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.

Effect of age at exposure in 11 underground miners studies.

Eleven underground miners studies evaluated the risk of lung cancer from exposure in underground mines. Nearly 68,000 miners were included in the joint study, contributing to nearly 2700 lung cancers. The resulting model of the Biological Effects of Ionizing Radiation (BEIR) VI Committee considered linear exposure response relationship, which was modified by time since exposure (TE), attained age and exposure rate. The effect of age at exposure (AE) was not explicitly evaluated. The presentation aims to show that the modifying effect of AE is substantial if time-since-exposure modification is simultaneously used in the model. When the excess relative risk per unit exposure (ERR/WLM) is adjusted for TE, the ERR/WLM corresponding to AE<15 is 0.013 and in subsequent categories decreased gradually up to the AE of 40 and more years, which was only 0.004. In comparison with the BEIR VI model, the present model predicts higher risks at younger ages and the risk decreases more rapidly.

Reassessment of individual dosimetry of long-lived alpha radionuclides of uranium miners through experimental determination of urinary excretion of uranium.

Urinary excretion of uranium of 40 uranium miners was determined by the high-resolution inductively coupled mass spectrometry method. The concentration of uranium in the urine of the miners was converted to daily excretion of (238)U either under the assumption that the daily urinary excretion is 1.6 l or daily urinary excretion of creatinine is 1.7 g and compared with the excretion of (238)U calculated with a biokinetic model. Input data to the excretion model were derived from personal three- component ALGADE dosemeters, using the component for the estimation of inhalation of long-lived alpha radionuclides. Experimentally found contents of uranium in the urine of uranium miners are generally lower than the modelled ones, which means that the dosimetric approach is conservative. The uncertainty of inhalation intakes, derived from the measurements of filters from personal dosemeters, and the uncertainty of the concentration of uranium in the urine are discussed.

Lung cancer mortality in the European uranium miners cohorts analyzed with a biologically based model taking into account radon measurement error.

The biologically based two-stage clonal expansion (TSCE) model is used to analyze lung cancer mortality of European miners from the Czech Republic, France, and Germany. All three cohorts indicate a highly significant action of exposure to radon and its progeny on promotion. The action on initiation is not significant in the French cohort. An action on transformation was tested but not found significant. In a pooled analysis, the results based on the French and German datasets do not differ significantly in any of the used parameters. For the Czech dataset, only lag time and two parameters that determine the clonal expansion without exposure and with low exposure rates (promotion) are consistent with the other studies. For low exposure rates, the resulting relative risks are quite similar. Exposure estimates for each calendar year are used. A model for random errors in each of these yearly exposures is presented. Depending on the used technique of exposure estimate, Berkson and classical errors are used. The consequences for the model parameters are calculated and found to be mostly of minor importance, except that the large difference in the exposure-induced initiation between the studies is decreased substantially.

Dosimetric calculations for uranium miners for epidemiological studies.

Epidemiological studies on uranium miners are being carried out to quantify the risk of cancer based on organ dose calculations. Mathematical models have been applied to calculate the annual absorbed doses to regions of the lung, red bone marrow, liver, kidney and stomach for each individual miner arising from exposure to radon gas, radon progeny and long-lived radionuclides (LLR) present in the uranium ore dust and to external gamma radiation. The methodology and dosimetric models used to calculate these organ doses are described and the resulting doses for unit exposure to each source (radon gas, radon progeny and LLR) are presented. The results of dosimetric calculations for a typical German miner are also given. For this miner, the absorbed dose to the central regions of the lung is dominated by the dose arising from exposure to radon progeny, whereas the absorbed dose to the red bone marrow is dominated by the external gamma dose. The uncertainties in the absorbed dose to regions of the lung arising from unit exposure to radon progeny are also discussed. These dose estimates are being used in epidemiological studies of cancer in uranium miners.

A review of exposures to radon, long-lived radionuclides and external gamma at the Czech uranium mine.

