Estelle Rage

Risk of Lung Cancer Mortality in Relation to Lung Doses among French Uranium Miners: Follow-Up 1956–1999

The aim of this study was to assess the risk of lung cancer death associated with cumulative lung doses from exposure to α-particle emitters, including radon gas, radon short-lived progeny, and long-lived radionuclides, and to external γ rays among French uranium miners. The French “post-55” sub-cohort included 3,377 uranium miners hired from 1956, followed up through the end of 1999, and contributing to 89,405 person-years. Lung doses were calculated with the ICRP Human Respiratory Tract Model (Publication 66) for 3,271 exposed miners. The mean “absorbed lung dose” due to α-particle radiation was 78 mGy, and that due to the contribution from other types of radiation (γ and β-particle radiation) was 56 mGy. Radon short-lived progeny accounted for 97% of the α-particle absorbed dose. Out of the 627 deaths, the cause of death was identified for 97.4%, and 66 cases were due to lung cancer. A significant excess relative risk (ERR) of lung cancer death was associated with the total absorbed lung dose (ERR/Gy = 2.94, 95% CI 0.80, 7.53) and the α-particle absorbed dose (4.48, 95% CI 1.27, 10.89). Assuming a value of 20 for the relative biological effectiveness (RBE) of α particles for lung cancer induction, the ERR/Gy-Eq for the total weighted lung dose was 0.22 (95% CI: 0.06, 0.53).

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.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Mortality from Circulatory System Diseases among French Uranium Miners: A Nested Case-Control Study

A significant association has been observed between radon exposure and cerebrovascular disease (CeVD) mortality among French uranium miners, but risk factors for circulatory system diseases (CSD) have not been previously considered. We conducted new analyses in the recently updated (through 2007) French cohort of uranium miners (n = 5,086), which included 442 deaths from CSD, 167 of them from ischemic heart disease (IHD) and 105 from CeVD. A nested case-control study was then set up to collect and investigate the influence of these risk factors on the relationships between mortality from CSD and occupational external gamma ray and internal ionizing radiation exposure (radon and long-lived radionuclides) in this updated cohort. The nested case-control study included miners first employed after 1955, still employed in 1976 and followed up through 2007. Individual information about CSD risk factors was collected from medical files for the 76 deaths from CSD (including 26 from IHD and 16 from CeVD) and 237 miners who had not died of CSD by the end of follow-up. The exposure-risk relationships were assessed with a Cox proportional hazard model weighted by the inverse sampling probability. A significant increase in all CSD and CeVD mortality risks associated with radon exposure was observed in the total cohort [hazard ratios: HRCSD/100 working level months (WLM) = 1.11, 95% confidence interval (1.01; 1.22) and HRCeVD/100 WLM = 1.25 (1.09; 1.43), respectively]. A nonsignificant exposure-risk relationship was observed for every type of cumulative ionizing radiation exposure and every end point [e.g., HRCSD/100WLM = 1.43 (0.71; 2.87)]. The adjustment for each CSD risk factor did not substantially change the exposure-risk relationships. When the model was adjusted for overweight, hypertension, diabetes, hypercholesterolemia and smoking status, the HR/100WLM for CSD, for example, was equal to 1.21 (0.54; 2.75); and when it was adjusted for risk factors selected with the Akaike information criterion, it was equal to 1.44 (0.66; 3.14). To our knowledge, this is the first study to use a uranium miner cohort to consider the major standard CSD risk factors in assessing the relationships between ionizing radiation exposure and the risk of death from these diseases. These results suggest that the significant relationship between CeVD risk and radon exposure observed in the total French cohort is probably not affected by the CSD risk factors. Extending the collection of information about CSD risk factors to a larger subsample would be useful to confirm this result.

