Analysis of the association between ionizing radiation and mortality in uranium workers from five plants involved in the nuclear fuel production cycle in France.

PURPOSE: The aim is to investigate associations between mortality and exposure to ionizing radiation in a cohort of uranium workers with potential for internal and external radiation exposures. METHODS: Workers employed for at least 6 months between 1958 and 2006 in five plants involved in the French nuclear fuel cycle were included and followed up between 1968 and 2013. Cause-specific standardized mortality ratios were calculated. Analyses of associations between individual cumulative radiation dose (both internal and external, lagged by 5-15 years) and mortality were conducted using Poisson regression. RESULTS: The cohort includes 4541 workers. The mean cumulative external dose was 11.12 mGy. Mean cumulative internal doses ranged, depending on modelling hypotheses, from 0.05 to 0.09 mGy (liver) and from 4.22 to 10.90 mGy (lung). At the end of the follow-up, 838 workers were deceased and 28 lost to follow-up. A healthy worker effect was observed. The risk of prostate and lung cancers mortality was significantly higher for workers exposed to cumulative external dose above 50 mGy compared to non-exposed, but these associations were based only on three cases and became non-significant, although of similar magnitude, after adjustment for smoking. Associations with internal dose showed no consistent pattern. CONCLUSIONS: For the first time, a study was conducted in a French cohort of uranium workers with a complete reconstruction of internal dose. Results are preliminary and must be interpreted with caution because of the limited cohort size and significant sources of uncertainty. Future steps of this study will overcome these limitations.

The performance of functional methods for correcting non-Gaussian measurement error within Poisson regression: corrected excess risk of lung cancer mortality in relation to radon exposure among French uranium miners.

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.

Assessment of uncertainty associated with measuring exposure to radon and decay products in the French uranium miners cohort.

The reliability of exposure data directly affects the reliability of the risk estimates derived from epidemiological studies. Measurement uncertainty must be known and understood before it can be corrected. The literature on occupational exposure to radon ((222)Rn) and its decay products reveals only a few epidemiological studies in which uncertainty has been accounted for explicitly. This work examined the sources, nature, distribution and magnitude of uncertainty of the exposure of French uranium miners to radon ((222)Rn) and its decay products. We estimated the total size of uncertainty for this exposure with the root sum square (RSS) method, which may be an alternative when repeated measures are not available. As a result, we identified six main sources of uncertainty. The total size of the uncertainty decreased from about 47% in the period 1956-1974 to 10% after 1982, illustrating the improvement in the radiological monitoring system over time.

Impact of measurement error in radon exposure on the estimated excess relative risk of lung cancer death in a simulated study based on the French Uranium Miners' Cohort.

Measurement error (ME) can lead to bias in the analysis of epidemiologic studies. Here a simulation study is described that is based on data from the French Uranium Miners' Cohort and that was conducted to assess the effect of ME on the estimated excess relative risk (ERR) of lung cancer death associated with radon exposure. Starting from a scenario without any ME, data were generated containing successively Berkson or classical ME depending on time periods, to reflect changes in the measurement of exposure to radon ((222)Rn) and its decay products over time in this cohort. Results indicate that ME attenuated the level of association with radon exposure, with a negative bias percentage on the order of 60% on the ERR estimate. Sensitivity analyses showed the consequences of specific ME characteristics (type, size, structure, and distribution) on the ERR estimates. In the future, it appears important to correct for ME upon analyzing cohorts such as this one to decrease bias in estimates of the ERR of adverse events associated with exposure to ionizing radiation.

The influence of multiple types of occupational exposure to radon, gamma rays and long-lived radionuclides on mortality risk in the French "post-55" sub-cohort of uranium miners: 1956-1999.

The adverse health effects of radon on uranium miners, especially on their lungs, are well documented, but few studies have considered the effects of other radiation exposures. This study examined the mortality risks associated with exposure to radon, external γ rays and long-lived radionuclides (LLR) in the French "post-55" sub-cohort, which includes uranium miners first employed between 1956 and 1990 for whom all three types of exposure were assessed individually. Exposure-risk relationships were estimated with linear excess relative risk models and a 5-year lag time. The post-55 sub-cohort includes 3377 miners, contributing 89,405 person-years, followed up through the end of 1999 with a mean follow-up of 26.5 years. Mean cumulative exposure was 17.8 WLM for radon, 54.7 mSv for γ rays, and 1,632 Bq.m(-3).h for LLR. Among the 611 deaths observed, 66 were due to lung cancer. Annual individual exposures were significantly correlated. Increased mortality was observed for lung cancer (SMR = 1.30; 95% CI: 1.01, 1.65) and for brain and central nervous system (CNS) cancer (SMR = 2.00; 95% CI: 1.09, 3.35). Cumulative exposure to radon, γ rays and LLR was associated only with a significant risk of lung cancer. These new results could suggest an association between lung cancer and exposure to γ rays and LLR. They must nonetheless be interpreted with caution because of the correlation between the types of exposure. The calculation of organ doses received by each of these exposures would reduce the collinearity.

Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners.

A combined analysis of three case-control studies nested in three European uranium miner cohorts was performed to study the joint effects of radon exposure and smoking on lung cancer death risk. Occupational history and exposure data were available from the cohorts. Smoking information was reconstructed using self-administered questionnaires and occupational medical archives. Linear excess relative risk models adjusted for smoking were used to estimate the lung cancer risk associated with radon exposure. The study includes 1046 lung cancer cases and 2492 controls with detailed radon exposure data and smoking status. The ERR/WLM adjusted for smoking is equal to 0.008 (95% CI: 0.004-0.014). Time since exposure is shown to be a major modifier of the relationship between radon exposure and lung cancer risk. Fitting geometric mixture models yielded arguments in favor of a sub-multiplicative interaction between radon and smoking. This combined study is the largest case-control study to investigate the joint effects of radon and smoking on lung cancer risk among miners. The results confirm that the lung carcinogenic effect of radon persists even when smoking is adjusted for, with arguments in favor of a sub-multiplicative interaction between radon and smoking.

