Quantitative relationship between silica exposure and lung cancer mortality in German uranium miners, 1946-2003.
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ABSTRACT:
SUBMITTER: Sogl M
PROVIDER: S-EPMC3461166 | biostudies-other | 2012 Sep
REPOSITORIES: biostudies-other
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Project description:A determination of the risk of lung cancer at low levels of radon exposure is important for occupational radiation protection.The risk of death from lung cancer at low radon exposure rates was investigated in the subcohort of 26,766 German uranium miners hired in 1960 or later.A clear association between lung cancer mortality (n=334 deaths) and cumulative exposure to radon in working level months (WLM) was found. The excess relative risk per WLM was 0.013 (95% confidence intervals: 0.007; 0.021).The present findings provide strong evidence for an increased lung cancer risk after long-term exposure to low radon exposure rates among Wismut miners. The results are compatible to those from residential radon studies and miner studies restricted to low levels.
| S-EPMC4815799 | biostudies-other
Project description:ObjectiveA recent study and comprehensive literature review has indicated that mining could be protective against prostate cancer. This indication has been explored further here by analysing prostate cancer mortality in the German 'Wismut' uranium miner cohort, which has detailed information on the number of days worked underground.DesignAn historical cohort study of 58?987 male mine workers with retrospective follow-up before 1999 and prospective follow-up since 1999.Setting and participantsUranium mine workers employed during the period 1970-1990 in the regions of Saxony and Thuringia, Germany, contributing 1.42 million person-years of follow-up ending in 2003.Outcome measureSimple standardised mortality ratio (SMR) analyses were applied to assess differences between the national and cohort prostate cancer mortality rates and complemented by refined analyses done entirely within the cohort. The internal comparisons applied Poisson regression excess relative prostate cancer mortality risk model with background stratification by age and calendar year and a whole range of possible explanatory covariables that included days worked underground and years worked at high physical activity with ? radiation treated as a confounder.ResultsThe analysis is based on miner data for 263 prostate cancer deaths. The overall SMR was 0.85 (95% CI 0.75 to 0.95). A linear excess relative risk model with the number of years worked at high physical activity and the number of days worked underground as explanatory covariables provided a statistically significant fit when compared with the background model (p=0.039). Results (with 95% CIs) for the excess relative risk per day worked underground indicated a statistically significant (p=0.0096) small protective effect of -5.59 (-9.81 to -1.36) ×10(-5).ConclusionEvidence is provided from the German Wismut cohort in support of a protective effect from working underground on prostate cancer mortality risk.
| S-EPMC3371580 | biostudies-literature
Project description:BackgroundHigh radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development.ObjectivesWe assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.MethodsGenetic associations were assessed in a case-control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches.ResultsWe found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments.ConclusionsAn IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion.CitationLeng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445-451; http://dx.doi.org/10.1289/ehp.1409437.
| S-EPMC4829998 | biostudies-literature
Project description:BackgroundTo 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.MethodsStandardized 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.ResultsWe 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.ConclusionsUranium 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.
| S-EPMC10031748 | biostudies-literature
Project description:BackgroundRadon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners.Methodology/principal findingsParaffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%.Conclusions/significanceThese results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.
| S-EPMC3444449 | biostudies-literature
Project description:ObjectivesUranium miners in Příbram, 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.MethodsA 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.ResultsUnderground workers in the Příbram 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.ConclusionsOccupational exposure to the Příbram 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.
| S-EPMC8477988 | biostudies-literature
Project description:OBJECTIVES:Uranium miners are chronically exposed to radon and its progeny, which are known to cause lung cancer and may be associated with leukemia. This study was undertaken to evaluate risk of non-lung solid cancers among uranium miners in P?íbram region, Czech Republic. METHODS:A retrospective stratified case-cohort study in a cohort of 22,816 underground miners who were employed between 1949 and 1975. All incident non-lung solid cancers were ascertained among miners who worked underground for at least 12 months (n=1020). A subcohort of 1707 subjects was randomly drawn from the same population by random sampling stratified on age. The follow-up period lasted from 1977 to 1996. RESULTS:Relative risks comparing 180 WLM (90th percentile) of cumulative lifetime radon exposure to 3 WLM (10th percentile) were 0.88 for all non-lung solid cancers combined (95% CI 0.73-1.04, n=1020), 0.87 for all digestive cancers (95% CI 0.69-1.09, n=561), 2.39 for gallbladder cancer (95% CI 0.52-10.98, n=13), 0.79 for larynx cancer (95% CI 0.38-1.64, n=62), 2.92 for malignant melanoma (95% CI 0.91-9.42, n=23), 0.84 for bladder cancer (95% CI 0.43-1.65, n=73), and 1.13 for kidney cancer (95% CI 0.62-2.04, n=66). No cancer type was significantly associated with radon exposure; only malignant melanoma and gallbladder cancer showed elevated but non-significant association with radon. CONCLUSIONS:Radon was not significantly associated with incidence of any cancer of interest, although a positive association of radon with malignant melanoma and gallbladder cancer cannot be entirely ruled out.
| S-EPMC3064710 | biostudies-literature
Project description:BackgroundDespite reductions in exposure for workers and the general public, radon remains a leading cause of lung cancer. Prior studies of underground miners depended heavily upon information on deaths among miners employed in the early years of mine operations when exposures were high and tended to be poorly estimated.ObjectivesTo strengthen the basis for radiation protection, we report on the follow-up of workers employed in the later periods of mine operations for whom we have more accurate exposure information and for whom exposures tended to be accrued at intensities that are more comparable to contemporary settings.MethodsWe conducted a pooled analysis of cohort studies of lung cancer mortality among 57,873 male uranium miners in Canada, Czech Republic, France, Germany, and the United States, who were first employed in 1960 or later (thereby excluding miners employed during the periods of highest exposure and focusing on miners who tend to have higher quality assessments of radon progeny exposures). We derived estimates of excess relative rate per 100 working level months (ERR/100 WLM) for mortality from lung cancer.ResultsThe analysis included 1.9 million person-years of observation and 1,217 deaths due to lung cancer. The relative rate of lung cancer increased in a linear fashion with cumulative exposure to radon progeny (ERR/100 WLM=1.33; 95% CI: 0.89, 1.88). The association was modified by attained age, age at exposure, and annual exposure rate; for attained ages <55 y, the ERR/100 WLM was 8.38 (95% CI: 3.30, 18.99) among miners who were exposed at ≥35 years of age and at annual exposure rates of <0.5 working levels. This association decreased with older attained ages, younger ages at exposure, and higher exposure rates.DiscussionEstimates of association between radon progeny exposure and lung cancer mortality among relatively contemporary miners are coherent with estimates used to inform current protection guidelines. https://doi.org/10.1289/EHP10669.
| S-EPMC9126132 | biostudies-literature
Project description:PURPOSE:Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS:Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS:We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR?=?0.26, 95% CI 0.11-0.60, p?=?0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p?=?1.2?×?10-6), 5q23.2 (p?=?2.5?×?10-6), 1q21.3 (p?=?3.2?×?10-6), 10p13 (p?=?1.3?×?10-5) and 12p12.1 (p?=?7.1?×?10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p?=?0.0139) or the gene family HGNC:476 "microRNAs" (p?=?0.0159) were enriched with LD-blockwise significance. CONCLUSION:The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.
| S-EPMC6375683 | biostudies-literature
Project description:Cohort mortality studies of underground miners have been used to estimate the number of lung cancer deaths attributable to radon exposure. However, previous studies of the radon-lung cancer association among underground miners may have been subject to healthy worker survivor bias, a type of time-varying confounding by employment status. We examined radon-mortality associations in a study of 4,124 male uranium miners from the Colorado Plateau who were followed from 1950 through 2005. We estimated the time ratio (relative change in median survival time) per 100 working level months (radon exposure averaging 130,000 mega-electron volts of potential ? energy per liter of air, per working month) using G-estimation of structural nested models. After controlling for healthy worker survivor bias, the time ratio for lung cancer per 100 working level months was 1.168 (95% confidence interval: 1.152, 1.174). In an unadjusted model, the estimate was 1.102 (95% confidence interval: 1.099, 1.112)-39% lower. Controlling for this bias, we estimated that among 617 lung cancer deaths, 6,071 person-years of life were lost due to occupational radon exposure during follow-up. Our analysis suggests that healthy worker survivor bias in miner cohort studies can be substantial, warranting reexamination of current estimates of radon's estimated impact on lung cancer mortality.
| S-EPMC4506325 | biostudies-literature