Cohort profile: ORICAMs, a French cohort of medical workers exposed to low-dose ionizing radiation.

Medical personnel represent the largest group of workers occupationally exposed to ionizing radiation. Although the health risks associated with occupational exposure to low doses of ionizing radiation in the medical field have been investigated in several national cohorts, no study has been conducted in France to date. The ORICAMs (Occupational Radiation Induced Cancer in Medical staff) cohort is a nationwide French longitudinal cohort of medical workers exposed to ionizing radiation aiming to investigate the risk of radiation-associated cancer and non-cancer mortality. The ORICAMs cohort was set up in 2011 and includes all medical personnel monitored for ionizing radiation exposure with at least one dosimetric record in the SISERI database (the national registry for monitoring ionizing radiation exposure in workers) over the period 2002-2012. Causes of death were abstracted from death certificates and coded according to ICD-10. The follow-up ended on 31/12/2013. Standardized mortality ratios (SMRs) were calculated by cause of death to compare the mortality in the cohort to that in the French population, by gender, age group and calendar period. Among the 164,015 workers included in the cohort (60% women) a total of 1,358 deaths (892 in male and 466 in female) were reported. The observed number of all-cause deaths was significantly lower than expected based on national rates in both male (SMR = 0.35; 95% CI: 0.33, 0.38; ndeaths = 892) and female (SMR = 0.41; 95% CI: 0.38, 0.45; ndeaths = 466). This analysis leads to the conclusion that mortality in French workers exposed to medical radiation is significantly lower than the national reference rates. However, these results based on a comparative analysis with national rates may be impacted by the healthy worker effect towards low SMRs, and do not enable to establish a potential relationship between occupational exposure and mortality risk, even if we may suspect an impact of high SES of these professionals on the observed decreased mortality. Thus, further dose-response analyses based on individual ionizing radiation exposure and job's type will be conducted to characterize correlation between risk of cancer mortality and occupational exposure.

Childhood cancer risks estimates following CT scans: an update of the French CT cohort study.

OBJECTIVES: Increased risks of central nervous system (CNS) tumors and leukemia associated with computed tomography (CT) exposure during childhood have been reported in recent epidemiological studies. However, no evidence of increased risks was suggested in a previous analysis of the French CT cohort. This study benefits from an updated cohort with a longer follow-up and a larger sample size of patients. METHODS: The patients were followed from the date of their first CT (between 2000 and 2011) until their date of cohort exit defined as the earliest among the following: 31 December 2016, date of death, date of first cancer diagnosis or date of their 18th birthday. Cancer incidence, vital status, cancer predisposing factors (PFs), and additional CT scans were collected via external national databases. Hazard ratios (HRs) associated to cumulative organ doses and sex were estimated from Cox models. RESULTS: At the end of follow-up, mean cumulative doses were 27.7 and 10.3 mGy for the brain and the red bone marrow (RBM), respectively. In patients without PFs, an HR per 10 mGy of 1.05 (95% CI: 1.01-1.09) for CNS tumors, 1.17 (95% CI: 1.09-1.26) for leukemia, and 0.96 (95% CI: 0.63-1.45) for lymphoma was estimated. These estimates were not modified by the inclusion of CT scans performed outside the participating hospitals or after the inclusion period. CONCLUSIONS: This study shows statistically significant dose-response relationships for CNS tumors and leukemia for patients without PFs. KEY POINTS: • Computed tomography is the most important contributor to the collective dose for diagnostic imaging to the French population. • Concerns have been raised about possible cancer risks, particularly after exposure to CT in childhood, due to the greater radiation sensitivity of children and to their longer life expectancy. • Analysis of the updated French CT cohort shows statistically significant dose-response relationships for CNS tumors and leukemia.

Updated Mortality Analysis of SELTINE, the French Cohort of Nuclear Workers, 1968-2014.