Mortality from circulatory system diseases and low-level radon exposure in the French cohort study of uranium miners, 1946-1999.

OBJECTIVES: The few studies examining the risk of circulatory system diseases (CSD) associated with ionizing radiation have reported inconsistent results. Radon, a known pulmonary carcinogen, emits ionizing radiation. The aim of this study was to examine CSD mortality in a French cohort of uranium miners and evaluate the plausibility of an association with radon exposure. METHODS: The cohort included men employed as uranium miners for >/=1 year between 1946-1990. We obtained vital status and cause of death from national registers and reconstructed radon exposure for each year. Exposure--risk relations were estimated with a linear excess relative risk (ERR) model using a 5-year lag time. RESULTS: The cohort comprised 5086 miners, followed up for a mean duration of 30.1 years. The average cumulative exposure of the radon-exposed miners was 36.6 working level months (WLM). A total of 1411 deaths were observed, including 319 deaths due to CSD. No excess risk was found for this overall cause of death. A significant positive trend was observed between deaths from cerebrovascular diseases (CeVD) and cumulative radon exposure, together with a significant ERR per 100 WLM [ERR per 100 WLM 0.49, 95% confidence interval (95% CI) 0.07-1.23)]. Hard physical activity was identified as a potential modifying factor of the exposure-risk relation. CONCLUSIONS: For the first time in a cohort of uranium miners, our results suggest an association between CeVD mortality and cumulative radon exposure. Due to a lack of data, which limited our ability to assess possible confounding by cardiovascular risk factors, these findings should be interpreted with caution.

Multifactorial study of the risk of lung cancer among French uranium miners: radon, smoking and silicosis.

This case-control study nested in the French cohort of uranium miners provides an opportunity to take account of silicosis and smoking in the assessment of the relation between radon and lung cancer. The study includes 100 miners who died of lung cancer and 500 matched controls born within the same period of birth and of the same age at the time of death of the matching case. Data on radon exposure are obtained from individual monitoring of the miners, and data on smoking come from medical records and interviews. To identify cases of silicosis among the 600 miners surveyed, appraisals carried out as part of the compensation process for occupational diseases are used. Statistical analyses are based on a conditional logistic regression, and the linear model for excess relative risk was used to model the risk of death due to lung cancer according to cumulative radon exposure. The percentage of missing data on silicotic status is less than 20%. The study reveals a significant association between the relative risk of lung cancer and silicosis (ORsilicosis = 3.6; 95% CI: 1.4-8.9), and the relation between radon and lung cancer persists after adjusting for smoking and silicotic status (ERRradon per WLM = 1.0%; 95% CI: 0.1-3.5%). Radon, cigarette smoking and silicotic status appear to be three factors that each have a specific effect on the risk of lung cancer. This study reminds us of the complexity involved in assessing occupational risks in the case of multiple sources of exposure.

Radon-associated lung cancer risk among French uranium miners: modifying factors of the exposure-risk relationship.

Radon is classified as a known pulmonary carcinogen in humans. A better understanding of the effects of low exposure and time-dependent factors, modifying the lung cancer risk is of continued interest. We present analyses of the exposure-risk relationship in the French cohort of uranium miners updated until 1999 and including five additional years of follow-up. These new analyses provide a better opportunity to look at low radon exposures with longer follow-up intervals, and allow consideration of new modifying factors, such as physical activity, mine location and job type. The cohort includes 5,086 miners, and 159 lung cancer deaths have been observed among these over a follow-up of more than 30 years. The exposure-risk relationship was estimated using excess relative risk models, which allow investigation of several modifying factors such as period of exposure, time since exposure, age at exposure, duration of exposure, exposure rate, job type, mine type and physical activity. The analysis confirms the association between radon exposure and lung cancer risk (ERR per 100 WLM = 0.58, P < 0.01). Period of exposure and physical activity appear as major modifying factors. Higher risks are observed for hard physical activity works. The effect of hard physical activity persists when the period of exposure is taken into account (ERR per 100 WLM = 2.95, P < 0.01).

Lung cancer risk associated to exposure to radon and smoking in a case-control study of French uranium miners.

A case-control study nested in the cohort of French uranium miners took smoking information into account in investigating the effect of radon exposure on lung cancer risk. This study included 100 miners who died of lung cancer and 500 controls matched for birth period and attained age. Data about radon exposure came from the cohort study, and smoking information was retrospectively determined from a questionnaire and occupational medical records. Smoking status (never vs. ever) was reconstructed for 62 cases and 320 controls. Statistical analyses used conditional logistic regression. The effect of radon exposure on lung cancer risk was assessed with a linear excess relative risk model, and smoking was considered as a multiplicative factor. Mean cumulative radon exposures were 114.75 and 70.84 Working Level Months (WLM) among exposed cases and controls, respectively. The crude excess risk of lung cancer per 100 WLM was 0.98 (95% CI: 0.18-3.08%). When adjusted for smoking, the excess risk was 0.85 per 100 WLM (95% CI: 0.12-2.79%), which is still statistically significant. The relative risk related to smoking was equal to 3.04 (95% CI: 1.20-7.70). This analysis shows a relative risk of lung cancer related to smoking similar to that estimated from previous miners' cohorts. After adjustment for smoking, the effect of radon exposure on lung cancer risk persists, and its estimated risk coefficient is close to that found in the French cohort without smoking information.