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Comparative Dosimetry of Radon in Mines and Homes 4 Other Considerations BIOLOGICAL FACTORS Using the lung cancer risk due to radon progeny that is observed among miners to estimate this risk among members of the general population requires the consideration of two different kinds of variables: Physical and biological factors that affect the dose to the bronchial mucosa where lung cancers occur. A comparison of the effect of these factors on the bronchial dose in miners and in the general population is the primary subject of this report. The tumorigenic responsiveness of miners' lung tissues to given alpha particle doses from radon decay products as compared to tumorigenic responsiveness in the more heterogeneous general population. The second of these components is discussed in the BEIR IV report (NRC, 1988) and this chapter as it is a major source of uncertainty in extrapolating risks due to radon and its decay products. Factors that need to be considered here include age, gender, and concurrent exposure to domestic sources of radon and airborne pollutants such as cigarette smoke. This chapter is not meant to be comprehensive in scope or in its discussion of any of these issues. Rather, the intent is to provide a perspective on the potential importance and the extent of the evidence on some of these factors.
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Comparative Dosimetry of Radon in Mines and Homes GENDER Because the data on lung cancer in underground miners involves observations in males only (Samet, 1989), the question arises as to whether females are likely to exhibit a significantly different susceptibility to lung cancer induction by radon. The effect of gender on lung cancer risk has not been comprehensively studied, but there is no strong evidence that females have lung cancer susceptibilities different from those of males (NRC, 1988). In the United States, females have had lower lung cancer incidence and mortality than males, the lower rates reflecting differences in smoking by gender across the twentieth century (U.S. Department of Health and Human Services, 1989). Susceptibility to the induction of lung cancer by ionizing radiation in atom bomb survivors in Japan appears to be about the same for males and females in terms of absolute risk, although the relative risk is higher in females because they have a lower incidence of lung cancer (NRC, 1990; Kopecky et al., 1988). Comparable responsiveness to radon progeny in males and females was assumed in the BEIR IV (NRC, 1988) and ICRP 50 reports (International Commission on Radiation Protection [ICRP], 1987). AGE, GROWTH, AND INJURY IN RELATION TO CELL PROLIFERATION The issue of greater susceptibility to lung cancer induction by radon progeny in infants and children requires consideration; growing individuals have relatively high rates of cell proliferation and growth has been implicated as a factor in carcinogenesis. Cell proliferation can also be an expression of the regenerative repair of tissues that have sustained injury from chemical toxicants or wounding. Tissue damage can also promote tumorigenesis, as discussed below. Increased cell proliferation is a characteristic manifestation of the action of chemical and physical agents that are promoters of tumorigenicity (Slaga et al., 1974) and may play a role in the conversion of normal cells to neoplastic transformants and in the progression of such transformants to increasing degrees of malignancy. Heightened cell proliferation may also reflect a state of tissue injury that may facilitate the outgrowth of transformed cells into tumors, but the proliferation per se may not be the proximate cause of the enhanced clonal expansion of transformed cells. The importance of tissue factors on tumor formation has been shown in experiments that demonstrate the presence of a large number of transformed cells in the carcinogen-treated rat tracheal epithelium under conditions that produce few tumors (Terzaghi, 1979); also, neoplastic transformants have been shown to be nontumorigenic when used, together with normal cells, to repopulate the denuded tracheal epithelium (Terzaghi-Howe, 1987). It is possible that tissue damage may be relevant to the extrapolation of lung cancer responses to radon
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Comparative Dosimetry of Radon in Mines and Homes in miners and the general population since miners and cigarette smokers are exposed to agents which cause injury of the bronchial mucosa. Such damage is probably infrequent among nonsmokers in the general population. As discussed below, there is evidence at the cellular level that while cell proliferation has a marked effect on the neoplastic transformation caused by low-LET radiation, it is less important for high-LET radiation such as the alpha particles emitted by radon progeny in the lung. However, smoking appears to be an important risk factor even if proliferation is not (see below). AGE While there is little evidence of any age effect for tumorigenesis due to radon progeny, the relevant experimental and epidemiological data supporting the absence of an age effect are not extensive. Children under the age of 13 who worked in a Chinese tin mine, where they were exposed to radon and arsenic, did not show a higher incidence of lung cancer than those who began work as adults (Lubin et al., 1990), but