Cohorts of nuclear workers are particularly relevant to study the health effects of protracted exposures to low doses at low dose-rates of ionizing radiation (IR). In France, a cohort of nuclear workers badge-monitored for external IR exposure has been followed-up for several decades. Its size and follow-up period have recently been extended. The present paper focuses on mortality from both cancer and non-cancer diseases in this cohort. The SELTINE cohort of nuclear workers employed by CEA, Orano, and EDF companies was followed-up for mortality from 1968 to 2014. Mortality in the cohort was compared to that in the French general population. Poisson regression methods were used to estimate excess relative rates of mortality per unit of cumulative dose of IR, adjusted for calendar year, age, company, duration of employment, and socioeconomic status. The cohort included 80,348 workers. At the end of the follow-up, the mean attained age was 63 years, and 15,695 deaths were observed. A strong healthy worker effect was observed overall. A significant excess of pleural cancer mortality was observed but not associated with IR dose. Death from solid cancers was positively but non-significantly associated with radiation. Death from leukaemia (excluding chronic lymphocytic leukaemia), dementia, and Alzheimer's disease were positively and significantly associated with IR dose. Estimated dose-risk relationships were consistent with those from other nuclear worker studies for all solid cancers and leukaemia but remained associated with large uncertainty. The association between IR dose and dementia mortality risk should be interpreted with caution and requires further investigation by other studies.

Low radon exposure and mortality among Jouac uranium miners: an update of the French cohort (1946-2007).

After the extension of the French cohort of uranium miners with the inclusion of workers employed in the Jouac mines, this article seeks to describe the new Jouac cohort and to estimate mortality risks, as well as to quantify their relation to radon exposure in this extended cohort. The Jouac cohort includes 458 miners hired by the Société des Mines de Jouac between 1957 and 2001. There is no measurement of radon exposure before 1978 and so no data were available. Consequently, only the post-1977 Jouac cohort (n = 314) has been included in the French cohort, creating an extended cohort of 5400 French uranium miners followed up from 1946 to 2007. Mortality analyses computed the standardised mortality ratios (SMRs). Excess relative risks (ERRs) were assessed using Poisson regression models. No evidence of a significant excess risk of overall mortality (n = 66, SMR = 0.93; 95% CI = 0.72-1.19) or any specific mortality was observed in the Jouac cohort. In the extended cohort, overall mortality did not increase, but a significant excess of deaths was observed for all cancers (SMR = 1.11, 95% CI = 1.03-1.19), lung cancer (SMR = 1.32, 95% CI = 1.14-1.51), and kidney cancer (SMR = 1.58, 95% CI = 1.01-2.35). Cumulative exposure to radon was 3.9 working level month (WLM) and 35.1 WLM in the post-1977 Jouac and extended cohorts, respectively. Cumulative radon exposure was significantly associated with an excess risk of death from lung cancer (ERR/100 WLM = 0.73, 95% CI = 0.32-1.33) and from cerebrovascular diseases (ERR/100 WLM = 0.42 95% CI = 0.04-1.04). In conclusion, the Jouac cohort is still a young cohort and its inclusion leads to slight modifications compared to previous analyses of the French cohort. The already known relation between radon exposure and lung cancer death as well as the excess risk of death from cerebrovascular diseases persisted in the extended cohort.

Impact of considering non-occupational radiation exposure on the association between occupational dose and solid cancer among French nuclear workers.

