Lung cancer risk of low-level exposures to alpha emitters: critical reappraisal and experiments based on a new cytodynamic model

Ecologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM)-inconsistent with clearly positive associations revealed by occupational data on individual miners, but perhaps explained by competing effects of cell killing vs. mutations in alpha-exposed bronchial epithelium. To assess the latter possibility, a biologically based �cytodynamic 2-stage� (CD2) cancer-risk model was fit to combined 1950-54 age- specific person-year data on lung cancer mortality (LCM) in white females of age 40+ y in 2,821 U.S. counties (-90% never-smokers), and in 5 cohorts of underground miners who never smoked. New estimates of household annual average radon exposure in U.S. counties were used, which were found to have a significant negative ecologic association with 1950-54 LCM in U.S. white females, adjusted for age and all subsets of two among 21 socioeconomic, climatic and other factors considered. A good CD2 fit was obtained to the combined residential/miner data, using biologically plausible parameter values. Without further optimization, the fit also predicted independent inverse dose-rate effects shown (for the first time) to occur in nonsmoking miners. Using the same U.S. county-level LCM data, a separate study revealed a positive ecologic association between LCM and bituminous coal use in the U.S., in agreement with epidemiological data on LCM in women in China. The modeling results obtained are consistent with the CD2-based hypothesis that residential radon exposure has a nonlinear U-shaped relation to LCM risk, and that current linear no-threshold extrapolation models substantially overestimate such risk. A U-shaped dose-response corresponds to a CD2-model prediction that alpha radiation kills more premalignant cells than it generates at low exposure levels, but not at higher levels. To test this hypothesis, groups of Japanese medaka (ricefish minnows) were exposed for 10 to 14 weeks to different concentrations of aqueous radon; histological and quantitative-morphometry analysis of proliferative (premalignant) foci in livers from these fish are currently being completed