. PETERS I. Introduction . . . . 387 II. Occurrence in nature 388 III. Chemistry . . . . . 389 A. Introduction . . 389 B. Isolation of fluorine compounds from plants and animals 389 I. Fluoroacetic acid, FCH2COOH ...... 389 2. w-Fluoro-oleic acid, F(CH2) 8CH=CH(CH2),COOH(cis) 390 3. Fluorocitric acid, HOOCCHFC(OH)(COOH)CH2COOH 391 C. Preparative procedures ...... 393 I. Methods for forming the C-F bond . . . . 393 a) Halogen exchange ...... 393 b) From sulphonate esters ...... 394 c) Decomposition of 01:-fluorinated amines . 394 d) Epoxides plus hydrogen fluoride . . . 394 e) Diazoketones plus hydrogen fluoride. . 394 f) Reactions involving perchloryl fluoride. 394 g) Addition of BrF . . . . 395 h) Miscellaneous procedures . 395 2. Fluoroacetates...... 395 a) Fluoroacetyl choline. . . 396 b) Fluoroacetyl coenzyme A 396 c) Fluoroacetyl phosphate . 396 d) 2-Fluoroacetohydroxamic acid 396 3. w-Fluorocarboxylic acids . . . . 396 a) Saturated unbranched acids, F(OH2).COOH . 396 b) w-Fluoro-oleic acid, F(CH2) 8CH=CH(CH2) 7COOH. 397 c) Branched w-fluorocarboxylic acids. 397 d) Other branched acids ...... 398 4. Other fluoro acids and derivatives ...... 398 a) Fluoropyruvic acid, FCH2COCOOH . . . . 398 b) Fluoromalonic acid and esters, CHF(COOR) 2 398 c) Fluoromalic acid, ROOCCHFCH(CH)COOR 399 d) Fluoroacetoacetates ...... 399 e) Fluoro-oxalacetic acids and esters, ROOCCHFCOCOOR 399 f) Fluorocitric acid and esters, HOOCCHFC(OH)(COOH)CH2COOH 401 g) Triethyl 01:-fluoroaconitate, EtOOCCHFC(COOEt)= CHCOOEt 401 h) Fluoromevalonic acids ...... 402 i) Fluorinated amino-acids ...... 403 j) 2-Deoxy-2-fluoroglyceric acid, HOCH2CHFCOOH . 403 5. Other w-fluoro series ...... 403 D. Chemical properties ...... 405 I. Stability of compounds containing the C-F bond . 405 2. Chemical reactions ...... 408 a) Halide substitution reactions . 408 b) Organometallic reactions . 408 c) Anodic coupling reactions . . 408 d) Cyanoethylation ...... 408 e) Diels-Alder reactions . . . . 409 f) Lithium aluminum hydride reductions . 409 Contents XVII

g) Barbier-Wieland degradation . 409 h) Arndt-Eistert synthesis 409 i) Acetylenic syntheses. 409 IV. Physiology and biochemistry 409 A. The toxic signs ...... 409 B. The biochemistry . . . . . 4ll C. Some practical applications 415 D. Citrate accumulation in other animals . 415 E. Effects on the kidney in vivo . 416 F. The biochemical lesion . . . . 417 G. Reactions of 418 H. Other reactions of fluoroacetate 419 I. Protection and antidotes . . . 420 J. The biochemical behaviour of fluoro-oleic and other long chain w-fluoro fatty acids ...... 422 l. Fluoro-oleic acid ...... 422 2. Other long-chain w-fluoro fatty acids . 423 K. The actual activating substance 423 L. Fluoroacetate activation. . 424 M. Kidney and renal transport 425 N. Effects on the whole animal 426 l. Effect upon ketone and glucose metabolism 426 0. Effects upon isolated muscle tissue . . . . 428 l. Smooth muscle from the rabbit intestine 428 2. Muscles poisoned in vivo ...... 429

3. Cardiac muscle ...... 0 429 P. Studies on acids and other compounds related to the cycle 429 l. Fluoromalamide H 2NCOCHFCH(OH)CONH2 • 429 2. 2-Fluoroacetohydroxamic acid FCH2CONHOH 429 3. Fluoromalic acid HOOCCHFCH(OH)COOH 430 4. ,6-Fluoro-oxalacetic acid HOOCCHFCOCOOH . . 432 5. Fluoroacetoacetates (2,4-difluoroacetoacetate FCH2COCHFCOOR; 4-fluoro• acetoacetate FCH2COCH2COOR) 432 6. Fluoromalonate, HOOCCHFCOOH. 433 7. Microorganisms 433 a) Bacteria ...... 433 b) Yeast ...... 434 Q. Other compounds of interest . 436 l. Deoxyfluoroglycerols . . . 436 a) 1-Deoxy-1-fluoroglycerol, FCH2CH(OH)CH20H . 437 b) 2-Deoxy-2-fluoroglycerol, HOCH2CHFCH20H and 2-Deoxy-2-fluoro- glyceraldehyde, HOCH2CHFCHO 437 2. Fluorocarbohydrates . . . . . 437 3. Fluoroethanol, FCH2CH20H . 438 4. Fluoropyruvate, FCH2COCoo- 438 5. Synthetic w-fluoro compounds . 440 R. Fluoroacetate and convulsions . . 444 + l. Fluoroacetylcholine, Me3NCH2CH20COCH2F 446 V. Concluding remarks 447 References ...... 448 Chapter 9: The Mammalian Toxicology of Organic Compounds Containing Fluorine By J. w. CLAYTON JR. I. Introduction ...... 459 A. Definitions and objectives 459 XVIII Contents

