Biologically Based Prediction of Empirical Nonlinearity in Lung Cancer Risk vs. Residential/ Occupational Radon Exposure

Abstract

ABBREVIATIONS: BEIR = U.S. National Research Council Committee on the Biological Effects of Ionizing Radiations; CD2 = cytodynamic 2-stage; CL = confidence limit; LCM = lung cancer mortality; PY = personyear; RR = relative risk; SE = standard error; WF = U.S. white female; WLM = Working Level Month. ABSTRACTEcologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM) that are inconsistent with clearly positive ones revealed by individual data on underground miners. If this inconsistency is due to competing effects of induced cell killing vs. mutations in alpharadiation exposed bronchial epithelium, then linear extrapolation from miner data may overestimate typical residential radon risks. To investigate the plausibility of this hypothesis, a biologically based "cytodynamic 2-stage" (CD2) cancer-risk model was fit to combined 1950 to 1954 age-specific person-year data on white females of age 40+ y in 2821 U.S. counties (~90% never-smokers), and on five cohorts of underground miners who never smoked, conditional on a realistic rate of alpha-radiationinduced killing of human lung cells, and on linear-no-threshold dose-response relations for both processes assumed to affect cancer risk (alpha-induced mutations and cell killing). As summarized previously (Bogen, K.T., Hum. Exper. Toxicol. 17:691-6, 1998), a good CD2 fit was obtained that involved biologically plausible parameter values and (without further optimization) also predicted inverse doserate effects observed in the nonsmoking miners. The present paper reports mathematical details of the CD2 model used, as well as additional modeling results involving the same combined data set. The results obtained are consistent with the hypotheses that low-level radon exposure is nonlinearly related to LCM risk, and that current linear no-threshold extrapolation models overestimate LCM risk assoBogen ciated with relatively low residential radon concentrations (< ~200 Bq m -3 ). Testing this hypothesis would require more extensive individual-level epidemiological data relating residential radon exposures to LCM than are currently available.

Lung Cancer Risk from Radon in Marcellus Shale Gas in Northeast U.S. Homes

“…However, there is evidence for threshold or other nonlinear response models at low doses. (22)(23)(24)(25)(26)(27) The U.S. Environmental Protection Agency (EPA) recommends mitigation if radon levels are higher than 148 Bq/m 3 (4 pCi/L) in indoor air, which it associates with a 7 in 1,000 (7×10 −3 ) lifetime lung cancer risk. (28) In the last 10 years there have been numerous studies of residential exposure to radon and lung cancer risk.…”

“…This implies that there is no safe level of exposure to radon. However, there is evidence for threshold or other nonlinear response models at low doses . The U.S. Environmental Protection Agency (EPA) recommends mitigation if radon levels are higher than 148 Bq/m 3 (4 pCi/L) in indoor air, which it associates with a 7 in 1,000 (7×10 −3 ) lifetime lung cancer risk…”

An Examination of Radiation Hormesis Mechanisms Using a Multistage Carcinogenesis Model

“…Scott et al (2003Scott et al ( , 2004 use the concept of a radiation-induced bystander effect for apoptosis that protects the cell community from problematic mutations, neoplastic transformation and cancer. The concept of cell killing has also been used by Radivoyevitch et al (2002) and Bogen (1997Bogen ( , 1998Bogen ( , 2001 to develope hormesis models. Barcellos-Hoff and Brooks (2001) propose that very low doses of IR could stimulate the extracellular signaling that eliminates abnormal cells.…”

“…Some studies have also been performed to explain hormetic effects with mechanism-based cancer models (Bogen, 1997(Bogen, , 1998(Bogen, , 2001Andersen and Conolly, 1998;Downs and Frankowski, 1998;Schöllnberger et al, 2001a;Radivoyevitch et al, 2002).…”

Hormesis Without Cell Killing

“…Even for very simple specifications of the dose‐response relations for rate parameters, such as the linear no‐threshold model: this system can exhibit interesting nonlinear behaviors, including hormesis (similar to Bogen, 2001). For example, Fig.…”