Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Radon and lung cancer in the pooled uranium miners analysis (PUMA): highly exposed early miners and all miners.

OBJECTIVES: Radon is a ubiquitous occupational and environmental lung carcinogen. We aim to quantify the association between radon progeny and lung cancer mortality in the largest and most up-to-date pooled study of uranium miners. METHODS: The pooled uranium miners analysis combines 7 cohorts of male uranium miners with 7754 lung cancer deaths and 4.3 million person-years of follow-up. Vital status and lung cancer deaths were ascertained between 1946 and 2014. The association between cumulative radon exposure in working level months (WLM) and lung cancer was modelled as the excess relative rate (ERR) per 100 WLM using Poisson regression; variation in the association by temporal and exposure factors was examined. We also examined analyses restricted to miners first hired before 1960 and with <100 WLM cumulative exposure. RESULTS: In a model that allows for variation by attained age, time since exposure and annual exposure rate, the ERR/100 WLM was 4.68 (95% CI 2.88 to 6.96) among miners who were less than 55 years of age and were exposed in the prior 5 to <15 years at annual exposure rates of <0.5 WL. This association decreased with older attained age, longer time since exposure and higher annual exposure rate. In analyses restricted to men first hired before 1960, we observed similar patterns of association but a slightly lower estimate of the ERR/100 WLM. CONCLUSIONS: This new large, pooled study confirms and supports a linear exposure-response relationship between cumulative radon exposure and lung cancer mortality which is jointly modified by temporal and exposure factors.

Association between exposures to radon and γ-ray radiation and histologic type of lung cancer in Eldorado uranium mining and milling workers from Canada.

BACKGROUND: The authors assessed the association between radon decay products (RDP) exposure and histologic types of incident lung cancer in a cohort of 16,752 (91.6% male) Eldorado uranium workers who were first employed from 1932 to 1980 and were followed through 1969-1999. METHODS: Substantially revised identifying information and RDP exposures were obtained on workers from the Port Radium and Beaverlodge uranium mines and from the Port Hope radium and uranium refinery and processing facility in Canada. Poisson regression was conducted using the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VI-type models to estimate the risks of lung cancer by histologic type from RDP exposures and γ-ray doses. RESULTS: Lung cancer incidence was significantly higher in workers compared with the general Canadian male population. Radiation risks of lung cancer for all histologic types (n = 594; 34% squamous cell, 16% small cell, 17% adenocarcinoma) increased with increasing RDP exposure, with no indication of curvature in the dose response (excess relative risk per 100 working level months = 0.61; 95% confidence interval, 0.39-0.91). Radiation risks did not differ by histologic type (p = .144). The best-fitting BEIR VI-type model included adjustments for the significant modifying effects of time since exposure, exposure rate, and attained age. The addition of γ-ray doses to the model with RDP exposures improved the model fit, but the risk estimates remained unchanged. CONCLUSIONS: The first analysis of radiation risks of lung cancer histologic types in the Eldorado cohort supported the use of BEIR VI-type models to predict the future risk of histologic types of lung cancer from past and current RDP exposures. LAY SUMMARY: Lung cancer survival depends strongly on the cell type of lung cancer. The best survival rates are for patients who have the adenocarcinoma type. This study included 16,752 Eldorado uranium workers who were exposed to radon and γ-ray radiation during 1932-1980, were alive in 1969, and were followed for the development of new lung cancer during 1969-1999. One third of all lung cancers were of the squamous cell type, whereas the adenocarcinoma and small cell types accounted for less than 20% each. Radiation risks of lung cancer among men increased significantly with increasing radon exposure for all cell types, with the highest risks estimated for small cell and squamous cell lung cancers.

Nonmalignant respiratory disease mortality in male Colorado Plateau uranium miners, 1960-2016.

