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.

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.

Lifetime Carcinogenic Risk Proportions from Inhalation Exposures in Industrial and Non-Industrial Regions.

The aim of this work was to estimate the share of selected significant risk factors for respiratory cancer in the overall incidence of this disease and their comparison in two environmentally different burdened regions. A combination of a longitudinal cross-sectional population study with a US EPA health risk assessment methodology was used. The result of this procedure is the expression of lifelong carcinogenic risks and their contribution in the overall incidence of the disease. Compared to exposures to benzo[a]pyrene in the air and fibrogenic dust in the working air, several orders of magnitude higher share of the total incidence of respiratory cancer was found in radon exposures, for women 60% in the industrial area, respectively 100% in the non-industrial area, for men 24%, respectively 15%. The share of risks in workers exposed to fibrogenic dust was found to be 0.35% in the industrial area. For benzo[a]pyrene, the share of risks was below 1% and the share of other risk factors was in the monitored areas was up to 85%. The most significant share in the development of respiratory cancer in both monitored areas is represented by radon for women and other risk factors for men.

EFFECTIVE DOSE COEFFICIENTS FOR RADON AND PROGENY: A REVIEW OF ICRP AND UNSCEAR VALUES.

The International Commission on Radiological Protection (ICRP) publishes guidance on protection against radon exposure in homes and workplaces. ICRP Publication 137 recommends a dose coefficient of 3 mSv per mJ h m-3 (~10 mSv WLM-1) to be used in most circumstances of radon exposure, for workers in buildings and in underground mines. Recently, United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) reviewed radon epidemiology and dosimetry and concluded that its established dose coefficient of 1.6 mSv per mJ h m-3 (5.7 mSv WLM-1) should be retained for use in its comparisons of radiation exposures from different sources in a population. This paper explains and compares the reviews of the scientific evidence from UNSCEAR and ICRP. It is shown that the UNSCEAR and ICRP reviews are consistent and support the use of the ICRP reference dose coefficients for radiation protection purposes. It is concluded that the ICRP dose coefficient should be used to calculate doses to workers.

LUNG CANCER LIFETIME RISKS IN COHORT STUDIES OF URANIUM MINERS.

The article summarizes the most recent results from the cohorts of uranium miners, particularly the risks at low exposures and the risk models with modifying effects of exposure rate, age and time since exposure, which are used for the calculation of lifetime risks (LRs). The excess relative risks per unit exposure (ERR/WLM) arising from low exposures were found up to 10 times higher than the crude risk coefficients. For studies that reported models with modifying effect of age, time since exposure and exposure rate, LRs were calculated using the BEIR VI projection. These LRs were also calculated for a model with effect modification on the annual exposure rate. The results were prepared for the UNSCEAR report on 'Lung cancer from exposure to radon.'(1).

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.

Low radon exposures and lung cancer risk: joint analysis of the Czech, French, and Beaverlodge cohorts of uranium miners.

It is well established that high radon exposures increase the risk of lung cancer mortality. The effects of low occupational exposures and the factors that confound and modify this risk are not clear and are needed to inform current radiation protection of miners. The risk of lung cancer mortality at low radon exposures (< 100 working-level months) was assessed in the joint cohort analysis of Czech, French, and Canadian uranium miners, employed in 1953 or later. Statistical analysis was based on linear Poisson regression modeling with grouped cohort survival data. Two sensitivity analyses were used to assess potential confounding from tobacco smoking. A statistically significant linear relationship between radon exposure and lung cancer mortality was found. The excess relative risk per working-level month was 0.022 (95% confidence intervals: 0.013-0.034), based on 408 lung cancer deaths and 394,236 person-years of risk. Time since exposure was a statistically significant modifier; risk decreased with increasing time since exposure. A tendency for a decrease in risk with increasing attained age was observed, but this was not statistically significant. Exposure rate was not found to be a modifier of the excess relative risk. The potential confounding effect of tobacco smoking was estimated to be small and did not substantially change the radon-lung cancer mortality risk estimates. This joint cohort analysis provides strong evidence for an increased risk of lung cancer mortality from low occupational radon exposures. The results suggest that radiation protection measures continue to be important among current uranium miners.

