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.

Mortality among uranium miners in North America and Europe: the Pooled Uranium Miners Analysis (PUMA).

BACKGROUND: The Pooled Uranium Miners Analysis (PUMA) study draws together information from cohorts of uranium miners from Canada, the Czech Republic, France, Germany and the USA. METHODS: Vital status and cause of death were ascertained and compared with expectations based upon national mortality rates by computing standardized mortality ratios (SMRs) overall and by categories of time since first hire, calendar period of first employment and duration of employment as a miner. RESULTS: There were 51 787 deaths observed among 118 329 male miners [SMR = 1.05; 95% confidence interval (CI): 1.04, 1.06]. The SMR was elevated for all cancers (n = 16 633, SMR = 1.23; 95% CI: 1.21, 1.25), due primarily to excess mortality from cancers of the lung (n = 7756, SMR = 1.90; 95% CI: 1.86, 1.94), liver and gallbladder (n = 549, SMR = 1.15; 95% CI: 1.06, 1.25), larynx (n = 229, SMR = 1.10; 95% CI: 0.97, 1.26), stomach (n = 1058, SMR = 1.08; 95% CI: 1.02, 1.15) and pleura (n = 39, SMR = 1.06; 95% CI: 0.75, 1.44). Lung-cancer SMRs increased with duration of employment, decreased with calendar period and persisted with time since first hire. Among non-malignant causes, the SMR was elevated for external causes (n = 3362, SMR = 1.41; 95% CI: 1.36, 1.46) and respiratory diseases (n = 4508, SMR = 1.32; 95% CI: 1.28, 1.36), most notably silicosis (n = 814, SMR = 13.56; 95% CI: 12.64, 14.52), but not chronic obstructive pulmonary disease (n = 1729, SMR = 0.98; 95% CI: 0.93, 1.02). CONCLUSIONS: Whereas there are important obstacles to the ability to detect adverse effects of occupational exposures via SMR analyses, PUMA provides evidence of excess mortality among uranium miners due to a range of categories of cause of death. The persistent elevation of SMRs with time since first hire as a uranium miner underscores the importance of long-term follow-up of these workers.

Risk of Bias Assessments and Evidence Syntheses for Observational Epidemiologic Studies of Environmental and Occupational Exposures: Strengths and Limitations.

BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis. https://doi.org/10.1289/EHP6980.

Dose Estimation for a Study of Nuclear Workers in France, the United Kingdom and the United States of America: Methods for the International Nuclear Workers Study (INWORKS).

In the framework of the International Nuclear Workers Study conducted in France, the UK and the U.S. (INWORKS), updated and expanded methods were developed to convert recorded doses of ionizing radiation to estimates of organ doses or individual personal dose equivalent [H(p)(10)] for a total number of 308,297 workers, including 40,035 women. This approach accounts for differences in dosimeter response to predominant workplace energy and geometry of exposure and for the recently published ICRP report on dose coefficients for men and women separately. The overall mean annual individual personal dose equivalent, including zero doses, is 1.73 mSv [median = 0.42; interquartile range (IQR): 0.07, 1.59]. Associated individual organ doses were estimated. INWORKS includes workers who had potential for exposure to neutrons. Therefore, we analyzed neutron dosimetry data to identify workers potentially exposed to neutrons. We created a time-varying indicator for each worker, classifying them according to whether they had a positive recorded neutron dose and if so, whether their neutron dose ever exceeded 10% of their total external penetrating radiation dose. The number of workers flagged as being exposed to neutrons was 13% for the full cohort, with 15% of the cohort in France, 12% of the cohort in the UK and 14% in the U.S. We also used available information on in vivo and bioassay monitoring to identify workers with known depositions or suspected internal contaminations. As a result of this work, information is now available that will allow various types of sensitivity analyses.

A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation.

CONTEXT: More than 400,000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure. OBJECTIVE: We conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia. DATA SOURCES: Reviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009. STUDY SELECTION: We selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case-control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure-response analyses using relative or excess RR per unit exposure. METHODS: Studies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods. RESULTS: We found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99). CONCLUSIONS: Protracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of protracted radiation exposures.

Adjustment for temporal confounders in a reanalysis of a case-control study of beryllium and lung cancer.

OBJECTIVES: To evaluate potential confounding of the association between beryllium and lung cancer in a reanalysis of data from a published case-control study of workers at a beryllium processing facility. METHODS: The association of cumulative and average beryllium exposure with lung cancer among 142 cases and five age-match controls per case was reanalysed using conditional logistic regression. Adjustment was made independently for potential confounders of hire age and birth year. Alternative adjustments to avoid taking the logarithm of zero were explored. RESULTS: Adjustment for either birth cohort or hire age (two highly correlated factors) attenuated lung cancer risk associated with cumulative exposure; however, lung cancer risk was significantly associated with average exposure using a 10-year lag following adjustment. Stratification of analyses by birth cohort found greater lung cancer risk from cumulative and average exposure for workers born before 1900 than for workers born later. The magnitude of the association between lung cancer and average exposure was not reduced by modifying the method used to take the log of exposure. CONCLUSION: In this reanalysis, average, but not cumulative, beryllium exposure was related to lung cancer risk after adjustment for birth cohort. Confounding by birth cohort is likely related to differences in smoking patterns for workers born before 1900 and the tendency for workers hired during the World War II era to have been older at hire.

