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4. Other Data Relevant to an Evaluation of Carcinogenicity and Its Mechanisms

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4. Other Data Relevant to an Evaluation of Carcinogenicity and Its Mechanisms 4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms 4.1 Absorption, distribution, metabolism and excretion of radionuclides The most important routes of intake of radionuclides are by inhalation and ingestion, for both workers and members of the public. Ingestion is a less important route for workers, but a proportion of inhaled material is escalated from the trachea and lungs and swallowed. Entry through contaminated wounds may also occur in certain industrial situations. Entry through intact skin is rare, although exposure to 3 H2O vapour can lead to appreciable doses by this route. Entry of radionuclides into the body by inhalation and ingestion leads to irradiation of the respiratory and gastrointestinal tracts. Entry through contaminated wounds also results in local irradiation of tissues. After intake by any route, the subsequent behaviour of the radionuclide depends on the element concerned and its chemical form during exposure. These factors determine its solubility and the extent to which it is dissolved and absorbed into the blood. On reaching the blood, the distri- bution to and retention in body tissues depend on the chemical nature of the element. If a radionuclide that enters the bloodstream is an isotope of an element that is normally present (e.g. sodium, potassium, chlorine), it will behave like the stable element. If it has similar chemical properties to an element normally present, it will tend to follow the metabolic pathways of that element (e.g. 90Sr and 226Ra behave similarly to calcium and 137Cs and 86Rb similarly to potassium), although the rate of transfer between the various compartments in the body may be different. For other radionuclides, the behaviour in the body depends on their affinity for biological ligands and other transport systems. Radionuclides entering the bloodstream may be distributed throughout the body (e.g. 3H, 42K, 137Cs), be deposited selectively in a particular tissue (e.g. 131I in the thyroid, 90Sr in bone) or be deposited in significant quantities in a number of different tissues (e.g. 239Pu, 241Am, 144Ce). While dissolved radionuclides are distributed in the body directly via the blood, insoluble materials may be transported slowly as small particles through the lymphatic system, which can lead to accumulation of radionuclides in regional lymph nodes (e.g. tracheobronchial lymph nodes after transport from the lungs; axillary lymph nodes after transfer from a wound in the hand). Particles may reach the bloodstream slowly and then be removed rapidly from the circulation by phagocytic cells of the reticulo- endothelial system in the liver, spleen and bone marrow. The ICRP has reviewed the data on the biokinetics of radionuclides in humans and animals after intake by inhalation and ingestion and has developed biokinetics and –329– 330 IARC MONOGRAPHS VOLUME 78 dosimetric models for calculating organ and tissue doses (ICRP, 1979, 1980, 1981, 1986, 1989, 1993c, 1995a,b). The dose coefficients of ICRP for intake of radio- nuclides (dose per unit intake) have been incorporated into legislation in Europe (EURATOM, 1996) and other parts of the world. The following sections describe the biokinetics of individual radionuclides after intake by inhalation and ingestion, including their distribution after absorption into the blood, the duration of retention in organs and tissues and the routes of excretion. Information on placental transfer is also provided. For each radionuclide, the data on humans and animals are considered together. In a final section, the use of biokinetics and dosimetric models to estimate organ and tissue doses is described, and examples are given of doses from intakes of the radionuclides considered. 4.1.1 Hydrogen-3 (a) Inhalation 3 3 3 Tritium ( H) may be inhaled as elemental tritium gas ( H2), as H-labelled water 3 ( H2O), in the form of organic compounds or in particulate aerosols (reviewed by Hill 3 & Johnson, 1993). H2 is relatively insoluble, and < 0.1% of an inhaled dose was taken 3 up to the blood in one study in humans. H2O vapour is rapidly absorbed from the lungs to blood. Small amounts of volatile, highly soluble organic acids may be released as effluent from tritium facilities and, because of their chemical characteristics, it is reasonable to assume that absorption to the blood will be high. Studies of the absorption of 3H to blood after intratracheal installation of 1-μm (count median diameter) titanium tritide particles in rats indicated intermediate solubility (ICRP, 1995b). (b) Dermal intake 3 Exposure to an atmosphere contaminated by H2O results in absorption through intact skin as well as from the lungs. In an adult person at rest, about 1% of the radio- activity in 1 m3 of air was absorbed through the intact skin per