BACKGROUND: To evaluate trends of nonmalignant respiratory disease (NMRD) mortality among US underground uranium miners on the Colorado Plateau, and to estimate the exposure-response association between cumulative radon progeny exposure and NMRD subtype mortality. METHODS: Standardized mortality ratios (SMRs) and excess relative rates per 100 working level months (excess relative rate [ERR]/100 WLM) were estimated in a cohort of 4021 male underground uranium miners who were followed from 1960 through 2016. RESULTS: We observed elevated SMRs for all NMRD subtypes. Silicosis had the largest SMR (n = 52, SMR = 41.4; 95% confidence interval [CI]: 30.9, 54.3), followed by other pneumoconiosis (n = 49, SMR = 39.6; 95% CI: 29.6, 52.3) and idiopathic pulmonary fibrosis (IPF) (n = 64, SMR = 4.77; 95% CI 3.67, 6.09). SMRs for silicosis increased with duration of employment; SMRs for IPF increased with duration of employment and calendar period. There was a positive association between cumulative radon exposure and silicosis with evidence of modification by smoking (ERR/100 WLM≥10 pack-years = 0.78; 95% CI: 0.05, 24.6 and ERR/100 WLM<10 pack-years = 0.01; 95% CI: -0.03, 0.52), as well as a small positive association between radon and IPF (ERR/100 WLM = 0.06, 95% CI: 0.00, 0.24); these associations were driven by workers with prior employment in hard rock mining. CONCLUSIONS: Uranium mining workers had excess NMRD mortality compared with the general population; this excess persisted throughout follow-up. Exposure-response analyses indicated a positive association between radon exposure and IPF and silicosis, but these analyses have limitations due to outcome misclassification and missing information on occupational co-exposures such as silica dust.

[Silica-induced scleroderma in miners in former uranium ore mining (Wismut AG)]. / Quarzinduzierte Sklerodermie bei Bergleuten im früheren Uranerzbergbau (Wismut AG).

As part of the reappraisal of the legacy of Wismut AG, 12 patients with silica-induced scleroderma among underground uranium ore mine workers (Wismut AG) under long-term exposure to silica fine dust, as well as radon and its daughter products, during the 1960s and 1970s are reported on. Silica-induced scleroderma is clinically, serologically and immunologically indistinguishable from idiopathic systemic sclerosis. In experimental studies, endothelial cells, monocytes and fibroblasts, as well as their synthesis rates and the release of cytokines and chemokines, were activated by silica fine dust in a way that is consistent with the pathophysiological processes in idiopathic systemic sclerosis. It was not possible to achieve recognition of silica-induced systemic sclerosis as an occupational disease in Germany.

A Bayesian hierarchical approach to account for left-censored and missing radiation doses prone to classical measurement error when analyzing lung cancer mortality due to γ-ray exposure in the French cohort of uranium miners.

Epidemiological data on cohorts of occupationally exposed uranium miners are currently used to assess health risks associated with chronic exposure to low doses of ionizing radiation. Nevertheless, exposure uncertainty is ubiquitous and questions the validity of statistical inference in these cohorts. This paper highlights the flexibility and relevance of the Bayesian hierarchical approach to account for both missing and left-censored (i.e. only known to be lower than a fixed detection limit) radiation doses that are prone to measurement error, when estimating radiation-related risks. Up to the authors' knowledge, this is the first time these three sources of uncertainty are dealt with simultaneously in radiation epidemiology. To illustrate the issue, this paper focuses on the specific problem of accounting for these three sources of uncertainty when estimating the association between occupational exposure to low levels of γ-radiation and lung cancer mortality in the post-55 sub-cohort of French uranium miners. The impact of these three sources of dose uncertainty is of marginal importance when estimating the risk of death by lung cancer among French uranium miners. The corrected excess hazard ratio (EHR) is 0.81 per 100 mSv (95% credible interval: [0.28; 1.75]). Interestingly, even if the 95% credible interval of the corrected EHR is wider than the uncorrected one, a statistically significant positive association remains between γ-ray exposure and the risk of death by lung cancer, after accounting for dose uncertainty. Sensitivity analyses show that the results obtained are robust to different assumptions. Because of its flexible and modular nature, the Bayesian hierarchical models proposed in this work could be easily extended to account for high proportions of missing and left-censored dose values or exposure data, prone to more complex patterns of measurement error.

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation.

Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.