Accounting for Berkson and Classical Measurement Error in Radon Exposure Using a Bayesian Structural Approach in the Analysis of Lung Cancer Mortality in the French Cohort of Uranium Miners

Many occupational cohort studies on underground miners have demonstrated that radon exposure is associated with an increased risk of lung cancer mortality. However, despite the deleterious consequences of exposure measurement error on statistical inference, these analyses traditionally do not account for exposure uncertainty. This might be due to the challenging nature of measurement error resulting from imperfect surrogate measures of radon exposure. Indeed, we are typically faced with exposure uncertainty in a time-varying exposure variable where both the type and the magnitude of error may depend on period of exposure. To address the challenge of accounting for multiplicative and heteroscedastic measurement error that may be of Berkson or classical nature, depending on the year of exposure, we opted for a Bayesian structural approach, which is arguably the most flexible method to account for uncertainty in exposure assessment. We assessed the association between occupational radon exposure and lung cancer mortality in the French cohort of uranium miners and found the impact of uncorrelated multiplicative measurement error to be of marginal importance. However, our findings indicate that the retrospective nature of exposure assessment that occurred in the earliest years of mining of this cohort as well as many other cohorts of underground miners might lead to an attenuation of the exposure-risk relationship. More research is needed to address further uncertainties in the calculation of lung dose, since this step will likely introduce important sources of shared uncertainty.

Chest X-ray screening examinations among French uranium miners: exposure estimation and impact on radon-associated lung cancer risk.

Background Medical surveillance of uranium miners can include periodic chest X-ray examinations. This study aimed to assess the X-ray exposure due to occupational health monitoring in the French cohort of uranium miners, and to test whether consideration of this additional radiation exposure impacts the excess risk of lung cancer death associated with radon exposure. Method X-ray exposure due to occupational health monitoring was estimated retrospectively based on review of a sample of miners’ medical records and bibliographic data. Four exposure scenarios were designed, differing in their assumptions about the type of procedures performed, their frequency, and the lung dose delivered. Radon exposure and lung doses from exposure to α-particle emitters and external γ rays have previously been individually assessed. Exposure-risk and dose-risk relations were estimated by Poisson regression with a linear excess relative risk (ERR) model. Results The cohort included 5086 miners with a mean follow-up duration of 30.1 years. The mean number of chest X-ray examinations ranged from 15.1 in the lowest to 34 in the highest-exposure scenario, and produced a mean cumulative lung dose ranging from 4.6 to 34.2 mGy. The role of occupation-related imaging screening X-ray procedures in total equivalent lung dose appeared insignificant compared to α-emitter exposure. X-ray exposure was not associated with lung cancer mortality risk. The ERR associated with radon remained significantly positive when X-ray exposure was included in the multivariate analysis. Conclusions X-ray exposure did not confound the exposure-risk relation between radon and lung cancer.

Shared and unshared exposure measurement error in occupational cohort studies and their effects on statistical inference in proportional hazards models

Exposure measurement error represents one of the most important sources of uncertainty in epidemiology. When exposure uncertainty is not or only poorly accounted for, it can lead to biased risk estimates and a distortion of the shape of the exposure-response relationship. In occupational cohort studies, the time-dependent nature of exposure and changes in the method of exposure assessment may create complex error structures. When a method of group-level exposure assessment is used, individual worker practices and the imprecision of the instrument used to measure the average exposure for a group of workers may give rise to errors that are shared between workers, within workers or both. In contrast to unshared measurement error, the effects of shared errors remain largely unknown. Moreover, exposure uncertainty and magnitude of exposure are typically highest for the earliest years of exposure. We conduct a simulation study based on exposure data of the French cohort of uranium miners to compare the effects of shared and unshared exposure uncertainty on risk estimation and on the shape of the exposure-response curve in proportional hazards models. Our results indicate that uncertainty components shared within workers cause more bias in risk estimation and a more severe attenuation of the exposure-response relationship than unshared exposure uncertainty or exposure uncertainty shared between individuals. These findings underline the importance of careful characterisation and modeling of exposure uncertainty in observational studies.