the interpretation of this finding is limited by the number of subjects in the study. The BEIR IV committee (NRC, 1988) found there was no improvement in fit of the data when a term for age-at-exposure was added to their regression model for respiratory cancer among underground miners. By contrast, bone tumor induction in humans by radium-224 shows only a marginal increase in susceptibility at early ages (Mays et al., 1978). The induction of liver cancer in humans by alpha-emitting (high-LET) thorotrast does not show an age dependence (Kaick et al., 1989). The experimental studies of the lung tumor response of dogs exposed to the high-LET alpha radiation of plutonium (239PuO2) at an early age (3 months) was not significantly different from the response of older dogs (18 months), basing the comparison on the cumulative radiation dose (Guilmette, 1990). CELL PROLIFERATION There is in vitro evidence that cell proliferation affects the tumorigenic response to low-LET but not high-LET radiations. Cells that are held in a confluent state in tissue culture, with very little cell proliferation, rapidly repair tumorigenic damage caused by low-LET radiation (Borek and Sachs, 1968); in contrast, alpha-particle irradiation of confluent cells in culture shows no evidence of such repair (Robertson et al., 1983). Reversal of the tumorigenic effect of low-LET radiation, ranging from 0.1 to 10 keV/µm, in the rat skin with dose fractionation has a half-life of several hours and eventually reaches about 90% completion; the time pattern is about the same as that in tissue culture and may correspond to the repair of chromosomal breaks (Bums and Albert, 1986; Bums et al., 1979). In contrast, skin tumorigenesis in the rat shows no recovery with fractionated irradiations when high-LET radiation is used (Bums
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Comparative Dosimetry of Radon in Mines and Homes and Albert, 1987). Thus it can be inferred that, with low-LET radiation, for which rapid and almost complete repair of tumorigenic injury occurs, the rate of cell transformation depends on the proliferative rate since the cells that become neoplastically transformed are those that were close to or in the S period of the cell cycle at the time of irradiation. A similar dependence has been shown with chemical carcinogens in the liver (Kaufman and Cordiero-Stone, 1990). Cells of the bronchial mucosa, where most lung cancers arise, have one of the lowest proliferative rates in the adult body (Kaufman, 1980); thus a very small fraction of the cells are candidates for neoplastic transformation by low-LET radiation, unless the proliferation rate is increased by growth. On the other hand, damage due to high-LET alpha radiation, such as that from radon, is less repairable so that the effect of cell proliferation would be less. These arguments suggest that there may be little or no age dependence on the susceptibility of the lung to tumor induction by radon. DOSE RATE, FRACTIONATION, AND DURATION OF EXPOSURE Fractionation of low-LET radiation exposure reduces the carcinogenic action because time is available for repair. This reduction of carcinogenic action with fractionation of the radiation does not occur with high-LET radiation, as that from radon progeny, because repair does not appear to take place. The Armitage-Doll multistage model (Doll, 1971), currently used for carcinogen risk assessment, assumes the same mechanism of action of specific carcinogens as for the determinants of background cancer. Thus, as the dose rate diminishes, the time of carcinogen-induced tumor formation is assumed to gradually approach that of background tumor formation with a resultant linear, nonthreshold relationship between dose rate and tumor incidence (Crump and Howe, 1984). However, this assumption is not based on strong evidence, and the temporal and tumor incidence patterns have not been characterized at very low dose rates. The BEIR IV committee's examination of the miners experience indicates that the tumorigenic effect of radon exposure fades with time after the exposure is discontinued (NRC, 1988). Nevertheless, uncertainty remains concerning the effects of dose rate and duration of exposure at very low levels of exposure. TISSUE DAMAGE Tissue wounding by mechanical injury is clearly a strong promoting agent for tumorigenesis by carcinogens of many types. In the case of lung cancer induction in rodents by the intratracheal instillation of benzo[a]pyrene, cancers do not arise in the trachea unless it is traumatized by the endotracheal injection needle, which causes wounding with increased cell proliferation (Keenan et al., 1989). The induction of bronchial tumors in the hamster lung by instillation