Study of coverage of confidence intervals for the standardized mortality ratio in studies with missing death certificates.

This paper assesses the coverage probability of commonly used confidence intervals for the standardized mortality ratio (SMR) when death certificates are missing. It also proposes alternative confidence interval approaches with coverage probabilities close to .95. In epidemiology, the SMR is an important measure of risk of disease mortality (or incidence) to compare a specific group to a reference population. The appropriate confidence interval for the SMR is crucial, especially when the SMR is close to 1.0 and the statistical significance of the risk needs to be determined. There are several ways to calculate confidence intervals, depending on a study characteristics (ie, studies with small number of deaths, studies with small counts, aggregate SMRs based on several countries or time periods, and studies with missing death certificates). This paper summarizes the most commonly used confidence intervals and newly applies several existing approaches not previously used for SMR confidence intervals. The coverage probability and length of the different confidence intervals are assessed using a simulation study and different scenarios. The performance of the confidence intervals for the lung cancer SMR and all other cancer SMR is also assessed using the dataset of French and Czech uranium miners. Finally, the most appropriate confidence intervals to use under different study scenarios are recommended.

Paediatric Home Parenteral Nutrition in the Czech Republic and Its Development: Multicentre Retrospective Study 1995-2011.

BACKGROUND: Treatment quality and outcomes of paediatric home parenteral nutrition (HPN) program during its development in the Czech Republic. METHODS: A retrospective study of patients receiving HPN from May 1995 till June 2011. RESULTS: Sixty-six patients were treated in 8 centres. In 48 patients, long-term PN began in the first year of life and in 35 of them in the first month. Sixty children had gastrointestinal and 6 had non-gastrointestinal disease. In a majority of the patients, the Broviac catheter was used. Thirty-two (48.5%) patients were weaned from PN after 1-117 months, 21 (32.8%) continued on HPN after 7-183 months, and 13 (19.7%) patients died, all on PN. The mortality in patients with primary gastrointestinal disease was significantly lower than in patients with non-gastrointestinal disease. Thirty-one paediatric patients were receiving HPN for 14,480 catheter days in 2009-2010. Fourteen patients had 23 Catheter Related Blood Stream Infections (CRBSI) episodes. The incidence of CRBSI in 2009-2010 was 1.58/1,000 catheter days. CONCLUSION: Submitted data showed that even in the absence of expert centres, patient care may achieve results comparable to countries with well-developed HPN program. A majority of Czech HPN patients are at present treated in specialized centres, following the most desirable pattern of care.

238U CONTENT IN URINE OF URANIUM MINERS AND ITS MODELED VALUES.

The aim of the study is to make a comparison of daily 238U excretion in urine among 115 active uranium miners and its modeled values obtained from inhalation intake of long-lived alpha emitters as measured by personal dosemeters and assessed by biokinetic models for different absorption parameters settings for inhaled uranium. A total of 144 spot samples of urine were collected. The 238U content was measured using high-resolution inductively coupled plasma mass spectrometry method. To obtain estimates of the daily excreted values, the daily values were calculated according to the expected daily excretion of creatinine assessed individually for each miner. When determining the relation between the experimentally found data and the modeled data, a high emphasis was placed on uncertainty of the both compared quantities. All the tested absorption parameters settings produced in average 1.4-4.7-fold higher values than the experimentally found values in the urine.

Biomarkers for Uranium Risk Assessment for the Development of the CURE (Concerted Uranium Research in Europe) Molecular Epidemiological Protocol.

