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Radon is a chemically inert radioactive gas of natural origin, produced by the disintegration of uranium and radium located in the earth’s crust. Radon exposure, at various levels, is omnipresent for the general public. Radon inhalation is the main source of exposure to radioactivity for most people throughout the world [National Research Council’s (NRC) Committee on the Biological Effects of Ionizing Radiation (BEIR) 1999; National Council for Radiation Protection and Measurements 1984a, 1984b; U.S. Environmental Protection Agency (EPA) 2003; United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2000]. Most inhaled radon is rapidly exhaled, but the inhaled decay products—readily deposited in the lung epithelium—irradiate sensitive cells in the airways and thereby enhance the risk of lung cancer. In 1988, the International Agency for Research on Cancer (IARC) declared radon to be carcinogenic for humans (lung cancer) and classified as a group 1 carcinogen (IARC 1988), based on the results of experimental animal and epidemiologic studies, in particular among uranium miners. In 1988, the available results came from studies of high exposure levels. Extrapolation of this risk to the general population, who are exposed to lower levels in residential settings, raised numerous questions. In recent years, the average annual exposure of uranium miners has fallen to levels similar to the concentrations inhaled in some homes, and discussion today focuses on the transposition of the risk from occupational to general populations. Miners are almost all adult males, exposed in conditions different from residential exposure: they perform substantial amounts of heavy labor in an atmosphere polluted by dust and fumes. Several case-control studies of residential radon have tested the validity of this risk transposition in the past decade (Auvinen et al. 1996; Kreienbrock et al. 2001; Letourneau et al. 1994; Schoenberg et al. 1990), but lack of statistical power prevented most of them from showing a significant risk. To deal with this problem, several joint analyses have been conducted in recent years. They report a significant lung cancer risk after domestic radon exposure (Darby et al. 2005; Krewski et al. 2005; Lubin 2003). Scientists have used all of these data to assess the lung cancer risk associated with indoor radon. The principal risk assessments come from the United States, the United Kingdom, and Canada (BEIR 1999; Darby et al. 2005; Krewski et al. 2005). These studies have two principal methodologic problems. The first is related to the choice of the exposure–response relation and its use in the context of general population exposure. Past risk assessment studies generally used exposure–response relations derived from miners’ cohorts as recommended by BEIR (1990, 1999). The second methodologic problem involves the role of the uncertainty analysis in the risk assessment process. Uncertainty analysis is an essential step that is too seldom performed. The aim of this study was to assess the lung cancer risk associated with indoor radon exposure in France on the basis of French measurements and the major epidemiologic results available. Specifically, we applied several different exposure–response relations obtained from miners’ cohorts and from joint analyses of residential case-control studies to estimate the number of lung cancer deaths in 1999 that may have been associated with residential radon exposure. The analysis considers the variability of indoor radon exposure in France and allows the quantification of uncertainties related to each of the exposure–response relations.

International audience; A broad variety of methods for measurement error (ME) correction have been developed, but these methods have rarely been applied possibly because their ability to correct ME is poorly understood. We carried out a simulation study to assess the performance of three error-correction methods two variants of regression calibration (the substitution method and the estimation calibration method) and the simulation extrapolation (SIMEX) method. Features of the simulated cohorts were borrowed from the French Uranium Miners' Cohort in which exposure to radon had been documented from 1946 to 1999. In the absence of ME correction, we observed a severe attenuation of the true effect of radon exposure, with a negative relative bias of the order of 60% on the excess relative risk of lung cancer death. In the main scenario considered, that is, when ME characteristics previously determined as most plausible from the French Uranium Miners' Cohort were used both to generate exposure data and to correct for ME at the analysis stage, all three error-correction methods showed a noticeable but partial reduction of the attenuation bias, with a slight advantage for the SIMEX method. However, the performance of the three correction methods highly depended on the accurate determination of the characteristics of ME. In particular, we encountered severe overestimation in some scenarios with the SIMEX method, and we observed lack of correction with the three methods in some other scenarios. For illustration, we also applied and compared the proposed methods on the real data set from the French Uranium Miners' Cohort study. © 2012 John Wiley and Sons, Ltd.

