Do US county data disprove linear no-threshold predictions of lung cancer risk for residential radon? A preliminary assessment of biological plausibility

Lung-cancer mortality (LCM) is elevated in underground miners who chronically inhaled the mutagenic, cytotoxic alpha-decay products of radon gas. Epidemiologic studies of LCM rates vs. residential-radon concentration levels are generally considered inconclusive. However, Cohen (Health Physics 68, 157-174, 1995) has hypothesized that data on LCM vs. residential radon concentrations at the U.S. county level are clearly inconsistent with a linear no-threshold (LN) dose-response model, and rather are consistent with threshold or hormesis model. Cohen's hypothesis has been criticized as ''ecological fallacy,'' particularly because LN (but not threshold or hormesis) models are generally considered biologically plausible for agents like a radiation that damage DNA in linear proportion to dose. To assess the biological plausibility of Cohen's hypothesis, a preliminary study was made of whether a biologically realistic, cytodynamic 2-stage (CD2) cancer model can provide a good, joint fit to Cohen's set of U.S. county data as well as to underground-miner data. The CD2 model used adapts a widely applied, mechanistic, 2-stage stochastic model of carcinogenesis to realistically account for interrelated cell killing and mutation (both assumed to have a EN dose-response), cell turnover, and incomplete exposure of stem cells. A CD2 fit was obtained to combined summary data on ECM vs. radon-exposure in white males in 1,601 U.S. counties (from Cohen) and in white male Colorado Plateau (CP) uranium miners (from the National Research Council's ''BEIR IV'' report). The CD2 fit is shown to: (if be consistent with the combined data; (ii) have parameter values all consistent with biological data; and (iii) predict inverse dose-rate-effects data for CP and other radon-exposed miners, despite the fact that optimization had not involved any of these dose-rate data. The latter data were not predicted by a simplified CD2 model in which all stem cells were presumed to be exposed. It is concluded that this study provides preliminary evidence that Cohen's hypothesis is biologically plausible.