0194 Circulatory system disease mortality among French uranium miners

Objectives There is currently no consensus for an association between risk of Circulatory System Diseases (CSD) and low exposure to ionising radiation. The aim is to study the relationship between CSD mortality and radon exposure in the French cohort of uranium miners considering classical CSD risk factors. Method The French cohort includes 5086 uranium miners followed from 1946 through 2007. Among the 1935 deaths, 442 were from CSD, including 167 cases of IHD and 105 cases of CVD. Annual radon exposures were assessed individually. A nested case-control study was performed to collect individual information concerning classical CSD risk factors (weight, height, smoking status, blood pressure, blood glucose and cholesterolemia) from medical files for 76 cases of death from CSD (including 26 from IHD and 16 from CVD) and 237 controls, matched for attained age and birth date and counter-matched for cumulative radon exposure. Results In the whole cohort, a significant association with cumulative radon exposure was observed for CVD mortality, but not for CSD or IHD mortality. In the case-control study, no significant unadjusted Odd-Ratio for cumulative radon exposure was observed for any endpoint. Analyses adjusted on CSD risk factors, for which missing data do not exceed 25%, are ongoing. Conclusions The issue of CSD associated to ionising radiation is crucial for radiation protection. The present study, allowing to consider individual data on major classical CSD risk factors, will contribute to improve knowledge on the effects of low dose exposure.

0138 Pooled uranium miners analysis: goals and challenges

Epidemiological studies of uranium miners helped to establish radon as a human carcinogen. However, radon remains a leading occupational cause of cancer mortality, and many workers are exposed to radon at levels at which excess risk of lung cancer has been observed in occupational cohort studies. Prior pooled studies of underground miners provided important quantitative estimates of radon-associated lung cancer risk. Recently, efforts have been undertaken to strengthen uranium miner studies to address contemporary occupational safety concerns. New cohorts of underground miners have been enumerated, existing cohorts have been expanded, and follow-up of the major cohorts of miners has been extended substantially. An international collaborative study has been undertaken to combine information from many of the world’s most informative cohort studies of uranium miners; the combined study cohort encompasses more than 1 00 000 miners. This talk will describe the major themes of this project, the goals of the collaborators and the challenges that we have encountered to-date. We will describe similarities and differences between findings from these key cohorts and identify some major gaps in current knowledge about radon’s effects on human health. Finally, we will discuss how international collaborative studies can strengthen our understanding of risks associated with occupational and environmental radon exposures.

Lung doses due to multiple radiation exposures and risk of lung cancer death among French uranium miners

Objectives The study aims to assess the risk of lung cancer death associated with lung doses due to radon gas and its short-lived progeny (RnP), long-lived radionucleides (LLR) and external γ rays in the French cohort of uranium miners. Methods The cohort included 3271 exposed miners followed from 1956 through 1999. Annual exposures were assessed individually and lung doses were calculated according to the Human Respiratory Tract Model (Publication 66 of the International Commission on Radiological Protection). Poisson regression was used to fit linear excess relative risk (ERR) models to estimate dose-risk relationships. Results The mean absorbed lung dose due to α emitters was 78 milliGray (mGy), and to non-α emitters, 56 mGy. RnP accounted for 97% of the α absorbed dose. A significant ERR of lung cancer death was associated with the total absorbed lung dose (ERR/Gy (95% CI) = 2.9 (0.8–7.5)), the α absorbed dose (4.58 (1.3–10.9)) and RnP (4.6 (1.3–11.2)). Assuming a value of 20 for the relative biological effectiveness of α particles in lung cancer induction, the ERR/Gy-equivalent for the total-weighted lung dose was 0.2 (0.1–0.5), similar to that for the α-weighted and RnP-weighted lung dose. Conclusions These first results about lung doses from the European Alpha-Risk project, with regard to the lung dose distribution, support the major role of RnP in the risk of lung cancer death.