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.

Mortality associated with chronic external radiation exposure in the French combined cohort of nuclear workers.

OBJECTIVE: The long-term effects of protracted low level ionising radiation exposure are investigated in a combined analysis of French nuclear workers employed by the Commissariat à l'Energie Atomique (CEA), AREVA Nuclear Cycle (AREVA NC) and Electricité de France (EDF). Associations between cumulative external radiation dose and mortality due to solid cancers, leukaemia and circulatory disease were examined. METHODS: All workers hired by CEA, AREVA NC and EDF between 1950 and 1994 who were employed for at least 1 year, badge-monitored for radiation exposure and alive on 1 January 1968 were included. Individual data of annual exposure to penetrating photons (X-rays and gamma rays) were reconstructed for each worker. Estimates of radiation dose-mortality associations were obtained using a linear excess relative risk (ERR) Poisson regression model. RESULTS: Among the 59 021 nuclear workers, 2312 died of solid cancer, 78 of leukaemia and 1468 of circulatory diseases during the 1968-2004 period. Approximately 72% of the cohort had a non-zero cumulative radiation dose estimate, with a mean cumulative dose of 22.5 mSv. Positive but non-significant ERR/Sv were observed for all solid cancers, leukaemia excluding chronic lymphocytic leukaemia (CLL), ischaemic heart diseases and cerebrovascular diseases. A significant ERR/Sv was found for myeloid leukaemia. CONCLUSIONS: This is the first combined analysis of major French cohorts of nuclear workers. Results were consistent with risks estimated in other nuclear worker cohorts and illustrate the potential of a further joint international study to yield direct risk estimates in support to radiation protection standards.

Discrete time hazards models for occupational and environmental cohort analyses.

OBJECTIVE: To discuss the use of discrete time hazards models for the analysis of occupational and environmental cohort data. METHODS: Analytical data structures and regression methods for discrete time hazards models are described. This approach is illustrated via analyses of data from a study of mortality in a cohort of chemical workers exposed to dioxin. RESULTS AND CONCLUSIONS: Analyses employing a discrete time hazards model facilitate examination of observed and expected counts, the calculation of attributable fractions, and empirical description of the estimated hazard rates. In addition, this approach can be used to fit non-multiplicative models, such as the linear hazards ratio model (which has been employed in epidemiological analyses of a variety of environmental and occupational exposures).

Lung cancer mortality and fibre exposures among North Carolina asbestos textile workers.

OBJECTIVE: To describe mortality among workers exposed to chrysotile asbestos and evaluate the relationship between lung cancer and asbestos fibre exposure. METHODS: Workers employed for at least 1 day between 1 January 1950 and 31 December 1973 in any of four plants in North Carolina, USA that produced asbestos textile products were enumerated. Vital status was ascertained through 31 December 2003. Historical exposures to asbestos fibres were estimated from work histories and 3578 industrial hygiene measurements taken in 1935-1986. Mortality of the cohort was compared with that of the national population via standardised mortality ratios (SMRs). Exposure-response relationships for lung cancer were examined within the cohort using Poisson regression to compute adjusted mortality rate ratios. RESULTS: Follow-up of 5770 workers included in the cohort resulted in 181 640 person-years of observation, with 2583 deaths from all causes and 277 from lung cancer. Mortality from all causes, all cancers and lung cancer was significant higher than expected, with SMRs of 1.47 for all causes, 1.41 for all cancer and 1.96 (95% CI 1.73 to 2.20) for lung cancer. SMRs for pleural cancer, mesothelioma and pneumoconiosis were also elevated. The risk of lung cancer and asbestosis increased with cumulative fibre exposure (RR 1.102 per 100 fibre-year/ml, 95% CI 1.044 to 1.164, and RR 1.249 per 100 fibre-year/ml, 95% CI 1.186 to 1.316, respectively, for total career exposure). CONCLUSIONS: This study provides further evidence that exposure to chrysotile asbestos in textile manufacturing is associated with increased risk of lung cancer, asbestosis cancer of the pleura and mesothelioma.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.

A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Investigating time patterns of variation in radiation cancer associations.