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Comparative Dosimetry of Radon in Mines and Homes of radioactive polonium is markedly enhanced by subsequent intratracheal injections of saline, which also cause waves of cell proliferation (Little et al., 1978). Urethane administered to adult mice does not induce liver tumors unless there is a stimulation of cell replication in this proliferatively static organ by partial hepatectomy (Chernozemski and Warwick, 1970). Wounding of the mouse skin after initiation by a small dose of chemical carcinogen is an effective cancer-promoting factor (Argyris, 1980). Tissue damage induced by chemicals can also be a tumor promoter. After exposure to neutrons, the mouse liver responds to the proliferative stimulus of a damaging dose of carbon tetrachloride with enhanced tumor induction (Cole and Nowell, 1964). Tumor induction in the nasal mucosa of the rat by the inhalation of formaldehyde does not occur at doses that do not increase the normally very low level of cell proliferation in that tissue (Monticello and Morgan, 1990). Lung tumor induction by plutonium-238 appears to be much enhanced in regions of the lung where the radioactive particles cluster and produce local tissue damage (Sanders et al., 1988). Tissue wounding or damage with its associated regeneration appears to be an exaggerated form of tissue growth, because like growth, regenerative proliferation is associated with retention of the multiplying cells, and thus, clonal expansion of neoplastically transformed cells is favored. Tissue damage also frequently has an inflammatory reaction that may constitute an enhancing factor for tumorigenesis. Inhalation exposure of dusts, usually considered inert such as titanium and activated charcoal, produce hyperplasia or irritation and have been implicated in lung cancer (Heinrich, 1990; Lee et al., 1986). CIGARETTE SMOKING Cigarette smoking, the cause of most cases of lung cancer in the general population, has been shown to interact with exposure to radon progeny in a synergistic fashion. The BEIR IV report (NRC, 1988) reviewed potential mechanisms underlying this interaction as well as the relevant epidemiological evidence from studies of miners. Cigarette smoking has numerous effects on the lung that could contribute to the synergism between smoking and radon progeny. Chronic inhalation of cigarette smoke, even without other irritants, causes tissue damage in the respiratory mucosa, changing the relatively nonproliferative secretory and ciliary pattern to squamous metaplasia, with an increased rate of cell proliferation (Wehner, 1983). Patches of squamous metaplasia may not have a moving protective sheath of mucus to clear deposited radon progeny. Cells in such areas might not only be proliferating faster than the epithelial cells in the normal mucosa, but the nuclei might also be closer to the deposited progeny; an increased dose of alpha-particle energy could result. Increased central deposition of inhaled particles in smokers might also increase doses to the central airways where lung cancers arise.
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Comparative Dosimetry of Radon in Mines and Homes In extrapolating data from the studies of miners to the general population, consideration must be given separately to the risks of lung cancer for smokers and for never smokers. The risk estimates from the studies of miners largely reflect the occurrence of lung cancer in smokers; thus, in extrapolating risks from miners to the general population, an assumption needs to be made concerning the modification of the effect of radon by smoking. The BEIR IV committee assumed a multiplicative interaction between these two factors in producing lung cancer. The committee based this decision on the weight of the evidence from the literature and on its own analysis of data from two studies of uranium miners. Data from the study of atomic bomb survivors in Japan may not be relevant to the interaction between radon and smoking. REFERENCES Argyris, T. S. 1980. Tumor promotion by abrasion induced epidermal hyperplasia in the skin of mice. J. Invest. Dermatol 75:360-362. Borek, C., and L. Sachs. 1968. The number of cell generations required to fix the transformed state in X-ray induced transformation. Proc. Natl. Acad. Sci. 53:83-86. Bums, F. J., and R. E. Albert. 1986. Pp. 199-214 in Rodent Carcinogenesis in Rat Skin in Radiation Carcinogenesis, A. E. Upton, R. E. Albert, F. J. Bums, and R.E. Shore, eds. New York: Elsevier. Burns, F. J., and R. E. Albert. 1987. Dose-response for radiation-induced cancer in rat skin. Pp. 51-70 in Radiation Carcinogenesis and DNA Alterations, F. J. Bums, A. C. Upton, and G. Silini, eds. NATO ASI Series, Series A: Life Sciences, Vol. 124. Burns, F. J., R. E. Albert, M. Vanderlaan, and P. Strickland. 1979. The dose response curve for tumor induction with single and split doses of 10 Mev protons. Radiat. Res. 62:598-599. Chernozemski, I. M, and G. P. Warwick. 1970. Liver regeneration and induction of hepatomas in B6AF1 mice by urethane. Cancer Res. 30:2685-2690. Cole, L. J., and P. C. Nowell. 1964. Accelerated induction of hepatomas in fast neutron-irradiated mice injected with carbon tetrachloride. Ann. N.Y. Acad. Sci. 114:259-267. Cramp, K., and R. B. Howe. 1984. The multistage model with a time dependent dose pattern: Applications to carcinogen risk assessment. Risk Anal. 4:163-176. Doll, R. 1971. The age distribution of cancer: Implications for models of carcinogenesis. J. R. Stat. Soc. 134:133-155. Guilmette, R. 1990. Personal communication, Lovelace Inhalation Toxicology Research Institute. Heinrich, U. 1990. Tumorigenic effects of carbon black in the lung. Presented at an U.S. EPA Workshop on Diesel Emissions, Chapel Hill, N.C., July 18-19. International Commission on Radiation Protection (ICRP). 1987. Lung Cancer Risk from Indoor Exposures to Radon Daughters. ICRP Publ. No. 50. Oxford: Pergamon Press. Kaick, G. van, H. Wesch, H. Luhrs, D. Liebermann, A. Kaul, and H. Muth. 1989. The German Thorotrast Study—report on 20 years follow-up. Pp. 98-104 in Brit. Inst. Radiol. Report 21.