Despite substantial experimental and epidemiological research, there is limited knowledge of the uranium-induce health effects after chronic low-dose exposures in humans. Biological markers can objectively characterize pathological processes or environmental responses to uranium and confounding agents. The integration of such biological markers into a molecular epidemiological study would be a useful approach to improve and refine estimations of uranium-induced health risks. To initiate such a study, Concerted Uranium Research in Europe (CURE) was established, and involves biologists, epidemiologists and dosimetrists. The aims of the biological work package of CURE were: 1. To identify biomarkers and biological specimens relevant to uranium exposure; 2. To define standard operating procedures (SOPs); and 3. To set up a common protocol (logistic, questionnaire, ethical aspects) to perform a large-scale molecular epidemiologic study in uranium-exposed cohorts. An intensive literature review was performed and led to the identification of biomarkers related to: 1. retention organs (lungs, kidneys and bone); 2. other systems/organs with suspected effects (cardiovascular system, central nervous system and lympho-hematopoietic system); 3. target molecules (DNA damage, genomic instability); and 4. high-throughput methods for the identification of new biomarkers. To obtain high-quality biological materials, SOPs were established for the sampling and storage of different biospecimens. A questionnaire was developed to assess potential confounding factors. The proposed strategy can be adapted to other internal exposures and should improve the characterization of the biological and health effects that are relevant for risk assessment.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Size distribution of aerosol particles produced during mining and processing uranium ore.

The aerosol particle size distributions of uranium and its daughter products were studied and determined in the area of the Rozná mine, which is the last active uranium mine in the Czech Republic. A total of 13 samples were collected using cascade impactors from three sites that had the highest expected levels of dust, namely, the forefield, the end of the ore chute and an area close to workers at the crushing plant. The characteristics of most size distributions were very similar; they were moderately bimodal, with a boundary approximately 0.5 µm between the modes. The activity median aerodynamic diameter (AMAD) and geometric standard deviation (GSD) were obtained from the distributions beyond 0.39 µm, whereas the sizes of particles below 0.39 µm were not differentiated. Most AMAD and GSD values in the samples ranged between 3.5 and 10.5 µm and between 2.8 and 5.0, respectively. The geometric means of the AMADs and GSDs from all of the underground sampling sites were 4.2 µm and 4.4, respectively, and the geometric means of the AMADs and GSDs for the crushing plant samplings were 9.8 µm and 3.3, respectively. The weighted arithmetic mean of the AMADs was 4.9 µm, with a standard error of 0.7 µm, according to the numbers of workers at the workplaces. The activity proportion of the radon progeny to (226)Ra in the aerosol was 0.61.

Lung cancer risk from occupational and environmental radon and role of smoking in two Czech nested case-control studies.

The aim of the present study was to evaluate the risk of lung cancer from combined exposure to radon and smoking. Methodologically, it is based on case-control studies nested within two Czech cohort studies of nearly 11,000 miners followed-up for mortality in 1952-2010 and nearly 12,000 inhabitants exposed to high levels of radon in homes, with mortality follow-up in 1960-2010. In addition to recorded radon exposure, these studies use information on smoking collected from the subjects or their relatives. A total of 1,029 and 370 cases with smoking information have been observed in the occupational and environmental (residential) studies, respectively. Three or four control subjects have been individually matched to cases according to sex, year of birth, and age. The combined effect from radon and smoking is analyzed in terms of geometric mixture models of which the additive and multiplicative models are special cases. The resulting models are relatively close to the additive interaction (mixing parameter 0.2 and 0.3 in the occupational and residential studies, respectively). The impact of the resulting model in the residential radon study is illustrated by estimates of lifetime risk in hypothetical populations of smokers and non-smokers. In comparison to the multiplicative risk model, the lifetime risk from the best geometric mixture model is considerably higher, particularly in the non-smoking population.

Joint analysis of three European nested case-control studies of lung cancer among radon exposed miners: exposure restricted to below 300 WLM.

Analyses of lung cancer risk were carried out using restrictions to nested case-control data on uranium miners in the Czech Republic, France, and Germany. With the data restricted to cumulative exposures below 300 working-level-months (WLM) and adjustment for smoking status, the excess relative risk (ERR) per WLM was 0.0174 (95% CI: 0.009-0.035), compared to the estimate of 0.008 (95% CI: 0.004-0.014) using the unrestricted data. Analysis of both the restricted and unrestricted data showed that time since exposure windows had a major effect; the ERR/WLM was six times higher for more recent exposures (5-24 y) than for more distant exposures (25 y or more). Based on a linear model fitted to data on exposures <300 WLM, the ERR WLM of lung cancer at 30 y after exposure was estimated to be 0.021 (95% CI: 0.011-0.040), and the risks decreased by 47% per decade increase in time since exposure. The results from analyzing the joint effects of radon and smoking were consistent with a sub-multiplicative interaction; the ERR WLM was greater for non-smokers compared with current or ex-smokers, although there was no statistically significant variation in the ERR WLM by smoking status. The patterns of risk with radon exposure from the combined European nested case-control miner analysis were generally consistent with those based on the BEIR VI Exposure-Age-Concentration model. Based on conversions from WLM to time weighted averaged radon concentration (expressed per 100 Bq m), the results from this analysis of miner data were in agreement with those from the joint analysis of the European residential radon studies.