AIMS: In occupational settings, carcinogenic exposures are often repeated or protracted over time. The time pattern of exposure accrual may influence subsequent temporal patterns of cancer risk. The authors present several simple models that may be used to evaluate the influence of time since exposure or age at exposure on cancer incidence or mortality in an occupational cohort. METHODS: A cohort of 40,415 nuclear industry workers was identified via the Canadian National Dose Registry. Vital status and cause of death were ascertained through 1994. Associations between ionising radiation and mortality due to lung cancer, leukaemia, and cancers other than lung and leukaemia were quantified using conditional logistic regression models with risk sets constructed by incidence density sampling. A step function, a bilinear function, and a sigmoid function were used to evaluate temporal variation in exposure effects. RESULTS: Step and sigmoid functions were used to explore latency and morbidity periods. For analyses of lung cancer, leukaemia, and other cancers the best fitting models were obtained when exposure assignment was lagged by 13, 0, and 5 years, respectively. A bilinear function was used to evaluate whether exposure effects diminished with time since exposure. In analyses of lung cancer and leukaemia, there was evidence that radiation effects attenuated with protracted time since exposure. In analyses of age at exposure, there was evidence of variation in radiation mortality associations for analyses of lung cancer and leukaemia; discounting radiation doses accrued at younger ages (for example, 15-35 years) led to significant improvements in model fit. CONCLUSIONS: This paper illustrates empirical approaches to evaluating temporal variation in the effect of a protracted exposure on disease risk.

Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries.

OBJECTIVES: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. DESIGN: Multinational retrospective cohort study of cancer mortality. SETTING: Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. MAIN OUTCOME MEASUREMENTS: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. RESULTS: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. CONCLUSIONS: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

Age at exposure to ionising radiation and cancer mortality among Hanford workers: follow up through 1994.

BACKGROUND: Studies of workers at the plutonium production factory in Hanford, WA have led to conflicting conclusions about the role of age at exposure as a modifier of associations between ionising radiation and cancer. AIMS: To evaluate the influence of age at exposure on radiation risk estimates in an updated follow up of Hanford workers. METHODS: A cohort of 26 389 workers hired between 1944 and 1978 was followed through 1994 to ascertain vital status and causes of death. External radiation dose estimates were derived from personal dosimeters. Poisson regression was used to estimate associations between mortality and cumulative external radiation dose at all ages, and in specific age ranges. RESULTS: A total of 8153 deaths were identified, 2265 of which included cancer as an underlying or contributory cause. Estimates of the excess relative risk per Sievert (ERR/Sv) for cumulative radiation doses at all ages combined were negative for all cause and leukaemia and positive for all cancer and lung cancer. Cumulative doses accrued at ages below 35, 35-44, and 45-54 showed little association with mortality. For cumulative dose accrued at ages 55 and above (10 year lag), the estimated ERR/Sv for all cancers was 3.24 (90% CI: 0.80 to 6.17), primarily due to an association with lung cancer (ERR/Sv: 9.05, 90% CI: 2.96 to 17.92). CONCLUSIONS: Associations between radiation and cancer mortality in this cohort are primarily a function of doses at older ages and deaths from lung cancer. The association of older age radiation exposures and cancer mortality is similar to observations from several other occupational studies.

Poisson regression analysis of ungrouped data.

BACKGROUND: Poisson regression is routinely used for analysis of epidemiological data from studies of large occupational cohorts. It is typically implemented as a grouped method of data analysis in which all exposure and covariate information is categorised and person-time and events are tabulated. AIMS: To describe an alternative approach to Poisson regression analysis using single units of person-time without grouping. METHODS: Data for simulated and empirical cohorts were analysed by Poisson regression. In analyses of simulated data, effect estimates derived via Poisson regression without grouping were compared to those obtained under proportional hazards regression. Analyses of empirical data for a cohort of 138 900 electrical workers were used to illustrate how the ungrouped approach may be applied in analyses of actual occupational cohorts. RESULTS: Using simulated data, Poisson regression analyses of ungrouped person-time data yield results equivalent to those obtained via proportional hazards regression: the results of both methods gave unbiased estimates of the "true" association specified for the simulation. Analyses of empirical data confirm that grouped and ungrouped analyses provide identical results when the same models are specified. However, bias may arise when exposure-response trends are estimated via Poisson regression analyses in which exposure scores, such as category means or midpoints, are assigned to grouped data. CONCLUSIONS: Poisson regression analysis of ungrouped person-time data is a useful tool that can avoid bias associated with categorising exposure data and assigning exposure scores, and facilitate direct assessment of the consequences of exposure categorisation and score assignment on regression results.

Cancer risk from low-level ionizing radiation: the role of age at exposure.