Hydrogen sulfide alleviates uranium-induced rat hepatocyte cytotoxicity via inhibiting Nox4/ROS/p38 MAPK pathway.

As a gasotransmitter, hydrogen sulfide (H2 S) plays a crucial role in regulating the signaling pathway mediated by oxidative stress. The purpose of this study was to investigate the protective effects of H 2 S on uranium-induced rat hepatocyte cytotoxicity. Primary hepatocytes were isolated and cultured from Sprague Dawley rat liver tissues. After pretreating with sodium hydrosulfide (an H 2 S donor) for 1 hour (or GKT-136901 for 30 minutes), hepatocytes were treated by uranyl acetate for 24 hours. Cell viability, reactive oxygen species (ROS), malondialdehyde (MDA), NADPH oxidase 4 (Nox4), and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation were respectively determined. The effects of direct inhibition of Nox4 expression by GKT-136901 (a Nox4 inhibitor) on ROS and phospho-p38 MAPK levels were examined in uranium-treated hepatocytes. The results implicate that H 2 S can afford protection of rat hepatocytes against uranium-induced adverse effects through attenuating oxidative stress via prohibiting Nox4/ROS/p38 MAPK signaling.

Mortality and cancer incidence among underground uranium miners in the Czech Republic 1977-1992.

OBJECTIVES: Uranium miners in Príbram, Czech Republic were exposed to low and moderate levels of radon gas and other hazards. It is unknown whether these hazards increase the risk of mortality or cancer incidence when compared with the general Czech population. METHODS: A cohort of 16 434 male underground miners employed underground for at least 1 year between 1946 and 1976, and alive and residing in the Czech Republic in 1977, were followed for mortality and cancer incidence through 1992. We compared observed deaths and cancer incidence to expectation based on Czech rates. Standardised mortality ratios (SMRs), standardised incidence ratios (SIRs) and causal mortality ratios were calculated. RESULTS: Underground workers in the Príbram mines had higher rates of death than expected due to all causes (SMR=1.23, 95% CI 1.20 to 1.27), all cancers (SMR=1.52, 95% CI 1.44 to 1.60), lung cancer (SMR=2.12, 95% CI 1.96 to 2.28) and extrathoracic cancer (SMR=1.41, 95% CI 1.15 to 1.77). Similar excess was observed in cancer incidence analyses, with the addition of stomach cancer (SIR=1.37, 95% CI 1.11 to 1.63), liver cancer (SIR=1.70, 95% CI 1.16 to 2.25) and rectal cancer (SIR=1.41, 95% CI 1.16 to 1.66). The SIR was elevated for all leukaemias (SIR=1.51, 95% CI 1.08 to 2.07) and for lymphatic and haematopoietic cancers combined (SIR=1.31, 95% CI 1.05 to 1.61), but results for specific subtypes were imprecise. Deaths due to hazardous mining conditions resulted in 0.33 person-years of life lost per miner. CONCLUSIONS: Occupational exposure to the Príbram mines resulted in excess cancers at several sites, including sites previously linked to radon and uranium exposure. Incidence analyses showed relative excess of several additional cancer subtypes.

Bacterial Community Shift and Coexisting/Coexcluding Patterns Revealed by Network Analysis in a Uranium-Contaminated Site after Bioreduction Followed by Reoxidation.