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Comparative Dosimetry of Radon in Mines and Homes Kaufman, D. G., and M. Cordiero-Stone. 1990. Variations in suceptibility to initiation of carcinogenesis during the cell cycle . Pp. 1-27 in Transformation of Human Diploid Fibroblasts: Molecular and Genetic Mechanisms, G. E. Milo, ed. Boca Raton, Fla.: CRC Press. Kauffman, S. L. 1980. Cell proliferation in the mammalian lung. Int. Rev. Exp. Pathol. 22:131-191. Keenan, K. P., U. Saffiotti, S. F. Stinson, C. W. Riggs, and E. M. McDowell. 1989. Multifactorial hamster respiratory carcinogenesis with interdependent effects of cannula-induced mucosal wounding, saline, ferric oxide, benzo(a)pyrene and N-methyl-N-nitrosourea. Cancer Res. 49:1528-1540. Kopecky, K. J., E. Nakashima, T. Yamamoto, and H. Kato. 1988. Pp. 1-31 in Lung Cancer, Radiation, and Smoking Among A-Bomb Survivors, Hiroshima and Nagasaki. Radiation Effects Research Foundation. Lee, K. P., N. W. Henry, H. J. Trochimowitz, and C. F. Reinhardt. 1986. Pulmonary response to impaired lung clearance in rats following excessive TiO2 dust deposition. Environ. Res. 41:144-167. Little, J. B., R. B. McGandy, and A. R. Kennedy. 1978. Interactions between polonium-210 alpha radiation, benzo(a)pyrene, and 0.9% NaCl solution instillations in the induction of experimental lung cancer. Cancer Res. 38:1929-1935. Lubin, J. H., Y. Qiao, P. R. Taylor, S-X Yao, A. Schatzkin, B.-L. Mao, J.-Y. Rao, X.-Z. Xuan, and J.-Y. Li. 1990. Quantitative evaluation of the radon and lung cancer association in a case control study of Chinese tin miners. Cancer Res. 50:174-180. Mays, C. W., H. Spiess, and A. Gerspach. 1978. Skeletal effects following Ra224 injections into humans. Health Phys. 35:83-90. Monticello, T. M., and K. T. Morgan. 1990. Correlation of cell proliferation and inflammation with nasal tumors in F344 rats following chronic formaldehyde exposure. P. 138 in American Association of Cancer Research Proceedings No. 826. National Research Council (NRC). 1988. Health Risks of Radon and Other Internally Deposited Alpha-Emitters. BEIR IV. Washington, D.C.: National Academy Press. National Research Council (NRC). 1990. Health Effects of Exposure to Low Levels of Ionizing Radiation. BEIR V. Washington, D.C.: National Academy Press. Peraino, C., E. F. Staffeldt, and V. A. Ludeman. 1981. Early appearance of histochemically altered hepatocyte foci and liver tumors in female rats treated with carcinogens one day after birth. Carcinogenesis 2:463-475. Robertson, B., A. Koehler, J. George, and J. B. Little. 1983. Oveogenic transformation of mouse Balb 3T3 cells by plutonium-238 alpha particles. Radiat. Res. 96:261-274. Samet, J. S. 1989. Radon and lung cancer. J. Natl. Cancer Inst. 81:745-757. Sanders, C. L., K. E. McDonald, and K. E. Lauhala. 1988. Promotion of pulmonary carcinogenesis by plutonium article aggregation following inhalation of 239PuO2. Radiat. Res. 116:393-405. Slaga, T. J., J. D. Scribner, S. Thompson, and A. Viaje. 1974. Epidermal cell proliferation and promoting ability of phorbol esters. J. Natl. Cancer Inst. 52:1611. Terzaghi, M. 1979. Dynamics of neoplastic development in carcinogen exposed tracheal mucosa. Cancer Res. 39:4003-4010. Terzaghi-Howe, M. 1987. Inhibition of carcinogen altered rat tracheal epithelial cell proliferation by normal epithelial cells in-vivo . Carcinogenesis 8:145-150.
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Comparative Dosimetry of Radon in Mines and Homes U.S. Department of Health and Human Services. 1989. Reducing the Health Consequences of Smoking, 25 Years of Progress. A Report of the Surgeon General. Rockville, Md.: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Wehner, A. P. 1983. Cigarette smoke-induced alterations in the respiratory tract of man and experimental animals. Pp. 1-42 in Comparative Respiratory Tract Carcinogenesis. Vol. II: Experimental Respiratory Tract Carcinogenesis, H. Reznik-Schuller, ed. Boca Raton, Fla.: CRC Press.
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