Cancer mortality after low dose exposure to ionising radiation in workers in France, the United Kingdom, and the United States (INWORKS): cohort study.

OBJECTIVE: To evaluate the effect of protracted low dose, low dose rate exposure to ionising radiation on the risk of cancer. DESIGN: Multinational cohort study. SETTING: Cohorts of workers in the nuclear industry in France, the UK, and the US included in a major update to the International Nuclear Workers Study (INWORKS). PARTICIPANTS: 309 932 workers with individual monitoring data for external exposure to ionising radiation and a total follow-up of 10.7 million person years. MAIN OUTCOME MEASURES: Estimates of excess relative rate per gray (Gy) of radiation dose for mortality from cancer. RESULTS: The study included 103 553 deaths, of which 28 089 were due to solid cancers. The estimated rate of mortality due to solid cancer increased with cumulative dose by 52% (90% confidence interval 27% to 77%) per Gy, lagged by 10 years. Restricting the analysis to the low cumulative dose range (0-100 mGy) approximately doubled the estimate of association (and increased the width of its confidence interval), as did restricting the analysis to workers hired in the more recent years of operations when estimates of occupational external penetrating radiation dose were recorded more accurately. Exclusion of deaths from lung cancer and pleural cancer had a modest effect on the estimated magnitude of association, providing indirect evidence that the association was not substantially confounded by smoking or occupational exposure to asbestos. CONCLUSIONS: This major update to INWORKS provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality based on some of the world's most informative cohorts of radiation workers. The summary estimate of excess relative rate solid cancer mortality per Gy is larger than estimates currently informing radiation protection, and some evidence suggests a steeper slope for the dose-response association in the low dose range than over the full dose range. These results can help to strengthen radiation protection, especially for low dose exposures that are of primary interest in contemporary medical, occupational, and environmental settings.

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.

Ionizing radiation and solid cancer mortality among US nuclear facility workers.

BACKGROUND: The risk of solid cancers from low-level protracted ionizing radiation is not well characterized. Nuclear workers provide valuable information on the effects of ionizing radiation in contemporary exposure scenarios relevant to workers and the public. METHODS: We evaluated the association between penetrating ionizing radiation exposure and solid cancer mortality among a pooled cohort of nuclear workers in the USA, with extended follow-up to examine cancers with long latencies. This analysis includes 101 363 workers from five nuclear facilities, with 12 069 solid cancer deaths between 1944 and 2016. The association between cumulative equivalent dose measured in sieverts (Sv) and solid cancer subtypes were modelled as the excess relative rate per Sv (ERR Sv-1) using Cox regression. RESULTS: For the association between ionizing radiation exposure and all solid cancer mortality we observed an elevated rate (ERR Sv-1=0.19; 95% CI: -0.10, 0.52), which was higher among a contemporary sub-cohort of workers first hired in 1960 or later (ERR Sv-1= 2.23; 95% CI: 1.13, 3.49). Similarly, we observed an elevated rate for lung cancer mortality (ERR Sv-1= 0.65; 95% CI: 0.09, 1.30) that was higher among contemporary hires (ERR Sv-1= 2.90; 95% CI: 1.00, 5.26). CONCLUSIONS: Although concerns remain about confounding, measurement error and precision, this analysis strengthens the evidence base indicating there are radiogenic risks for several solid cancer types.

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.

Lung Cancer and Radon: Pooled Analysis of Uranium Miners Hired in 1960 or Later.

BACKGROUND: Despite 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. OBJECTIVES: To 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. METHODS: We 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. RESULTS: The 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. DISCUSSION: Estimates 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.

Lung and extrathoracic cancer incidence among underground uranium miners exposed to radon progeny in the Príbram region of the Czech Republic: a case-cohort study.

OBJECTIVES: Radon is carcinogenic, but more studies are needed to understand relationships with lung cancer and extrathoracic cancers at low exposures. There are few studies evaluating associations with cancer incidence or assessing the modifying effects of smoking. METHODS: We conducted a case-cohort study with 16 434 underground uranium miners in the Czech Republic with cancer incidence follow-up 1977-1996. Associations between radon exposure and lung cancer, and extrathoracic cancer, were estimated with linear excess relative rate (ERR) models. We examined potential modifying effects of smoking, time since exposure and exposure rate. RESULTS: Under a simple ERR model, assuming a 5-year exposure lag, the estimated ERR of lung cancer per 100 working level months (WLM) was 0.54 (95% CI 0.33 to 0.83) and the estimated ERR of extrathoracic cancer per 100 WLM was 0.07 (95% CI -0.17 to 0.72). Most lung cancer cases were observed among smokers (82%), and the estimated ERR of lung cancer per 100 WLM was larger among smokers (ERR/100 WLM=1.35; 95% CI 0.84 to 2.15) than among never smokers (ERR/100 WLM=0.12; 95% CI -0.05 to 0.49). Among smokers, the estimated ERR of lung cancer per 100 WLM decreased with time since exposure from 3.07 (95% CI -0.04 to 10.32) in the period 5-14 years after exposure to 1.05 (95% CI 0.49 to 1.87) in the period 25+ years after exposure. CONCLUSIONS: We observed positive associations between cumulative radon exposure and lung cancer, consistent with prior studies. We observed a positive association between cumulative radon exposure and extrathoracic cancers, although the estimates were small. There was evidence that the association between radon and lung cancer was modified by smoking in a multiplicative or super-multiplicative fashion.