OBJECTIVES: The French nuclear worker cohort allows for the assessment of cancer risk associated with occupational radiation exposure, but workers are also exposed to medical and environmental radiation which can be of the same order of magnitude. This study aims to examine the impact of non-occupational radiation exposures on the dose-risk analysis between occupational radiation exposure and cancer mortality. METHODS: The cohort included workers employed before 1995 for at least one year by CEA, AREVA NC or EDF and badge-monitored for external radiation exposure. Monitoring results were used to calculate occupational individual doses. Scenarios of work-related X-ray and environmental exposures were simulated. Poisson regression was used to quantify associations between occupational exposure and cancer mortality adjusting for non-occupational radiation exposure. RESULTS: The mean cumulative dose of external occupational radiation was 18.4 mSv among 59 004 workers. Depending on the hypotheses made, the mean cumulative work-related X-ray dose varied between 3.1 and 9.2 mSv and the mean cumulative environmental dose was around 130 mSv. The unadjusted excess relative rate of cancer per Sievert (ERR/Sv) was 0.34 (90% CI -0.44 to 1.24). Adjusting for environmental radiation exposure did not substantially modify this risk coefficient, but it was attenuated by medical exposure (ERR/Sv point estimate between 0.15 and 0.23). CONCLUSIONS: Occupational radiation risk estimates were lower when adjusted for work-related X-ray exposures. Environmental exposures had a very slight impact on the occupational exposure risk estimates. In any scenario of non-occupational exposure considered, a positive but insignificant excess cancer risk associated with occupational exposure was observed.

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.

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.

Impact of chemical exposure on cancer mortality in a French cohort of uranium processing workers.

BACKGROUND: Nuclear workers may be exposed to a variety of chemical hazards, in addition to radiation. We examined the effect of chemical exposures on cancer mortality among French uranium processing workers at the AREVA NC Pierrelatte facility. METHODS: A cohort of 2,897 uranium processing workers employed for at least 6 months was followed from 1968 through 2006. Exposure to uranium and potentially carcinogenic chemicals was assessed with a plant-specific job-exposure matrix. Mortality hazard ratios (HRs) for cancers of the lung, lymphohematopoietic system, kidney and bladder, brain and central nervous system (BCNS), and prostate were estimated for each specific chemical exposure, with Cox regression models stratified for sex and calendar period and adjusted for socioeconomic status. Additional adjustments enabled us to examine the effect of co-exposure to uranium and other chemicals. RESULTS: Exposure to aromatic solvents was associated with increased risk of BCNS malignancies after adjustment for other chemicals (HR=6.53, 95% CI=1.14-37.41; n=6) and for other chemicals and uranium (HR=7.26, 95% CI=0.90-58.19) in the annual exposure status model. Selected groups of lymphohematopoietic cancers were found associated with solvent exposure. Inconclusive results were found regarding chromium (VI) exposure, since only 2 workers died from lung cancer among 109 exposed. CONCLUSION: Based on our pilot study, it seemed important to take into account chemical exposures in the analyses of cancer mortality among French uranium processing workers.

Does uranium induce circulatory diseases? First results from a French cohort of uranium workers.

OBJECTIVES: Increased risk of circulatory system diseases (CSDs) was observed in nuclear workers handling uranium and plutonium in Russia and the UK. This work examines the CSD mortality after chronic intake of uranium among 2897 workers (79,892 person-years) at a uranium processing plant (1960-2006) in France. METHODS: Cumulative exposure to different uranium compounds, classified by their isotopic composition and solubility type, was quantified on the basis of a plant-specific job-exposure matrix and individual job histories. HRs and associated 95% CI for CSD (n = 111) and specific CSD categories were estimated using Cox regression models, stratified on sex and birth cohort and adjusted for potential confounders. The effect of smoking was analysed among 260 smokers (42 CSD deaths). RESULTS: Compared to unexposed workers, CSD mortality was increased among workers exposed to slowly soluble reprocessed uranium (RPU) (HR = 2.13, 95% CI = 0.96 to 4.70) and natural uranium (HR = 1.73, 95% CI = 1.11 to 2.69). The risk increased with cumulative exposure and exposure duration. In the subgroup of smokers, the risk estimates were higher but with larger CIs: HR=1.91 (95% CI = 0.92 to 3.98) for natural uranium and HR = 4.78 (95% CI = 1.38 to 16.50) for RPU. CONCLUSIONS: The authors observed that exposure to slowly soluble uranium, namely RPU, may increase the risk of CSD mortality. However, these results are preliminary since the study is lacking statistical power and many other biological and lifestyle-related factors may cause CSD. More detailed investigations are necessary to confirm these findings and analyse in depth the effects of internal radiation exposure on the circulatory system.

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 ß-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.

Cancer mortality among two different populations of French nuclear workers.

PURPOSE: The aim of this paper is to study the effect of external photon radiation on the mortality of two populations of French nuclear workers: workers exposed only to external photon radiation and workers potentially exposed also to internal contamination or to neutrons. METHOD: External photon radiation has been measured through individual dosimeters. Potential exposure to internal contamination or to neutrons has been assessed by experts on the basis of quantitative measurements or of worksite and type of activity. The mortality observed in each population was compared with that expected from national mortality statistics, by computing standardized mortality ratios. Dose-effect relationships were analyzed through trend tests and log-linear Poisson regressions. RESULTS: 14,796 workers were exposed only to external photon radiation; 14,408 workers were also potentially exposed to internal radiation or to neutrons. Between 1968 and 1994, the number of deaths is respectively, 645 and 1,197. The mean external photon dose was respectively, 3.7 and 12.9 mSv. Similar Healthy Worker Effects were observed in the two populations (SMR = 0.59). SMR of 2.41 90% CI [1.39-3.90] was observed for malignant melanoma among workers of the second population. Significant dose-effect relationships were observed: among workers exposed only to external photon radiation for leukemia except CLL and in the other population, for cancers and other diseases related to tobacco or alcohol consumption. CONCLUSIONS: Results differed between the two populations. The increase in leukemia risk with dose in the first population will have to be confirmed with extended follow-up. In the other population, results may have been confounded by alpha-emitters inhalation, tobacco, or alcohol consumption.

Reprocessed uranium exposure and lung cancer risk.

This study investigated the risk of lung cancer in regards to protracted occupational exposure to reprocessed uranium compounds. Two thousand seven hundred and nine male workers employed at the AREVA NC uranium processing plant between 1960 and 2005 in France were included in the cohort. Historical exposure to reprocessed uranium compounds classified by their solubility type was assessed on the basis of the plant's specific job-exposure matrix. Cox proportional hazard models adjusted for attained age, calendar period, and socioeconomic status were used to estimate relative risks in regards of each type of uranium compound. The relative risk of lung cancer tended to increase with decreasing solubility of reprocessed uranium compounds. The highest-though not statistically significant-relative risk was observed among workers exposed to slowly soluble reprocessed uranium dioxide. This study is the first suggesting an increasing risk of lung cancer associated with exposure to reprocessed uranium. Our results are consistent with data from experimental studies of biokinetics and the action mechanism of slowly soluble uranium compounds, but need to be confirmed in larger studies with more detailed dose-response analyses.

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.

French cohort of the uranium processing workers: mortality pattern after 30-year follow-up.

OBJECTIVE: To investigate mortality among nuclear workers with potential internal exposure to uranium. METHODS: The cohort included 2,709 workers employed at the AREVA NC Pierrelatte plant for at least 6 months (72,787 person-years). This plant processed uranium enrichment during the period 1960-1996 and chemical conversion since 1980. Mortality was compared to the national and regional mortality rates available for the period 1968-2005. For causes of death of interest with respect to occupational exposure, mortality trends according to occupational characteristics were assessed. RESULTS: As expected, an important healthy worker effect (all causes SMR = 0.55 (95% CI: 0.50-0.61), n = 411; all cancers SMR = 0.70 (95% CI: 0.60-0.81), n = 193) was observed. Among cancer sites a priori related to uranium exposure, only mortality for lymphatic cancer was increased among potentially exposed workers (SMR = 1.49 (95% CI: 0.68-2.82); n = 9). An important increase in mortality from pleural cancer was observed (SMR = 2.85 (95% CI: 0.93-6.66), n = 5); none of the deceased workers were exposed to radiation whereas all handled asbestos. CONCLUSION: In spite of limited statistical power, results show consistency with previous studies of nuclear workers potentially exposed to uranium. Further investigation based on more precise uranium exposure data should allow the estimation of uranium hazard effects among this cohort.

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.