This paper presents the results of the personal exposure monitoring conducted in the RoZná uranium mine in the Czech Republic. In this mine, which has been operated since the late 1950s, personal ALGADE dosemeters have been used since 1998. A group of 600 miners employed during the period 2000-09 has been analysed. Annual exposures to radon decay products, long-lived alpha emitters and external gamma radiation are described. These components play an essential role in the estimation of the total effective dose. The dependence of the exposures on the type of mining job is also assessed.

Interaction of radon and smoking among Czech uranium miners.

The study is based on a case-control study nested within a cohort study (11 000 miners and 1074 lung cancers). The controls were individually matched by year of birth and attained age. Smoking data were collected in person or from relatives of deceased subjects or from medical files. The study resulted in 850 cases of lung cancer with smoking data. The linear dependence of lung cancer relative risk (RR) on radon exposure adjusted for smoking was not substantially different from analyses when smoking was ignored and reflected mainly the risk among smokers. However, the excess RR per unit exposure among never smokers (70 cases) was substantially higher in comparison with that in smokers, reflecting differences in lung morphometry and clearance. The RRs from combined effects are substantially lower than the risk derived from the multiplicative model, but somewhat higher than those from the additive model. The work was supported by the Czech Ministry of Health (IGA NS 10596).

Content of uranium in urine of uranium miners as a tool for estimation of intakes of long-lived alpha radionuclides.

Uranium in the urine of 10 uranium miners (hewers), 27 members of general population and 11 family members of miners was determined by the High-Resolution ICP-MS method. Concentration of uranium in urine of the miners was converted to daily excretion of (238)U under the assumption that the daily excretion of urine is 2 l and compared with the modelled excretion of (238)U. Daily excretion of (238)U was modelled using input data from personal dosemeters from a component for measurement of intake of long-lived alpha radionuclides. A reasonable agreement between evaluated and measured values was found. The uncertainty of inhalation intakes, derived from measurements of filters from personal dosemeters, and uncertainty of concentration of uranium in urine are discussed.

Dosimetric models used in the Alpha-Risk project to quantify exposure of uranium miners to radon gas and its progeny.

The European project Alpha-Risk aims to quantify the cancer and non-cancer risks associated with multiple chronic radiation exposures by epidemiological studies, organ dose calculation and risk assessment. In the framework of this project, mathematical models have been applied to the organ dosimetry of uranium miners who are internally exposed to radon and its progeny as well as to long-lived radionuclides present in the uranium ore. This paper describes the methodology and the dosimetric models used to calculate the absorbed doses to specific organs arising from exposure to radon and its progeny in the uranium mines. The results of dose calculations are also presented.

A case-control study of lifestyle and lung cancer associations by histological types.

The objective of the study was to investigate the contribution of dietary factors and physical exercise to the variation in the risk of lung cancer and its major histological types among men and women in the Czech Republic, and reveal interactions between smoking and diet/physical exercise, if any. In a hospital based case-control study, data collected by in-person interviews from 1096 microscopically confirmed lung cancer cases (587 women, 509 men) and 2966 controls were analyzed using unconditional logistic regression stratified by appropriate factors. Among all nonsmoking women protective effects were observed for black tea (OR=0.69), among all smoking women for wine (OR=0.71), physical exercise (OR=0.64) and vitamin supplements (OR=0.71). Among all men, inverse associations were found in smokers between lung cancer risk and frequent intake of fruits (OR=0.69) or moderate intake of spirits (OR=0.64), and a direct association for fat foods (OR=1.68). Comparing the effects of diet/physical activity on lung cancer risk among nonsmokers versus smokers, interactions with smoking appeared for the intake of black tea and milk/dairy products among women, and for moderate intake of spirits in men. When the effects of diet/physical exercise on risk were analyzed by major cell types in women, the intake of wine and physical exercise were inversely associated with the risk of both adenocarcinoma and small cell cancer, the intakes of fruits and vitamin supplements were inversely associated with the risk of squamous cell cancer. In men, the intake of fat foods was directly associated with the risk of squamous cell cancer, while the frequent intake of apples was inversely associated with the risk of both squamous- and small cell cancers. In men an inverse association with the risk of squamous cell cancer was found for the intake of other fruits. These data suggest that diet/physical exercise may affect the risk of lung cancer and major cell types, and that interactions between some dietary items and smoking may occur. Lung cancer is a multifactorial disease, since smoking, its main determinant, and other environmental and lifestyle factors interact with one another and with genetic factors to cause the disease.