A site in Oak Ridge, TN, USA, has sediments that contain >3% iron oxides and is contaminated with uranium (U). The U(VI) was bioreduced to U(IV) and immobilized in situ through intermittent injections of ethanol. It then was allowed to reoxidize via the invasion of low-pH (3.6 to 4.0), high-nitrate (up to 200 mM) groundwater back into the reduced zone for 1,383 days. To examine the biogeochemical response, high-throughput sequencing and network analysis were applied to characterize bacterial population shifts, as well as cooccurrence and coexclusion patterns among microbial communities. A paired t test indicated no significant changes of α-diversity for the bioactive wells. However, both nonmetric multidimensional scaling and analysis of similarity confirmed a significant distinction in the overall composition of the bacterial communities between the bioreduced and the reoxidized sediments. The top 20 major genera accounted for >70% of the cumulative contribution to the dissimilarity in the bacterial communities before and after the groundwater invasion. Castellaniella had the largest dissimilarity contribution (17.7%). For the bioactive wells, the abundance of the U(VI)-reducing genera Geothrix, Desulfovibrio, Ferribacterium, and Geobacter decreased significantly, whereas the denitrifying Acidovorax abundance increased significantly after groundwater invasion. Additionally, seven genera, i.e., Castellaniella, Ignavibacterium, Simplicispira, Rhizomicrobium, Acidobacteria Gp1, Acidobacteria Gp14, and Acidobacteria Gp23, were significant indicators of bioactive wells in the reoxidation stage. Canonical correspondence analysis indicated that nitrate, manganese, and pH affected mostly the U(VI)-reducing genera and indicator genera. Cooccurrence patterns among microbial taxa suggested the presence of taxa sharing similar ecological niches or mutualism/commensalism/synergism interactions.IMPORTANCE High-throughput sequencing technology in combination with a network analysis approach were used to investigate the stabilization of uranium and the corresponding dynamics of bacterial communities under field conditions with regard to the heterogeneity and complexity of the subsurface over the long term. The study also examined diversity and microbial community composition shift, the common genera, and indicator genera before and after long-term contaminated-groundwater invasion and the relationship between the target functional community structure and environmental factors. Additionally, deciphering cooccurrence and coexclusion patterns among microbial taxa and environmental parameters could help predict potential biotic interactions (cooperation/competition), shared physiologies, or habitat affinities, thus, improving our understanding of ecological niches occupied by certain specific species. These findings offer new insights into compositions of and associations among bacterial communities and serve as a foundation for future bioreduction implementation and monitoring efforts applied to uranium-contaminated sites.

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.

Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort.

A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

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.

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.

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides.

BACKGROUND: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles-particularly through inhalation-occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose-response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. METHODS: We conducted a case-control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. RESULTS: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)-adjusted for external radiation, socioeconomic status, and smoking-was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (-1.9, 18) for uranium. CONCLUSIONS: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors.See video abstract at, http://links.lww.com/EDE/B232.

Natural uranium impairs the differentiation and the resorbing function of osteoclasts.

BACKGROUND: Uranium is a naturally occurring radionuclide ubiquitously present in the environment. The skeleton is the main site of uranium long-term accumulation. While it has been shown that natural uranium is able to perturb bone metabolism through its chemical toxicity, its impact on bone resorption by osteoclasts has been poorly explored. Here, we examined for the first time in vitro effects of natural uranium on osteoclasts. METHODS: The effects of uranium on the RAW 264.7 monocyte/macrophage mouse cell line and primary murine osteoclastic cells were characterized by biochemical, molecular and functional analyses. RESULTS: We observed a cytotoxicity effect of uranium on osteoclast precursors. Uranium concentrations in the µM range are able to inhibit osteoclast formation, mature osteoclast survival and mineral resorption but don't affect the expression of the osteoclast gene markers Nfatc1, Dc-stamp, Ctsk, Acp5, Atp6v0a3 or Atp6v0d2 in RAW 274.7 cells. Instead, we observed that uranium induces a dose-dependent accumulation of SQSTM1/p62 during osteoclastogenesis. CONCLUSIONS: We show here that uranium impairs osteoclast formation and function in vitro. The decrease in available precursor cells, as well as the reduced viability of mature osteoclasts appears to account for these effects of uranium. The SQSTM1/p62 level increase observed in response to uranium exposure is of particular interest since this protein is a known regulator of osteoclast formation. A tempting hypothesis discussed herein is that SQSTM1/p62 dysregulation contributes to uranium effects on osteoclastogenesis. GENERAL SIGNIFICANCE: We describe cellular and molecular effects of uranium that potentially affect bone homeostasis.

Leukaemia mortality and low-dose ionising radiation in the WISMUT uranium miner cohort (1946-2013).