Ischaemic heart and cerebrovascular disease mortality in uranium enrichment workers.

OBJECTIVE: Linear and non-linear dose-response relationships between radiation absorbed dose to the lung from internally deposited uranium and external sources and circulatory system disease (CSD) mortality were examined in a cohort of 23 731 male and 5552 female US uranium enrichment workers. METHODS: Rate ratios (RRs) for categories of lung dose and linear excess relative rates (ERRs) per unit lung dose were estimated to evaluate the associations between lung absorbed dose and death from ischaemic heart disease (IHD) and cerebrovascular disease. RESULTS: There was a suggestion of modestly increased IHD risk in workers with internal uranium lung dose above 1 milligray (mGy) (RR=1.4, 95% CI 0.76 to 2.3) and a statistically significantly increased IHD risk with external dose exceeding 150 mGy (RR=1.3, 95% CI 1.1 to 1.6) compared with the lowest exposed groups. ERRs per milligray were positive for IHD and uranium internal dose and for both outcomes per gray external dose, although the CIs generally included the null. CONCLUSIONS: Non-linear dose-response models using restricted cubic splines revealed sublinear responses at lower internal doses, suggesting that linear models that are common in radioepidemiological cancer studies may poorly describe the association between uranium internal dose and CSD mortality.

PUMA - pooled uranium miners analysis: cohort profile.

OBJECTIVES: Epidemiological studies of underground miners have provided clear evidence that inhalation of radon decay products causes lung cancer. Moreover, these studies have served as a quantitative basis for estimation of radon-associated excess lung cancer risk. However, questions remain regarding the effects of exposure to the low levels of radon decay products typically encountered in contemporary occupational and environmental settings on the risk of lung cancer and other diseases, and on the modifiers of these associations. These issues are of central importance for estimation of risks associated with residential and occupational radon exposures. METHODS: The Pooled Uranium Miner Analysis (PUMA) assembles information on cohorts of uranium miners in North America and Europe. Data available include individual annual estimates of exposure to radon decay products, demographic and employment history information on each worker and information on vital status, date of death and cause of death. Some, but not all, cohorts also have individual information on cigarette smoking, external gamma radiation exposure and non-radiological occupational exposures. RESULTS: The PUMA study represents the largest study of uranium miners conducted to date, encompassing 124 507 miners, 4.51 million person-years at risk and 54 462 deaths, including 7825 deaths due to lung cancer. Planned research topics include analyses of associations between radon exposure and mortality due to lung cancer, cancers other than lung, non-malignant disease, modifiers of these associations and characterisation of overall relative mortality excesses and lifetime risks. CONCLUSION: PUMA provides opportunities to evaluate new research questions and to conduct analyses to assess potential health risks associated with uranium mining that have greater statistical power than can be achieved with any single cohort.

Radon and cancer mortality among underground uranium miners in the Príbram region of the Czech Republic.

BACKGROUND: This study aims to estimate the association between radon and site-specific cancer mortality among a large contemporary cohort of male uranium miners. METHODS: Annual occupational radon exposure was estimated based on a worker's duration of underground mining in a year and estimates of potential alpha energy of radon progeny in their location of work. Cancer mortality over the period 1977-1992 was ascertained for a cohort of 16 434 male underground uranium miners employed in the Czech Republic between 1946 and 1992. Poisson regression was used to estimate relationships between cumulative radiation exposure (in working level months [WLM]) and site-specific cancer mortality. RESULTS: Radon is positively associated with lung cancer mortality (excess relative rate [ERR] per 100 WLM = 0.2; 95% confidence interval [CI]: 0.10, 0.37). The best fit of the dose-response relationship between radon and lung cancer mortality was linear and estimates of radon-lung cancer associations varied by windows of time-since-exposure. Positive associations between radon and several types of cancer other than lung cancer were identified, notably chronic lymphocytic leukemia (CLL) (ERR/100 WLM = 0.24; 95% CI: [not determined [ND], 5.10]) and extrathoracic cancer (ERR/100 WLM = 0.12; 95% CI: [ND, 0.69]). We observed no associations between radon and stomach cancer, nor between radon and several hematopoietic cancer subtypes. CONCLUSIONS: This study confirms the established radon-lung cancer association and suggests that radon may also be associated with other types of cancer mortality. Further investigations of extrathoracic and CLL cancer, with the aim of obtaining more precise estimates, are warranted to understand associations between radon and cancers other than lung.