Lung cancer mortality among Czech uranium miners-60 years since exposure.

The present study is based on 9978 Czech uranium miners with 1141 lung cancer deaths observed in an updated follow-up 1952-2010 and corresponding to 31 years of mean follow-up. The objectives of the study are to obtain more reliable estimates for the exposure-response relationship, including factors that modify this relationship. Lung cancer in relation to cumulative exposure to radon decay products is linear with substantial modifications by time since exposure, age at exposure and exposure rate using exposure windows. The crude excess relative risk (ERR) per unit exposure in working level months (WLM) in the cohort is 0.0097 (90% confidence interval (CI) 0.0074-0.0127). The ERR/WLM corresponding to exposure rates below 7 working levels (WL) is substantially higher - 0.0145 (90% CI 0.0109-0.0193). In the final model, the inverse effect of exposure rate is observed for high exposure rates >7 WL with the ERR/WLM reduced to 31%. The ERR/WLM decreases to 32% and 9% in periods 20-29 and 30 +years since exposure in comparison to the period of 5-19 years since exposure. Simultaneously, the ERR/WLM decreases with age at exposure - 63% and 49% at ages 30-39 and 40 +years in comparison to age at exposure <30 years.

Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners.

A combined analysis of three case-control studies nested in three European uranium miner cohorts was performed to study the joint effects of radon exposure and smoking on lung cancer death risk. Occupational history and exposure data were available from the cohorts. Smoking information was reconstructed using self-administered questionnaires and occupational medical archives. Linear excess relative risk models adjusted for smoking were used to estimate the lung cancer risk associated with radon exposure. The study includes 1046 lung cancer cases and 2492 controls with detailed radon exposure data and smoking status. The ERR/WLM adjusted for smoking is equal to 0.008 (95% CI: 0.004-0.014). Time since exposure is shown to be a major modifier of the relationship between radon exposure and lung cancer risk. Fitting geometric mixture models yielded arguments in favor of a sub-multiplicative interaction between radon and smoking. This combined study is the largest case-control study to investigate the joint effects of radon and smoking on lung cancer risk among miners. The results confirm that the lung carcinogenic effect of radon persists even when smoking is adjusted for, with arguments in favor of a sub-multiplicative interaction between radon and smoking.

Lung cancer in French and Czech uranium miners: Radon-associated risk at low exposure rates and modifying effects of time since exposure and age at exposure.

Radon is recognized as a public health concern for indoor exposure. Precise quantification derived from occupational exposure in miners is still needed for estimating the risk and the factors that modify the dependence on cumulated exposure. The present paper reports on relationship between radon exposure and lung cancer risk in French and Czech cohorts of uranium miners (n = 10,100). Miners from these two cohorts are characterized by low levels of exposure (average cumulated exposure of less than 60 WLM) protracted over a long period (mean duration of exposure of 10 years) and by a good quality of individual exposure estimates (95% of annual exposures based on radon measurements). The modifying effect of the quality of exposure on the risk is analyzed. A total of 574 lung cancer deaths were observed, which is 187% higher than expected from the national statistics. This significantly elevated risk is strongly associated with cumulated radon exposure. The estimated overall excess relative risk per WLM is 0.027 (95% CI: 0.017-0.043, related to measured exposures). For age at exposure of 30 and 20 years since exposure, the ERR/WLM is 0.042, and this value decreases by approximately 50% for each 10-year increase in age at exposure and time since exposure. The present study emphasizes that the quality of exposure estimates is an important factor that may substantially influence results. Time since exposure and simultaneously age at exposure were the most important effect modifiers. No inverse exposure-rate effect below 4 WL was observed. The results are consistent with estimates of the BEIR VI report using the concentration model at an exposure rate below 0.5 WL.