Assessment of plutonium exposures for an epidemiological study of US nuclear workers.

An ongoing case-control study evaluating the association between workplace external radiation exposures and leukaemia mortality required an assessment of internal plutonium exposures as a potential confounder. Of the study participants, 1,092 were employed at four Department of Energy sites where plutonium-bearing materials were processed or stored. Exposures were assessed by first categorising exposure potentials based on available bioassay data, then estimating doses for workers in the highest categories using recent recommendations of the International Commission on Radiological Protection. Given the aetiology of leukaemia, equivalent dose to active bone marrow was chosen as the exposure variable. There were 556 workers each with at least one plutonium bioassay result, assigned to one of three evaluation categories. Dose estimates were made for 115 workers resulting in a collective equivalent dose of 2.1 person-Sv for 2,822 exposure-years, compared with 29.8 person-Sv estimated from photon exposures. Modelling uncertainties were examined by comparison of results from independent analyses and by Monte Carlo simulation.

Bias and uncertainty of penetrating photon dose measured by film dosemeters in an epidemiological study of US nuclear workers.

A retrospective exposure assessment of 1269 study subjects was completed for use in a multi-site case-control study of the relationship between protracted workplace external radiation exposure and leukaemia mortality. The majority of exposure data result from film badge monitoring programmes at the four US weapons production facilities and a US Naval shipyard. Bias and uncertainty in reported exposures among study facilities and across time were as result of differences in incident photon energy, exposure geometry, dosemeter type and dosimetry methods. These sources of measurement uncertainty were examined by facility and time to derive bias factors (B) for normalising exposures. In conjunction with facility reported results, the bias factors provide a means to estimate the equivalent dose, penetrating to a depth of 10 mm [H(p)(10)] and the equivalent dose to the active bone marrow for use in the epidemiological study. Uncertainty was expressed as the constructed 95% confidence interval (i.e. the 2.5th-97.5th% range) of the estimated parameter. The bias factors indicate that recorded exposures provide a reasonable estimate of H(p)(10) (bias factor near unity) and overestimate equivalent dose to active bone marrow (H(T)) by a factor between 1.2 and 1.7. On average, dosemeter-response uncertainties estimated using Monte Carlo simulation were approximately +/-19 and +/-33% for H(p)(10) and H(T), respectively.

Breast dose variability in a bi-racial population undergoing screening mammography.

This study evaluated individual and population dose variability during screening mammography, among 570 white and black women in South Carolina, USA. Aspects of dosimetry that were considered include compressed breast thickness (CBT), number of films per screening session, and dose in previous or subsequent sessions. Breast dose was log-normally distributed in the population, with a geometric mean of 6.6 mGy per session. Doses were significantly higher for black women, for women with high CBT or who receive more than two views per breast, and for the mediolateral oblique, compared to the craniocaudal, view. No relationship was observed between age and dose. Total dose per breast varied by a factor of 20 across the study population, but the individual's dose varied little among repeat screening sessions, especially after adjusting for the number of films received per session. These results may inform assessments of the projected risks of inducing breast cancer from screening mammography.

Mammography dose in relation to body mass index, race, and menopausal status.

Mammography dose increases with compressed breast thickness (CBT), but few studies have examined other correlates of dose. The purpose of this study was to evaluate the relation between factors such as race, age, body mass index (BMI), CBT, and menopausal status and mammography screening dose, measured for 509 women in a US population. A multiple linear regression model was developed for dose, based on consideration of these factors as well as examination characteristics. BMI and number of films during examination were positively related to dose. After adjusting for these factors, high CBT also leads to higher dose. Whites receive lower doses than black women but differences are slight after controlling for the effects of CBT and BMI, which were significantly higher among black women. Pre-menopausal women receive higher doses, after adjusting for all other factors, than post-menopausal women. Jointly, these factors account for approximately 75% to 80% of the variability in dose among this study population. Because rates of overweight are increasing in the US, average doses from mammography may be increasing as well.

Leukemia mortality among radiation-exposed workers.

The qualitative leukemogenicity of ionizing radiation was firmly established by studies of medical workers and patients exposed to high radiation levels in the mid-1900s. Quantitative relationships were evaluated through extensive studies of atomic bomb survivors and patients who received therapeutic radiation, for whom the duration of exposure was brief. Although many studies have been conducted of nuclear workers and others exposed occupationally, uncertainty remains about quantitative aspects of the leukemia-radiation exposure relation for low dose-rate, fractionated exposures. Some studies have shown dose-related increases in leukemia risks for certain nuclear workers in the U.S. and Europe, although these findings are inconsistent across populations. Despite limitations in low-dose epidemiology, well-designed studies among nuclear workers should inform some controversial aspects of the relation between ionizing radiation exposure and leukemia risk.