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.

Employment characteristics and cause-specific mortality at automotive electronics manufacturing plants in Huntsville, Alabama.

BACKGROUND: This study was carried out in response to worker concerns over their exposure to lead solder and chlorinated solvents at automotive electronics manufacturing plants in Huntsville, Alabama. METHODS: A study of 4396 United Autoworkers members ever-employed at the plants between 1972 and 1993 was conducted with mortality follow-up through 2016. Poisson regression was used to estimate mortality rate ratios (RR) according to employment characteristics, including calendar period of employment. RESULTS: Pre-1977 hires exhibited elevated adjusted rates of all-cause (RR, 1.29; 95% confidence interval [CI], 1.09-1.52), cardiovascular (RR, 1.38; 95% CI, 1.03-1.86), and digestive system (RR, 2.31; 95% CI, 1.04-5.10) disease mortality relative to the most recent hire group (1984-1993). Never- versus ever-employment in a skilled trade job was associated with elevated adjusted rates of all-cause, all-cancer, and cardiovascular disease mortality. Nervous system disorder mortality was greatest among 1977-1983 hires. CONCLUSIONS: Elevated mortality among pre-1977 hires is consistent with worker concerns over greater exposure to hazards at the original plant building.

Cancer incidence surrounding the former Apollo nuclear facility 1990-2010.

Environmental radiation releases from a nuclear fuel fabrication facility in Apollo, Pennsylvania may have exposed the surrounding population to ionizing radiation. This study characterizes cancer incidence in the population living near the nuclear facility between 1990 and 2010. Cancer incidence in the minor civil divisions surrounding the Apollo facility was compared to a standard population of the state of Pennsylvania adjusted for calendar year, age, sex, and race. Bias due to residential misclassification was considered by adjustment of case count. We also evaluated whether birth cohort effects or changes in population distribution over time affected the standardized incidence rate ratio (SIR). From 1990 to 2010, the observed rate of cancer incidence among males in the Apollo area was 1.56 (95% CI 1.47-1.66) times the expected cancer rate, and among females was 1.38 (95% CI 1.30-1.47) times the expected cancer rate. Accounting for residential misclassification, the SIR for males and females combined was 1.16 (95% CI 1.10-1.21). Residents who were members of earlier birth cohorts had similar SIRs to those born later. This research suggests that cancer incidence among the population surrounding the former Apollo nuclear facility is greater than expected based on statewide rates.

General Relative Rate Models for the Analysis of Studies Using Case-Cohort Designs.

A standard approach to analysis of case-cohort data involves fitting log-linear models. In this paper, we describe how standard statistical software can be used to fit a broad class of general relative rate models to case-cohort data and derive confidence intervals. We focus on a case-cohort design in which a roster has been assembled and events ascertained but additional information needs to be collected on explanatory variables. The additional information is ascertained just for persons who experience the event of interest and for a sample of the cohort members enumerated at study entry. One appeal of such a case-cohort design is that this sample of the cohort may be used to support analyses of several outcomes. The ability to fit general relative rate models to case-cohort data may allow an investigator to reduce model misspecification in exposure-response analyses, fit models in which some factors have effects that are additive and others multiplicative, and facilitate estimation of relative excess risk due to interaction. We address model fitting for simple random sampling study designs as well as stratified designs. Data on lung cancer among radon-exposed men (Colorado Plateau uranium miners, 1950-1990) are used to illustrate these methods.

Mortality among autoworkers manufacturing electronics in Huntsville, Alabama.

BACKGROUND: Workers raised concerns over suspected excesses of mortality at automotive electronics manufacturing facilities in Huntsville, Alabama. METHODS: A study of 4396 UAW members ever-employed at Huntsville facilities between 1972 and 1993 was conducted with mortality follow-up through 2016. Standardized Mortality Ratios (SMRs) were estimated using U.S. and Alabama reference rates. RESULTS: Relative to U.S. rates, there was a modest excess of all-cause mortality among White female workers (SMR 1.08, 95%CI: 0.99-1.18) and among all workers hired <1977 at the original plant building (SMR 1.10, 95%CI: 0.99-1.22). There was excess nervous system disorder (SMR 1.24, 95%CI: 0.91-1.65) and brain and nervous system cancer (SMR 1.31, 95%CI: 0.67-2.28) mortality. Estimates for several causes of interest were imprecise. CONCLUSIONS: All-cause mortality estimates were greater than anticipated based on results from other UAW cohorts. The excess of nervous system disease mortality is consistent with other studies of electronics workers exposed to lead-solder and chlorinated solvents.

Understanding asthma-chronic obstructive pulmonary disease overlap syndrome.

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely-defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition. This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%-61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking. Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment.