Influence of exposure assessment methods on associations between long-term exposure to outdoor fine particulate matter and risk of cancer in the French cohort Gazel.

BACKGROUND: Many studies investigated the relationship between outdoor fine particulate matter (PM2.5) and cancer. While they generally indicated positive associations, results have not been fully consistent, possibly because of the diversity of methods used to assess exposure. OBJECTIVES: To investigate how using different PM2.5 exposure assessment methods influences risk estimates in the large French general population-based Gazel cohort (20,625 participants at enrollment) with a 26-year follow-up with complete residential histories. METHODS: We focused on two cancer incidence outcomes: all-sites combined and lung. We used two distinct exposure assessment methods: a western European land use regression (LUR), and a chemistry-dispersion model (Gazel-Air) for France, each with a time series ≥20-years annual concentrations. Spearman correlation coefficient between the two estimates of PM2.5 was 0.71 across all person-years; the LUR tended to provide higher exposures. We used extended Cox models with attained age as time-scale and time-dependent cumulative exposures, adjusting for a set of confounders including sex and smoking, to derive hazard ratios (HRs) and their 95% confidence interval, implementing a 10-year lag between exposure and incidence/censoring. RESULTS: We obtained similar two-piece linear associations for all-sites cancer (3711 cases), with a first slope of HRs of 1.53 (1.24-1.88) and 1.43 (1.19-1.73) for one IQR increase of cumulative PM2.5 exposure for the LUR and the Gazel-Air models respectively, followed by a plateau at around 1.5 for both exposure assessments. For lung cancer (349 cases), the HRs from the two exposure models were less similar, with largely overlapping confidence limits. CONCLUSION: Our findings using long-term exposure estimates from two distinct exposure assessment methods corroborate the association between air pollution and cancer risk.

Contribution of Long-Term Exposure to Outdoor Black Carbon to the Carcinogenicity of Air Pollution: Evidence regarding Risk of Cancer in the Gazel Cohort.

BACKGROUND: Black carbon (BC), a component of fine particulate matter [particles with an aerodynamic diameter ≤2.5 µm (PM2.5)], may contribute to carcinogenic effects of air pollution. Until recently however, there has been little evidence to evaluate this hypothesis. OBJECTIVE: This study aimed to estimate the associations between long-term exposure to BC and risk of cancer. This study was conducted within the French Gazel cohort of 20,625 subjects. METHODS: We assessed exposure to BC by linking subjects' histories of residential addresses to a map of European black carbon levels in 2010 with back- and forward-extrapolation between 1989 and 2015. We used extended Cox models, with attained age as time-scale and time-varying cumulative exposure to BC, adjusted for relevant sociodemographic and lifestyle variables. To consider latency between exposure and cancer diagnosis, we implemented a 10-y lag, and as a sensitivity analysis, a lag of 2 y. To isolate the effect of BC from that of total PM2.5, we regressed BC on PM2.5 and used the residuals as the exposure variable. RESULTS: During the 26-y follow-up period, there were 3,711 incident cancer cases (all sites combined) and 349 incident lung cancers. Median baseline exposure in 1989 was 2.65 10-5/m [interquartile range (IQR): 2.23-3.33], which generally slightly decreased over time. Using 10 y as a lag-time in our models, the adjusted hazard ratio per each IQR increase of the natural log-transformed cumulative BC was 1.17 (95% confidence interval: 1.06, 1.29) for all-sites cancer combined and 1.31 (0.93, 1.83) for lung cancer. Associations with BC residuals were also positive for both outcomes. Using 2 y as a lag-time, the results were similar. DISCUSSION: Our findings for a cohort of French adults suggest that BC may partly explain the association between PM2.5 and lung cancer. Additional studies are needed to confirm our results and further disentangle the effects of BC, total PM2.5, and other constituents. https://doi.org/10.1289/EHP8719.

Long-term exposure to atmospheric metals assessed by mosses and mortality in France.

BACKGROUND: Long-term exposure to air pollution affects health, but little is known about exposure to atmospheric metals. Estimating exposure to atmospheric metals across large spatial areas remains challenging. Metal concentrations in mosses could constitute a useful proxy. Here, we linked moss biomonitoring and epidemiological data to investigate the associations between long-term exposure to metals and mortality. METHODS: We modelled and mapped 13 atmospheric metals from a 20-year national moss biomonitoring program to derive exposure estimates across France. In the population-based Gazel cohort, we included 11,382 participants from low to intermediate population density areas and assigned modelled metals to their residential addresses. We distinguished between airborne metals that are primarily of natural origin and those primarily of anthropogenic origin. Associations were estimated between exposure to metals and mortality (natural-cause, cardiovascular and respiratory), using Cox models, with confounder adjustment at individual level. FINDINGS: Between 1996 and 2017, there were 1313 deaths in the cohort (including 181 cardiovascular and 33 respiratory). Exposure to the anthropogenic metals was associated with an increased risk of natural-cause mortality (hazard ratio of 1.16 [1.08-1.24] per interquartile range of exposure), while metals from natural sources were not. INTERPRETATION: Some atmospheric anthropogenic metals may be associated with excess mortality - even in areas with relatively low levels of exposure to air pollution. Consistent with the previous literature, our findings support the use of moss biomonitoring as a tool to assess health effects of air pollution exposure at individual level.

Analysis of mortality in a pooled cohort of Canadian and German uranium processing workers with no mining experience.

PURPOSE: Long-term health risks of occupational exposures to uranium processing were examined to better understand potential differences with uranium underground miners and nuclear reactor workers. METHODS: A cohort study of mortality of workers from Port Hope, Canada (1950-1999) and Wismut, Germany (1946-2008) employed in uranium milling, refining, and processing was conducted. Poisson regression was used to evaluate the association between cumulative exposures to radon decay products (RDP) and gamma-rays and causes of death potentially related to uranium processing. RESULTS: The pooled cohort included 7431 workers (270,201 person-years of follow-up). Mean RDP exposures were lower than in miners while gamma-ray doses were higher than in reactor workers. Both exposures were highly correlated (weighted rho = 0.81). Radiation risks of lung cancer and cardiovascular diseases (CVD) in males were increased but not statistically significant and compatible with risks estimated for miners and reactor workers, respectively. Higher RDP-associated CVD risks were observed for exposures 5-14 years prior to diagnosis compared to later exposures and among those employed <5 years. Radiation risks of solid cancers excluding lung cancer were increased, but not statistically significant, both for males and females, while all other causes of death were not associated with exposures. CONCLUSIONS: In the largest study of uranium processing workers to systematically examine radiation risks of multiple outcomes from RDP exposures and gamma-rays, estimated radiation risks were compatible with risks reported for uranium miners and nuclear reactor workers. Continued follow-up and pooling with other cohorts of uranium processing workers are necessary for future comparisons with other workers of the nuclear fuel cycle.

Circulatory disease in French nuclear fuel cycle workers chronically exposed to uranium: a nested case-control study.

OBJECTIVES: There is growing evidence of an association between low-dose external γ-radiation and circulatory system diseases (CSDs), yet sparse data exist about an association with chronic internal uranium exposure and the role of non-radiation risk factors. We conducted a nested case-control study of French AREVA NC Pierrelatte nuclear workers employed between 1960 and 2005 to estimate CSD risks adjusting for major CSD risk factors (smoking, blood pressure, body mass index, total cholesterol and glycaemia) and external γ-radiation dose. METHODS: The study included 102 cases of death from CSD and 416 controls individually matched on age, gender, birth cohort and socio-professional status. Information on CSD risk factors was collected from occupational medical records. Organ-specific absorbed doses were estimated using biomonitoring data, taking into account exposure regime and uranium physicochemical properties. External γ-radiation was measured by individual dosimeter badges. Analysis was conducted with conditional logistic regression. RESULTS: Workers were exposed to very low radiation doses (mean γ-radiation dose 2 and lung uranium dose 1 mGy). A positive but imprecise association was observed (excess OR per mGy 0.2, 95% CI 0.004 to 0.5). Results obtained after adjustment suggest that uranium exposure might be an independent CSD risk factor. CONCLUSIONS: Our results suggest that a positive association might exist between internal uranium exposure and CSD mortality, not confounded by CSD risk factors. Future work should focus on numerous uncertainties associated with internal uranium dose estimation and on understanding biological pathway of CSD after protracted low-dose internal radiation exposure.

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.

Cancer and non-cancer mortality among French uranium cycle workers: the TRACY cohort.

OBJECTIVES: The health effects of internal contamination by radionuclides, and notably by uranium, are poorly characterised. New cohorts of uranium workers are needed to better examine these effects. This paper analyses for the first time the mortality profile of the French cohort of uranium cycle workers. It considers mortality from cancer and non-cancer causes. METHODS: The cohort includes workers employed at least 6 months between 1958 and 2006 in French companies involved in the production of nuclear fuel. Vital status and causes of death were collected from French national registries. Workers were followed-up from 1 January 1968 to 31 December 2008. Standardised mortality ratios (SMRs) were computed based on mortality rates for the French general population. RESULTS: The cohort includes 12,649 workers (88% men). The average length of follow-up is 27 years and the mean age at the end of the study is 60 years. Large mortality deficits are observed for non-cancer causes of death such as non-cancer respiratory diseases (SMR=0.51 (0.41 to 0.63)) and circulatory diseases (SMR=0.68 (0.62 to 0.74)). A mortality deficit of lower magnitude is also observed for all cancers combined (SMR (95% CI): 0.76 (0.71 to 0.81)). Pleural mesothelioma is elevated (SMR=2.04 (1.19 to 3.27)). CONCLUSIONS: A healthy worker effect is observed in this new cohort of workers involved in the uranium cycle. Collection of individual information on internal uranium exposure as well as other risk factors is underway, to allow for the investigation of uranium-related risks.

Mortality (1968-2008) in a French cohort of uranium enrichment workers potentially exposed to rapidly soluble uranium compounds.

OBJECTIVES: Until recently, enrichment of uranium for civil and military purposes in France was carried out by gaseous diffusion using rapidly soluble uranium compounds. We analysed the relationship between exposure to soluble uranium compounds and exposure to external γ-radiation and mortality in a cohort of 4688 French uranium enrichment workers who were employed between 1964 and 2006. METHODS: Data on individual annual exposure to radiological and non-radiological hazards were collected for workers of the AREVA NC, CEA and Eurodif uranium enrichment plants from job-exposure matrixes and external dosimetry records, differentiating between natural, enriched and depleted uranium. Cause-specific mortality was compared with the French general population via standardised mortality ratios (SMR), and was analysed via Poisson regression using log-linear and linear excess relative risk models. RESULTS: Over the period of follow-up, 131 161 person-years at risk were accrued and 21% of the subjects had died. A strong healthy worker effect was observed: all causes SMR=0.69, 95% CI 0.65 to 0.74. SMR for pleural cancer was significantly increased (2.3, 95% CI 1.06 to 4.4), but was only based on nine cases. Internal uranium and external γ-radiation exposures were not significantly associated with any cause of mortality. CONCLUSIONS: This is the first study of French uranium enrichment workers. Although limited in statistical power, further follow-up of this cohort, estimation of internal uranium doses and pooling with similar cohorts should elucidate potential risks associated with exposure to soluble uranium compounds.

Health effects of occupational exposure to uranium: do physicochemical properties matter?

PURPOSE: Physicochemical properties of uranium, including isotopic composition and solubility, are determinants of its toxicity. We reviewed epidemiological studies in civilian and military workers known to be exposed to uranium with different physicochemical properties to investigate its long-term effects, such as cancerous and circulatory diseases. MATERIALS AND METHODS: We systematically searched the Pubmed and the Scopus databases to identify studies of uranium- processing workers (published between 1980 and 2013) and veterans of the wars in the Persian Gulf and the Balkans (published between 1991 and 2013) in which defined outcomes, such as lung, lymphohematopoietic, kidney cancers, and circulatory diseases were examined. RESULTS from these studies in terms of risk of each health outcome (mortality or incidence) and analyses of dose-response relationship were examined to present the impact of uranium physicochemical properties on the observed results. RESULTS: Twenty-seven articles were reviewed. There is some evidence for increased lung cancer risk among uranium-processing workers. The evidence is less strong for lymphohematopoietic cancer. We found that most of the studies insufficiently assessed the physicochemical properties of uranium and some of them used proxies for the exposure assessment and risk estimation analyses. Studies of veterans of the wars in the Persian Gulf and the Balkans are uninformative in respect to internal uranium exposure. CONCLUSIONS: Existing epidemiological data on the physicochemical properties of uranium and associated health outcomes are inconclusive. Further studies among certain groups of uranium-processing workers (uranium-enrichment and fuel-fabrication workers) could contribute to our knowledge of the health effects of uranium with respect to its physicochemical properties.

Half-century archives of occupational medical data on French nuclear workers: a dusty warehouse or gold mine for epidemiological research?

This article discusses the availability and completeness of medical data on workers from the AREVA NC Pierrelatte nuclear plant and their possible use in epidemiological research on cardiovascular and metabolic disorders related to internal exposure to uranium. We created a computer database from files on 394 eligible workers included in an ongoing nested case-control study from a larger cohort of 2897 French nuclear workers. For each worker, we collected records of previous employment, job positions, job descriptions, medical visits, and blood test results from medical history. The dataset counts 9,471 medical examinations and 12,735 blood test results. For almost all of the parameters relevant for research on cardiovascular risk, data completeness and availability is over 90%, but it varies with time and improves in the latest time period. In the absence of biobanks, collecting and computerising available good-quality occupational medicine archive data constitutes a valuable alternative for epidemiological and aetiological research in occupational health. Biobanks rarely contain biological samples over an entire worker's carrier and medical data from nuclear industry archives might make up for unavailable biomarkers that could provide information on cardiovascular and metabolic diseases.

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.