Interactions between smoking and other exposures associated with lung cancer risk in women: diet and physical activity.

UNLABELLED: The objective of the study is to estimate the differences in the impact of diet and physical exercise on lung cancer risk in female nonsmokers vs. smokers, and reveal interactions, if any. In a hospital based case-control study, data collected by in-person interviews from 569 female lung cancer cases and 2120 controls were analyzed using unconditional logistic regression stratifying by appropriate factors. Protective effects were observed for intake of milk/dairy products (OR=0.57, 95%CI 0.35-0.94), vegetables (OR=0.60, 95%CI 0.40-0.91), apples (OR=0.69), wine (OR=0.77), and physical exercise (OR=0.59, 95%CI 0.42-0.83) among smokers only, while no similar effects were found among nonsmokers. In contrast, the intake of black tea was associated with a protective effect (OR=0.66, 95%CI 0.47-0.94) among nonsmokers only. Comparing the effects of dietary items and physical activity on lung cancer risk among nonsmokers versus smokers, statistically significant effect modifications were found for black tea (P 0.005), and milk/dairy products (P 0.047). Borderline effect modifications emerged for physical exercise (P 0.077). CONCLUSIONS: These results indicate protective effects of some components of healthful diet and physical exercise among smokers, and of the intake of black tea among nonsmokers. The observed interactions of the impact of black tea, milk/dairy products and physical activity upon lung cancer risk in women at different levels of the smoking habit deserve further studies.

Lung cancer risk among Czech tin and uranium miners--comparison of lifetime detriment.

First epidemiological evidence of lung cancer risk from exposure to radon was based on studies of uranium miners. The risk in other mines was reported later. The cohort study among 2466 Czech tin miners was conducted in order to estimate the size of the risk and to compare it to that in uranium mines. Based on 205 lung cancers, the estimate of excess relative risk per unit exposure in the simple linear model 0.011 is compatible with findings from two cohort studies of Czech uranium miners. This similarity holds in more complex models that include modifying effects of age and time since exposure. In addition, an alternative description of the risk in terms of lifetime risk was used. This approach provides summarized characteristics, in which modifying effects of time and age are incorporated. The attributive risk derived from the lifetime relative risk is proportional to cumulated exposure observed in both tin and uranium miners. On the other hand, the expected life shortening of 19 years among radiation induced deaths is similar in these studies.

Czech miner studies of lung cancer risk from radon.

Epidemiological evidence of lung cancer risk from radon is based mainly on studies of miners. Two such studies among Czech uranium miners were established in 1970 and 1980. A subcohort of 5002 miners and a nested-in case-control study contribute to a joint European project. In this paper, the subcohort of miners with 495 lung cancers is described. The excess relative risk depends linearly on cumulative exposure incurred more than 5 years before. The relative effect from exposures in the distant past decreases by 62% per decade. Simultaneously, the excess relative risk is lower by 43% per decade in dependence on age at exposure. The effect of smoking, partly analysed in the study, suggests a twofold elevation in the relative risk coefficient among non-smokers, but this difference is not significant.

Estimating lung cancer mortality from residential radon using data for low exposures of miners.