This article examines methodological issues related to epidemiologic investigations of the influence of age at exposure on radiation risk estimates; the epidemiologic literature on the role of age at exposure in radiation-cancer associations; and biological mechanisms that may account for associations observed in these studies. There is substantial evidence that young children, and especially the fetus, are highly vulnerable to ionizing radiation. Investigations also suggest that sensitivity may increase at the oldest ages of exposure. Further attention to modifying factors in radiation-cancer associations, such as age at exposure, may help to protect workers and the public by improving our understanding of sensitivity variation within populations.

Radiation and mortality of workers at Oak Ridge National Laboratory: positive associations for doses received at older ages.

We examined associations between low-level exposure to ionizing radiation and mortality among 14,095 workers hired at the Oak Ridge National Laboratory between 1943 and 1972. Workers at the facility were individually monitored for external exposure to ionizing radiation and have been followed through 1990 to ascertain cause of death information. Positive associations were observed between low-level exposure to external ionizing radiation and mortality. These associations were larger for doses received after 45 years of age, larger under longer lag assumptions, and primarily due to cancer causes of death. All cancer mortality was estimated to increase 4.98% [standard error (SE) = 1.5] per 10-mSv cumulative dose received after age 45 under a 10-year lag, and 7.31% (SE = 2.2) per 10-mSv cumulative dose received after age 45 under a 20-year lag. Associations between radiation dose and lung cancer were of similar magnitude to associations between radiation dose and all cancers except lung cancer. Nonmalignant respiratory disease exhibited a positive association with cumulative radiation dose received after age 45, whereas ischemic heart disease exhibited no association with radiation dose. These findings suggest increases in cancer mortality associated with low-level external exposure to ionizing radiation and potentially greater sensitivity to the carcinogenic effects of ionizing radiation with older ages at exposure.

Greater sensitivity to ionizing radiation at older age: follow-up of workers at Oak Ridge National Laboratory through 1990.

BACKGROUND: Workers at Oak Ridge National Laboratory (ORNL) were individually monitored for whole body exposure to ionizing radiation. Studies of these workers may provide valuable information about the long-term effects of occupational exposure to ionizing radiation. Since biological changes occur as adults age, a potentially important question in these investigations is whether sensitivity to the carcinogenic effects of ionizing radiation changes with age at exposure. METHODS: Vital status and cause of death were ascertained through 1990 for 8307 white males hired at ORNL from 1943 through 1972. Associations between whole body ionizing radiation dose and all-cancer mortality were quantified using life table regression methods for time dependent exposures. Analyses focused of differences in radiation-cancer associations with age at exposure. Length of follow-up, period of hire, and age at risk were considered as alternative explanations for effects of age at exposure. RESULTS: Cumulative radiation dose was associated with a 1.8% (SE = 0.9) increase in all-cancer mortality per 10 mSv, assuming a 10-year lag between exposure and mortality. However, radiation doses received at older ages exhibited larger associations with cancer mortality than doses received at younger ages. Doses received after age 45 were associated with a 5.9% (SE = 1.7) increase in cancer mortality per 10 mSv, adjusted for doses received before age 45. Dose-response associations between cancer mortality and doses received after age 45 appeared consistent across periods of follow-up, periods of hire, and ages at risk. CONCLUSIONS: Findings suggest that sensitivity to the carcinogenic effects of ionizing radiation may increase with older ages at exposure. More attention should be given to the role of age at exposure in studies of the health effects of low-level exposure to ionizing radiation, and to efforts to limit exposure to ionizing radiation.

Respiratory effects of chronic hydrogen sulfide exposure.

A cross-sectional study investigated whether the exposure of sewer workers to hydrogen sulfide (H2S) was associated with reduced lung function. Sixty-eight sewer workers and 60 water treatment workers performed spirometric tests. Job titles were used to classify the sewer workers according to presumed H2S exposure, and water treatment workers served as a comparison population presumed to have no occupational exposure to H2S. There was a statistically significant difference in mean FEV1/FVC values between sewer and water treatment workers of similar age, height, race, and smoking habits (-3.1, s.e. = 1.4). This deficit was greatest (-5.7, s.e. = 2.0) for sewer workers presumed to have high H2S exposure. Nonsmoking sewer workers presumed to have high H2S exposure achieved only 89% of their predicted FEV1/FVC value, whereas nonsmoking water treatment workers achieved nearly 98% of their predicted FEV1/FVC value. In conclusion, this study found evidence that chronic low level exposure to H2S may be associated with reduced lung function.