3
Exposure-Dose Relations

STATUS OF STUDIES

Extrapolation of the lung-cancer risks observed in underground miners to the risks for the general population, who are exposed to radon indoors, is subject to uncertainties related to the differences in physical environments between homes and mines, the circumstances and temporal patterns of exposure in the two environments, and the potential biologic differences between miners and the general population. For example, of the physical factors at issue, aerosols are present at greater concentrations in mines, and their size distributions differ between mines and homes. The unattached fraction of radon progeny—i.e., atoms of the radon progeny not attached to dust particles—is typically higher in homes. Ventilation is probably greater for working miners than for persons indoors in homes, although patterns of oral and nasal breathing have not been well characterized for those groups. As to important biologic factors, the miners have been exposed previously during adulthood but the entire population, including children, is exposed in homes; miners are exposed for variable periods during adulthood, but



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3 Exposure-Dose Relations STATUS OF STUDIES Extrapolation of the lung-cancer risks observed in underground miners to the risks for the general population, who are exposed to radon indoors, is subject to uncertainties related to the differences in physical environments between homes and mines, the circumstances and temporal patterns of exposure in the two environments, and the potential biologic differences between miners and the general population. For example, of the physical factors at issue, aerosols are present at greater concentrations in mines, and their size distributions differ between mines and homes. The unattached fraction of radon progeny—i.e., atoms of the radon progeny not attached to dust particles—is typically higher in homes. Ventilation is probably greater for working miners than for persons indoors in homes, although patterns of oral and nasal breathing have not been well characterized for those groups. As to important biologic factors, the miners have been exposed previously during adulthood but the entire population, including children, is exposed in homes; miners are exposed for variable periods during adulthood, but

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exposure in homes is lifelong for the population; and most of the miners studied have been smokers, but only a minority of U.S. adults in the general population are currently smokers. Those factors are potential determinants of the relationship between exposure to radon progeny (in working-level months) and equivalent dose of -energy (in sieverts) delivered to target cells in the respiratory tract. With models of the respiratory tract, the dose to target cells in the respiratory epithelium can be estimated for the circumstances of exposure of a miner in an underground mine and of a man, woman, or child in a home. Uncertainties arising from dosimetric differences between exposures in the two settings can be characterized by comparing the relationships between exposure and dose. Before the BEIR IV report (National Research Council, 1988) was issued, comparative analyses of dosimetry had been made for the mining and indoor environments. The BEIR IV report included a qualitative assessment of uncertainty associated with differences in lung dosimetry in the two environments. The report's analysis of dosimetry was based on the value of "K," the ratio of dose to exposure in homes divided by the ratio of dose to exposure in mines. Values above unity indicate greater dose and hence greater risk for those exposed in homes than for those exposed in mines; values less than unity indicate lesser risk in homes. The BEIR IV report considered the determinants of K in a qualitative fashion and found the value of K to be 1. The report did not include a detailed assessment of the evidence on the determinants of K, nor did the committee develop its own model. In followup to the BEIR IV report, EPA asked the National Research Council to study the dosimetry and related matters, considerations that affect the applications of lung-cancer risk estimates based on studies of miners to the general population. The resulting

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report of the Panel on Dosimetric Assumptions Affecting the Application of Radon Risk Estimates was published in 1991 (National Research Council, 1991). The report used a dosimetric model to estimate the relationship between exposure and dose of people working in mines and living in homes (see Figure 10). The committee determined that the value of K was 1 or less for exposures of infants, children, and adults in the general population (Table 1). The panel's literature review identified gaps and limitations in the evidence available through 1990 on the parameters of the lung-dosimetry model. Furthermore, although the panel followed the conventional approach of lung dosimetric modeling to estimate K, the predictions of the models could not be validated in biologic systems. The panel recommended more research on activity-weighted size distributions of radon progeny in various settings, including mines and buildings; on breathing by humans under diverse circumstances; on deposition patterns of submicrometer particles in the upper airways and lung; on hygroscopic growth of particles in the respiratory tract; on the physical behavior of progeny deposited in mucus; and on the cells at risk for transformation to lung cancer. Since the panel's report was published, new information has become available on several of those subjects. An automated instrument has been developed for field measurements of the concentration and activity-size distributions of radon progeny (Li and Hopke, 1991). This instrument has been used in the home environment to assess activity-weighted size distributions under typical conditions of home occupancy (Wasiolek, et al., 1992). Tu and colleagues (Tu et al., 1991) used other devices for the same objective. The data have shown that combustion sources affect the activity-weighted size distribution: particles from gas stoves and kerosene heaters measure less than 0.1 µm, and cigarette-smoking

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FIGURE 10. Factors influencing the relationship between radon exposures and the risk of lung cancer. (From National Research Council, 1991.)

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TABLE 1 Summary of K Factors for Bronchial Dose Calculated for Healthy People in the General Environment Relative to Health Underground Miners (From National Research Council, 1991)   Target-Cell K Factors Subjects Secretory Cells Basal Cells Infants, age 1 mo 0.74 0.64 Children, age 1 yr 1.00 0.87 Children, age 5-10 yr 0.83 0.72 Adult Females 0.72 0.62 Adult Males 0.76 0.69 tends to produce larger particles. Using the data from three homes, Wasiolek and colleagues (Wasiolek et al., 1992) found similar coefficients for the exposure-dose conversion that used the more refined data from the activity-weighted size distributions and the approach of truncating the distribution into “attached’ and “unattached” fractions used in the panel report. Little progress has been made in determining which respiratory epithelial cells give rise to lung cancer, in spite of additional experimental studies of greater sophistication. The proliferative potential of epithelial cell populations has been examined to gain insight into the target cells for malignant transformation. An assumption underlying interpretation of those experiments is that cells that show proliferative capacity are also the target cells for carcinogenesis-which is not necessarily the case. The radon panel had considered both basal and secretory cells to be at risk, largely on the basis of the work of McDowell and Trump (1983), which showed that secretory cells have proliferative potential. Using a rat tracheal system, Johnson and co-workers (Johnson and Hubbs, 1990; Johnson et al., 1990) confirmed the proliferative capacity of secretory cells. In one set of experiments,

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populations of basal and secretory cells from rat trachea were prepared with flow cytometry and inoculated into denuded tracheal grafts (Johnson and Hubbs, 1990), where the basal cell preparation produced an epithelium of basal and ciliated cells and the secretory cells yielded secretory cells as well as basal and ciliated cells. Similarly, using flow cytometry to obtain the two cell populations and growth in cell culture to assess proliferative potential, Johnson and colleagues (Johnson et al., 1990) found that secretory cells had substantially higher proliferative potential and greater metabolic capacity than basal cells. However, Ford and Terzaghi-Howe (1992), also working with cells from rat tracheal epithelium, found that basal cells, and not secretory cells, had proliferative potential. Like Johnson and coworkers, they used flow cytometry to sort cell populations, although they used different markers. Ford and Terzaghi-Howe examined the kinetics of cell death and proliferation in a suspension prepared from rat tracheal epithelium. Only cells with basal cell markers survived in the suspension and showed proliferative capacity in cell culture after cell sorting. The divergent findings of the two investigative groups, addressed at the workshop on dosimetry sponsored by the present committee, cannot be readily reconciled. Although both groups used rat tracheal epithelium, their experimental designs and their markers were distinct. Relatively sophisticated methods were used in these experiments, but the relevance of proliferative capacity in these systems to human lung cancer remains uncertain. Some additional information relevant to radon dosimetry has been reported. Noninvasive methods for monitoring ventilation in the field have been developed and applied to the general population (McCool and Paek, 1993; Samet et al., 1993) and to small numbers of underground miners (David James, personal communication). Li

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and Hopke (1993) assessed growth of particles from cigarettes, incense, a natural gas flame, a propane flame, and a candle flame. With humidification, particles from those sources showed growth of 10-120%. Substantial research is in progress on various aspects of lung dosimetry, and key uncertainties might be reduced over the next few years. The report of the radon panel, as well as previous analyses, indicated that differing exposure-dose relationships for exposures to radon progeny in mines and in homes are not associated with a high degree of uncertainty, given the inherent limitations of lung-dosimetry models. Current uncertainties related to the dosimetry of radon progeny in the lung would be best addressed by validation of the predictions of the models, by a more complete understanding of the cells at risk for oncogenesis, and by population-based data on the model parameters, including activity-size aerosol distributions and breathing and deposition patterns. However, only historical information is available on the activity-size distributions of aerosols in mines (Knutson and George, 1992). With the cessation of conventional underground uranium mining in the United States, it is no longer possible to make relevant activity-size distribution measurements in this country. Data could be gathered in Canada and other countries where underground uranium mining continues, but the relevance of such contemporary information to the historical cohorts would be uncertain. SUMMARY AND RECOMMENDATIONS The results of workshops conducted by the committee revealed that the proliferative capacity of basal or secretory cells is of uncertain relevance to human lung cancer, in light of conflicting

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evidence from experiments that used rat tracheal epithelium. Measurements of activity-weighted particle-size distributions relevant to the conditions experienced by historical cohorts of miners are unlikely to become available, because those conditions no longer occur. However, the committee recommends that a Phase II Research Council committee Use noninvasive methods for monitoring ventilation to obtain additional information that is relevant to radon dosimetry and an improved model. Continue to evaluate information on the cells at risk for radon-induced lung cancer. Use activity-weighted size-distribution data that have become available on residences. Use the recent data regarding growth of particles from various sources typically found in the home. Apply the reduced uncertainties in various aspects of lung dosimetry and use revised factors to reassess the uncertainties associated with the lung dosimetry in risk calculations.