OBJECTIVES: To examine the risk of death from leukaemia in relation to occupational chronic low-level external and internal radiation exposure in a cohort of 58 972 former German uranium miners with mortality follow-up from 1946 to 2013. METHODS: The red bone marrow (RBM) dose from low-linear energy transfer (LET) (mainly external γ-radiation) and high-LET (mainly radon gas) radiation was estimated based on a job-exposure matrix and biokinetic/dosimetric models. Linear excess relative risks (ERR) and 95% CIs were estimated via Poisson regression for chronic lymphatic leukaemia (CLL) and non-CLL. RESULTS: The mean cumulative low-LET and high-LET RBM doses among the 86% radiation-exposed workers were 48 and 9 mGy, respectively. There was a positive non-significant dose-response for mortality from non-CLL (n=120) in relation to low-LET (ERR/Gy=2.18; 95% CI -0.41 to 6.37) and high-LET radiation (ERR/Gy=16.65; 95% -1.13 to 46.75). A statistically significant excess was found for the subgroup chronic myeloid leukaemia (n=31) in relation to low-LET radiation (ERR/Gy=7.20; 95% CI 0.48 to 24.54) and the subgroup myeloid leukaemia (n=99) (ERR/Gy=26.02; 95% CI 2.55 to 68.99) for high-LET radiation. The ERR/Gy tended to be about five to ten times higher for high-LET versus low-LET radiation; however, the CIs largely overlapped. Results indicate no association of death from CLL (n=70) with either type of radiation. CONCLUSIONS: Our findings indicate an increased risk of death for specific subtypes from non-CLL in relation to chronic low-LET and high-LET radiation, but no such relation for CLL.

Mortality in a combined cohort of uranium enrichment workers.

OBJECTIVE: To examine the patterns of cause-specific mortality and relationship between internal exposure to uranium and specific causes in a pooled cohort of 29,303 workers employed at three former uranium enrichment facilities in the United States with follow-up through 2011. METHODS: Cause-specific standardized mortality ratios (SMRs) for the full cohort were calculated with the U.S. population as referent. Internal comparison of the dose-response relation between selected outcomes and estimated organ doses was evaluated using regression models. RESULTS: External comparison with the U.S. population showed significantly lower SMRs in most diseases in the pooled cohort. Internal comparison showed positive associations of absorbed organ doses with multiple myeloma, and to a lesser degree with kidney cancer. CONCLUSION: In general, these gaseous diffusion plant workers had significantly lower SMRs than the U.S. POPULATION: The internal comparison however, showed associations between internal organ doses and diseases associated with uranium exposure in previous studies. Am. J. Ind. Med. 60:96-108, 2017. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

[Ecological-hygienic evaluation of the environment of territories being adjacent to decultivated uranium mines].

On the territory of Kazakhstan there are uranium deposits, many ofwhich are in mothballed since times of perestroika. Often, the mines are flooded and represent a "time-delay bomb". Inside of mines various there are accumulated gases of both organic and inorganic nature, periodically thrown out and adversely affecting on the health of local populations. The aim of the study was the investigation of the state of the environment of Esilsky district of the Akmola region by common pollutants and chemicals. As the basic variable for the investigation of ambient air there was accepted the maximum one-time concentration of suspended substances, phenol, nitrogen dioxide, sulfur dioxide. The results were evaluated in relation to the MPC for the analyzed substance in the air according to maximal single MPC (MPCms) and daily average MPC (MPCda). The content of metals in the water was determined with the use of spectrophotometer PD-303S. Evaluation of the results was executed in relation of the MPC of substances in water, by means of the comparison with the requirements of Federal standards for drinking water, samples from drinking water sources. There were executed calculations of the overall index of water pollution (IWVgen), the index of water pollution by heavy metals (IWVhm). Chemical analysis of soil was carried out with the use of spectrophotometer PD- 303S (Japan), the photometer expert-003 "Ekoniks". Evaluation of the results was carried out with the respect to the MPC in the soil, the toxicity of all components. Summarizing soil pollution index was evaluated for metals contained in the soil at the level of more than or equal to 1 MAC. The settlement Krasnogorskiy and the village of Kalachi were found to be characterized by a low level of air pollution, increased rigidity of drinking water exceeded the maximum permissible concentrations of copper by 3.45 times and chloride by 1.17 times in the soil cover.

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.