International audience; Inhalation of radon is closely associated with an increased risk of lung cancers. While the involvement of Ink4a in lung tumor development has been widely described, the tumor suppressor gene has not been studied in radon-induced lung tumors. In this study, loss of heterozygosity (LOH) analysis of the Cdkn2a locus, common to the Ink4a and Arf genes, was performed on 33 radon-induced rat lung tumors and showed a DNA loss in 50% of cases. The analysis of p16(Ink4a) protein expression by immunohistochemistry revealed that 50% of the tumors were negative for this protein. Looking for the origin of this lack of expression, we observed a low frequency of homozygous deletion (6%), a lack of mutation, an absence of correlation between promoter methylation and Ink4a mRNA expression and no correlation between LOH and protein expression. However, a tendency for an inverse correlation between p16(Ink4a) and pRb protein expression was observed. The expressions of p19Arf, Mmd2 and Mdm4 were not deregulated and only 14% of the tumors were mutated for Tp53. These results indicated that Ink4a/Cdk4/Rb1 pathway deregulation, more than Arf/Mdm2/Tp53 pathway, has a major role in the development of these tumors through p16(Ink4a) deregulation. However, all known mechanisms of inactivation of the pathway do not play a recurrent role in these tumors and the actual origin of the lack of p16(Ink4a) protein expression remains to be established.

This study was undertaken to evaluate the ecological association between terrestrial and cosmic gamma radiation, indoor radon, and acute leukemia incidence among children under 15 y of age. From 1990 to 2001, 5,330 cases of acute leukemia were registered by the French National Registry of Childhood Leukemia and Lymphoma. Exposure to terrestrial gamma radiation was based on measurements, using thermoluminescent dosimeters, at about 1,000 sites covering all the "Départements." In addition, 8,737 indoor terrestrial gamma dose rate measurements covering 62% of the "Départements" and 13,240 indoor radon concentration measurements covering all the "Départements" were made during a national campaign. Cosmic ray doses were estimated in each of the 36,363 "Communes" of France. There was no evidence of an ecological association between terrestrial gamma dose (range: 0.22-0.90 mSv y) or total gamma dose (range: 0.49-1.28 mSv y) and childhood acute leukemia incidence, for acute myeloid leukemia (AML) or for acute lymphoblastic leukemia (ALL), in univariate or multivariate regression analyses including indoor radon. A significant positive association between indoor radon (range: 22-262 Bq m) and AML incidence among children was observed and remained significant in multivariate regression analyses including either terrestrial gamma dose [SIR per 100 Bq m = 1.29 (1.09-1.53)] or total gamma dose [SIR per 100 Bq m = 1.29 (1.09-1.53)]. The study showed no ecological association between terrestrial gamma radiation and childhood leukemia for the range of variation in gamma dose rates observed in France. The moderate ecological association between childhood AML incidence and indoor radon does not appear to be confounded by terrestrial gamma dose.

The objective of this study was to evaluate the ecological association between indoor radon concentration and acute leukaemia incidence among children under 15 years of age in the 348 geographical units (zones d'emploi, ZE) of France between 1990 and 1998. During that period, 4015 cases were registered by the French National Registry of Childhood Leukaemia and Lymphoma. Exposure assessment was based on a campaign of 13 240 measurements covering the whole country. The arithmetic mean radon concentration was 85 Bq/m (range, 15-387 Bq/m) and the geometric mean, 59 Bq/m (range: 13-228 Bq/m). A positive ecological association, on the borderline of statistical significance (P=0.053), was observed between indoor radon concentration and childhood leukaemia incidence. The association was highly significant for acute myeloid leukaemia (AML) (P=0.004) but not for acute lymphocytic leukaemia (ALL) (P=0.49). The standardized incidence ratio (SIR) increased by 7, 3 and 24% for all acute leukaemia, ALL and AML, respectively, when radon concentration increased by 100 Bq/m. In conclusion, the present ecological study supports the hypothesis of a moderate association between indoor radon concentration and childhood acute myeloid leukaemia. It is consistent with most previous ecological studies. Since the association is moderate, this result does not appear inconsistent with the five published case-control studies, most of which found no significant association.