B. Historical aspects 459 C. Uses of Fluorocarbons 460 II. Toxicology ...... 461 A. Fluoroalkanes - acute inhalation toxicity . 461 B. Fluoroalkanes- acute toxicity: oral, skin and eye . 470 C. Fluoroalkanes- chronic inhalation toxicity . 473 D. Fluoroalkanes - cyclic compounds . 473 E. Fluoroalkanes -biological action 477 F. Fluoroalkenes ...... 486 G. Fluoroalcohols ...... 491 H. Fluoro-aromatic compounds . 492 III. Discussion 493 References ...... 497

Chapter 10: The Fluorinated Anesthetics By J. C. KRANTZ JR. and F. G. Runo Experimental work with fluorinated anesthetics . 501 I. General introduction...... 501 II. Historical development of fluorinated hydrocarbons and ethers 501 A. Early studies of fluorinated hydrocarbons ...... 501 B. Further studies of fluorinated hydrocarbons and ethers . 504 1. Trifluoroethyl vinyl ether (Fluroxene, Fluoromar®) . 506 2. Halothane (Fluothane®) ...... 510 C. Recent studies of other fluorinated hydrocarbons and ethers 510 1. Methoxyflurane (Penthrane®) ...... 510 2. Halogenated propanes containing fluorine . . 510 3. Mixed halogenated ethers and a hydrocarbon 515 4. Cyclic fluorinated hydrocarbon . . . . 515 5. Teflurane . • . • ...... 516 6. Roflurane...... 517 7. Heavily halogenated fluorohydrocarbons 517 8. Fluoro-iodo hydrocarbon ...... 517 III. Summary tables of hydrocarbons and ethers containing fluorine . . 519 IV. Structure-activity relationships in fluorinated anesthetics . 528 A. Physicochemical properties and anesthetic activity . 528 1. Vapor pressure . . . . . 529 2. Molecular weight . . . . . 530 3. Boiling point ...... 531 4. Oil-water coefficient ...... 531 5. The blood-gas coefficient . . . . . 532 B. Halogenation and anesthetic potency . 533 1. Fluorine . 533 2. Chlorine ...... 536 3. Bromine ...... 537 4. Iodine ...... 538 C. Effects of saturated and unsaturated molecules . 538 D. Comparison of fluorinated hydrocarbons and ethers. 540 E. Summary of structure-activity observations . . . . 541 F. Mechanism of action of volatile anesthetics . . . . 541 The pharmacologic and clinical studies of the fluorinated anesthetics . 544 I. Trifluoroethyl vinyl ether (Fluroxene) . 544 A. Physical properties . . 544 B. Blood levels ...... 544 C. Pharmacologic studies ...... 545 Contents XIX

D. Clinical experience . 545 E. Fluroxene azoetrope 546 II. Halothane, fluothane . . 546 A. Physical properties . 546 B. Absorption, distribution and excretion 546 1. Mice and rats . . . 546 2. Tissue distribution ...... 547 3. Excretion...... 547 4. Placental transfer of halothane 548 C. Pharmacologic studies . . . . . 548 1. Effect on the liver ...... 548 2. Effect on heart and blood pressure . 551 3. Effect on cerebrospinal pressure . . 551 4. Effect on central nervous system . 551 D. Clinical experiences...... 552 E. Azeotrope (Halothane and ethyl ether) 552 III. Methoxyflurane, Penthrane ® . . 553 A. Physical properties . . . . 553 B. Distribution and excretion 553 1. Tissue levels . . . 553 2. Blood levels...... 554 C) Pharmacologic studies . . 554 1. Effect on electroencephalogram 554 2. Effect on respiration . . 554 3. Effect on blood pressure 554 4. Effect on blood elements 555 5. Effect on liver. . . . . 555 IV. Emulsions of fluorinated ethers . 555 A. Methoxyflurane . . . . . 555 B. Roflurane ...... 556 V. Comparative studies of fluorinated anesthetics 556 A. Halothane and fluroxene . . . 556 B. Halothane and chloroform ...... 557 C. Halothane and methoxyflurane . . . 558 D. Fluroxene and hexafluorodiethyl ether 558 VI. Conclusion . . 560 Acknowledgements 560 References . . 561

Author-Index 565 Subject-Index 595