minute. The ICRP (1995b) concluded that this route contributes about one-third to the total absorption of 3 H2O to blood. An increase in physical activity results in an increase in the proportion 3 of H2O absorbed through the lungs. (c) Ingestion 3 In volunteers, ingested H2O was rapidly and virtually completely absorbed from the gastrointestinal tract. A large proportion of organically bound 3H may be broken down 3 in the gastrointestinal tract, producing H2O. For example, studies in rodents indicated that 80–90% of ingested [3H]thymidine is catabolized before reaching the blood, and only a small proportion (< 5%) is incorporated into DNA in body tissues. The absorption of intact molecules of other forms of organically bound 3H, including 3H-labelled amino acids, and transfer to body tissues may be substantially greater. Although a proportion of OTHER RELEVANT DATA 331 ingested organically bound 3H may be unavailable for absorption, such as that in indi- gestible cellulose, it is generally assumed that absorption will be complete, either as 3 3 organically bound H or after catabolism to H2O (ICRP, 1979, 1989). (d) Systemic distribution, retention and excretion The radiobiology of tritium has been reviewed (Straume & Carsten, 1993). Studies 3 of the urinary excretion of H2O in humans after exposure by inhalation or ingestion 3 indicate rapid mixing of H2O with body water after absorption into the blood (see ICRP, 1979, 1989; Hill & Johnson, 1993). Since the body water is distributed fairly uniformly, it is generally assumed that all organs and tissues receive the same dose. 3 The half-time of retention of H2O corresponds to the loss of body water, with an average value of about 10 days for adult humans. In animals, however, a small 3 3 proportion of H absorbed as H2O is incorporated into organic molecules and retained for longer periods (ICRP, 1979, 1989). The half-times of retention attributable to organically bound 3H have not been characterized with precision in humans, but the range appears to be 20–80 days for the major component and 280–550 days for a smaller component (Etnier et al., 1984). It has been estimated that total incorporation 3 3 of H from H2O into organic molecules adds little (< 10%) to the total integrated activity and hence the dose (ICRP, 1979). Comparisons in animals of the relative incorporation of 3H into organic molecules 3 3 after intake of H2O and organically bound H indicated that 3–30 times more organi- cally bound 3H was present after intake of the radionuclide in this form (Rochalska & Szot, 1977; ICRP, 1989; Komatsu et al., 1990; Takeda, 1991). Takeda (1991) gave rats 3 3 H2O or H-labelled leucine, lysine, glucose, glucosamine, thymidine or uridine in the drinking-water for 22 days. At the end of this period, the highest concentrations of organically bound 3H were found in rats exposed to 3H-labelled amino acids (four to 3 nine times higher than those in rats exposed to H2O), with intermediate concen- trations after exposure to 3H-labelled DNA/RNA precursors. Rochalska and Szot 3 3 (1977) fed H-labelled food or H2O to rats for five days and determined organically bound 3H in the tissues on day 6. Incorporation, measured in dried tissues, was highest after intake of organically bound 3H by factors ranging from three for brain tissue to 15–17 for liver and small intestine. Takeda (1991) and Komatsu et al. (1990) con- 3 cluded that intake as organic molecules rather than H2O may increase the radiation dose by about a factor of 2. Although the distribution of organically bound 3H between 3 body organs and tissues has been shown to be less uniform than that of H2O in body water, greater uptake in certain organs is associated with greater metabolic activity in those organs (e.g. the liver and intestinal wall), and with shorter retention times. The doses from organically bound 3H are therefore generally calculated on the basis of 3 uniform distribution in the body, as for H2O (ICRP, 1979). Because of the low energy and short range of β-particle emissions from 3H (average energy, 5.7 keV; mean range, 0.7 μm), the doses to cell nuclei and DNA from 3H- labelled DNA precursors have been investigated. The National Council on Radiation 332 IARC MONOGRAPHS VOLUME 78 Protection and Measurements (1979) compared the calculated doses to human haemato- 3 3 poietic and spermatogonial stem-cell nuclei after ingestion of H2O and [ H]thymidine. After a single intake, [3H]thymidine was estimated to give the greater dose, by a factor of about 8. In studies with mice, administration of [3H]thymidine during gestation resulted in estimated doses to the offspring that were several times greater than those 3 from administration of H2O (Saito & Ishida, 1985). 3 3 Both the loss of H2O in body water and the turnover of organically bound H are 3 more rapid in children than in adults. The approach adopted by ICRP (1989) for the H2O component was to relate daily water balance to energy expenditure at different ages.
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