Some recent estimates of lung cancer risk from exposure to radon progeny in homes have been based on models developed from a pooled analysis of 11 cohorts of underground miners exposed to radon. While some miners were exposed to over 10,000 working level months (WLM), mean exposure among exposed miners was 162 WLM, about 10 times the exposure from lifetime residence in an average house and about three times the exposure from lifetime residence at the "action level" suggested by the U.S. Environmental Protection Agency. The extrapolation of lung cancer risk from the higher exposures in the miners to the generally lower exposures in the home is a substantial source of uncertainty in the assessment of the risk of indoor radon. Using the pooled data for the miners, analyses of lung cancer risk were carried out on data restricted to lower exposures, either <50 WLM or <100 WLM. In the pooled data, there were 115 lung cancer cases among workers with no occupational WLM exposure and 2,674 among exposed miners, with 353 and 562 lung cancer cases in miners with <50 WLM and <100 WLM, respectively. Relative risks (RRs) for categories of WLM based on deciles exhibited a statistically significant increasing trend with exposure in each of the restricted data sets. In the restricted data, there was little evidence of departures from a linear excess relative risk model in cumulative exposure, although power to assess alternative exposure-response trends was limited. The general patterns of declining excess RR per WLM with attained age, time since exposure and exposure rate seen in the unrestricted data were similar to the patterns found in the restricted data. Risk models based on the unrestricted data for miners provided an excellent fit to the restricted data, suggesting substantial internal validity in the projection of risk from miners with high exposures to those with low exposures. Estimates of attributable risk for lung cancer (10-14%) in the U.S. from residential radon based on models from the unrestricted data were similar to estimates based on the data for miners receiving low exposures.

Recent results from the study of West Bohemian uranium miners exposed to radon and its progeny.

A brief description is given of the study of West Bohemian uranium miners, and recent and ongoing efforts to improve the quality of the data are summarized. Three recent analyses of the data from the cohort have led to rather different estimates of the excess relative risk of mortality from lung cancer per working-level month. The reasons for these different estimates are described, and it is concluded that estimates of lung cancer risk are strongly influenced by the quality of the exposure estimates, especially by the omission of some exposures accumulated during employment at other uranium mines, following the closure of most of the shafts at the original two mines. The most recent analysis has shown that, in common with other cohorts of radon-exposed miners, the excess relative risk of lung cancer per working-level month is modified by age and time since exposure. An inverse effect of exposure rate was also demonstrated, but it affected only men at very high concentrations and appears to be related to the time pattern of exposure. In addition, the risk was found to differ between the two main mines, possibly due to the influence of arsenic in the dust of the mines.

Probability of causation for lung cancer after exposure to radon progeny: a comparison of models and data.

The estimates of lung cancer risk due to the exposure to radon decay products are based on different data sets from underground mining and on different mathematical models that are used to fit the data. Diagrams of the excess relative rate per 100 working level months in its dependence on age at exposure and age attained are shown to be a useful tool to elucidate the influence that is due to the choice of the model, and to assess the differences between the data from the major western cohorts and those from the Czech uranium miners. It is seen that the influence of the choice of the model is minor compared to the difference between the data sets. The results are used to derive attributable lifetime risks and probabilities of causation for lung cancer following radon progeny exposures.

Mortality in uranium miners in west Bohemia: a long-term cohort study.

A cohort of 4320 uranium miners in West Bohemia who started work at the mines during 1948 to 1959 and worked there for at least four years were followed up to the end of 1990 to determine cause specific mortality risks in relation to exposures in the mines. The miners had experienced high radon exposures, on average 219 working level months during their uranium mining careers, for which detailed measurements were available. They had also been exposed to high arsenic levels in one of the two major mines, and to dust. New follow up methods, not previously used for occupational cohorts in Czechoslovakia, were utilised. By the end of follow up 2415 (56%) of the cohort were known to have died. Overall mortality was significantly raised compared with that in the general population (relative risk (RR) = 1.56, 95% confidence interval (95% CI) 1.50-1.63), with significantly raised risks of lung cancer (RR = 5.08, 95% CI 4.71-5.47), accidents (RR = 1.59, 95% CI 1.34-1.87), homicide (RR = 5.57, 95% CI 2.66-10.21), mental disorders (RR = 5.18, 95% CI 2.83-8.70), cirrhosis (RR = 1.51, 95% CI 1.16-1.94), and non-rheumatic circulatory diseases (RR = 1.16, 95% CI 1.08-1.25). The relative risk of lung cancer was greatest four to 14 years after entry to the mines. Relative risks for homicide and accidents were raised up to 25 years from entry but not after this. Substantial significantly raised risks at 15 to 24 years after entry occurred for cirrhosis, non-rheumatic circulatory diseases,a nd pneumonia and other respiratory infections. Sizeable significantly raised risks at 25 and more years after entry, but not earlier, were present for mental disorders, tuberculosis, and non-malignant non-infectious respiratory conditions. No specific causes showed risks significantly related to age at entry to mining. Risk of lung cancer was significantly positively related to radon exposure, estimated arsenic exposure, and duration of work in the mines, but no other cause was significantly positively related to these variables. The raised risk of lung cancer in uranium miners, which is well established, is related aetiologically to radon exposure, and in the present cohort it may also in part have been due to exposure to arsenic. The raised risks of accidents, tuberculosis, and non-infectious respiratory diseases have also been seen in other uranium mining cohorts, and are likely to reflect the dangerous and dusty working conditions and the confined spaces in which work occurred. The cirrhosis and homicide deaths probably related to the lifestyle associated with mining. The raised risk of circulatory diseases does not seem to be related to radon or arsenic exposure; its causes are unclear. The use of multiple follow up methods was found to be mortality in the cohort.

Patterns of lung cancer mortality among uranium miners in West Bohemia with varying rates of exposure to radon and its progeny.

Lung cancer mortality in a cohort of 4320 miners first employed during 1948-1959 at the Jáchymov and Horní Slavkov uranium mines in West Bohemia and followed until 1 January 1991 has been studied to gain a greater understanding of the consequences of exposure to radon and its progeny. Among men whose exposure rates never exceeded 10 working levels, excess relative risks per unit exposure were greater in younger men, and exposures received in the periods 15-24, 25-34 and 35+ years previously were found to have 47, 24 and 0% of the effect of exposures 5-14 years previously. Within this low-exposure-rate group excess relative risk increased linearly with time-weighted cumulative exposure and did not depend on exposure rate or duration of exposure. For men who spent less than 20% of their employment at the Jáchymov mine the excess relative risk per working level month was 1.36% (95% confidence interval 0.52-3.54) in the baseline category (age group 55+ and exposure received 5-14 years previously). For men who spent more than 20% of their employment at Jáchymov, the corresponding excess relative risk per working level month was higher by a factor of 1.80 (95% confidence interval 1.27-2.97). The difference may be due to the fact that men who spent more than 20% of their employment at Jáchymov were exposed to the much higher levels of arsenic in the dust at the Jáchymov mine than at other mines. When men with exposure rates above 10 working levels were included in the analysis, patterns of risk were complex and depended on both exposure rate and duration of exposure in addition to the factors mentioned above. If these findings are confirmed elsewhere, calculation of risk estimates for extrapolation to modern occupational or environmental exposures should be based on miners with exposure rates below about 10 working levels. Further investigation is desirable of the influence of dusts containing arsenic on lung cancer risk in miners exposed to radon.

A survey of the Czechoslovak follow-up of lung cancer mortality in uranium miners.

The major Czechoslovak cohort of uranium miners (S-cohort) is surveyed in terms of diagrams illustrating dependences on calendar year, age, and exposure to radon and radon progeny. An analysis of the dose dependence of lung cancer mortality is performed by nonparametric and, subsequently, by parametric methods. In the first step, two-dimensional isotonic regression is employed to derive the lung cancer mortality rate and the relative excess risk as functions of age attained and of lagged cumulated exposure. In a second step, analytical fits in terms of relative risk models are derived. The treatment is largely analogous to the methods applied by the BEIR IV Committee to other major cohorts of uranium miners. There is a marked dependence of the excess risk on age attained and on time since exposure. A specific characteristic of the Czechoslovak data is the nonlinearity of the dependence of the lung cancer excess risk on the cumulated exposure; exposures on the order of 100 working level months or less appear to be more effective per working level month than larger exposures but, in the absence of an internal control group, this cannot be excluded to be due to confounders such as smoking or environmental exposures. A further notable observation is the association of larger excess risks with longer protraction of the exposures.