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.     

Calculation of the 1995 lung cancer incidence in the Netherlands and Sweden caused by smoking and radon: risk implications for radon

A two-mutation carcinogenesis model was used to calculate the expected lung cancer incidence caused by both smoking and exposure to radon in two populations, i.e. those of the Netherlands and Sweden. The model parameters were taken from a previous analysis of lung cancer in smokers and uranium miners and the model was applied to the two populations taking into account the smoking habits and exposure to radon. For both countries, the smoking histories and indoor radon exposure data for the period 1910-1995 were reconstructed and used in the calculations. Compared with the number of lung cancer cases observed in 1995 among both males and females in the two countries, the calculations show that between 72% and 94% of the registered lung cancer cases may be attributable to the combined effects of radon and smoking. In the Netherlands, a portion of about 4% and in Sweden, a portion of about 20% of the lung cancer cases (at ages 0-80 years) may be attributable to radon exposure, the numbers for males being slightly lower than for females. In the Netherlands, the proportions of lung cancers attributable to smoking are 91% for males and 71% for females; in Sweden, the figures are 70% and 56%, respectively. The risk from radon exposure is dependent on gender and cigarette smoking: the excess absolute risk for continuous exposure to 100 Bq m-3 ranges between 0.003 and 0.006 and compares well with current estimates, e.g. 0.0043 of the International Commission on Radiological Protection (ICRP). The excess relative risk for continuous exposure to 100 Bq m-3 shows a larger variation, ranging generally between 0.1 for smokers and 1.0 for non-smokers. The results support the assumption that exposure to (indoor) radon, even at a level as low as background radiation, causes lung cancer proportional to the dose and is consistent with risk factors derived from the miners data.     

Mortality (1950-1999) and cancer incidence (1969-1999) in the cohort of Eldorado uranium workers

This study assessed the relationship between radon decay product (RDP) exposure and mortality and cancer incidence in a cohort of 17,660 Eldorado uranium workers first employed in 1932-1980 and followed up through 1999. The analysis was based on substantially revised identifying information and dosimetry for workers from the Beaverlodge and Port Radium uranium mines and for the first time includes workers from a radium and uranium refinery and processing facility in Port Hope, Canada. Overall, male workers had lower mortality rates of all causes and all cancers and lower incidence rates of all cancers compared with the general Canadian male population, a likely healthy worker effect. Individual cancer rates were also reduced except for lung cancer mortality (SMR = 1.31, P < 0.001) and incidence (SIR = 1.23, P < 0.001). The excess relative risk per 100 WLM (ERR/100 WLM) of lung cancer mortality (N = 618, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.78, P < 0.01) and incidence (N = 626, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.81, P < 0.001) increased linearly with increasing RDP exposure. Adjustment for effect modification by time since exposure, exposure rate and age at risk resulted in comparable estimates of risk of lung cancer for all three uranium worksites. RDP exposures and γ-ray doses were not associated with any other cancer site or other cause of death. The risk estimates are in agreement with the results of the pooled analysis of 11 miner cohorts and more recent studies of uranium workers. The current analysis provides more precise risk estimates and compares the findings from the mortality study with the incidence study. Future follow-up of the cohort and joint analysis with other uranium miners' studies should shed more light on the effects of low RDP exposures as experienced by current workers as well as help to understand and address the health risks associated with residential radon.     

Models for the analysis of radon-exposed populations

Radon-222 is a radioactive decay product of radium-226 and uranium-238, which are found throughout the crust of the earth. Studies of underground miners clearly show that exposure to radon and its decay products increases the risk of developing lung cancer. Data on standardized mortality ratios from eight cohort studies indicate that the radon-lung cancer relationship is statistically homogeneous, even though cohorts are from different types of mines and from different countries. Regression methods for cohort data based on a Poisson probability model permit a thorough consideration of risk patterns. In this report, we review these methods, wherein the disease rate in each cell of a multi-way table is modeled as a function of the cross-classifying variables. The National Academy of Sciences' Committee on the Biological Effects of Ionizing Radiation uses the Poisson regression approach to develop a model for age-specific lung cancer risk which depends on cumulative exposure, age at risk, and time since exposure. This model is reviewed and its implications discussed. The most important determinant of lung cancer is cigarette smoking. This paper discusses relative risk models for analysis of joint exposure to radon and tobacco products. The review of available studies suggests that the joint relationship of radon and smoking with lung cancer is consistent with a multiplicative model, but a submultiplicative relationship is most likely. An additive model is rejected.     

Radon and risk of death from cancer and cardiovascular diseases in the German uranium miners cohort study: follow-up 1946–2003

Data from the German uranium miners cohort study were analyzed to investigate the radon-related risk of mortality from cancer and cardiovascular diseases. The Wismut cohort includes 58,987 men who were employed for at least 6 months from 1946 to 1989 at the former Wismut uranium mining company in Eastern Germany. By the end of 2003, a total of 3,016 lung cancer deaths, 3,355 deaths from extrapulmonary cancers, 5,141 deaths from heart diseases and 1,742 deaths from cerebrovascular diseases were observed. Although a number of studies have already been published on various endpoints in the Wismut cohort, the aim of the present analyses is to provide a direct comparison of the magnitude of radon-related risk for different cancer sites and cardiovascular diseases using the same data set, the same follow-up period and the same statistical methods. A specific focus on a group of cancers of the extrathoracic airways is also made here, due to the assumed high organ doses from absorbed radon progeny. Internal Poisson regression was used to estimate the excess relative risk (ERR) per unit of cumulative exposure to radon in working level months (WLM) and its 95% confidence limits (CI). There was a statistically significant increase in the risk of lung cancer with increasing radon exposure (ERR/WLM = 0.19%; 95% CI: 0.17%; 0.22%). A smaller, but also statistically significant excess was found for cancers of the extrathoracic airways and trachea (ERR/WLM = 0.062%; 95% CI: 0.002%; 0.121%). Most of the remaining nonrespiratory cancer sites showed a positive relationship with increasing radon exposure, which, however, did not reach statistical significance. No increase in risk was noted for coronary heart diseases (ERR/WLM = 0.0003%) and cerebrovascular diseases (ERR/WLM = 0.001%). The present data provide clear evidence of an increased radon-related risk of death from lung cancer, some evidence for an increased radon-related risk of death from cancers of the extrathoracic airways and some other extrapulmonary cancers, and no evidence for mortality from cardiovascular diseases. These findings are consistent with the results of other miner studies and dosimetric calculations for radon-related organ doses.     

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.     

The influence of multiple types of occupational exposure to radon, gamma rays and long-lived radionuclides on mortality risk in the French "post-55" sub-cohort of uranium miners: 1956-1999

The adverse health effects of radon on uranium miners, especially on their lungs, are well documented, but few studies have considered the effects of other radiation exposures. This study examined the mortality risks associated with exposure to radon, external γ rays and long-lived radionuclides (LLR) in the French "post-55" sub-cohort, which includes uranium miners first employed between 1956 and 1990 for whom all three types of exposure were assessed individually. Exposure-risk relationships were estimated with linear excess relative risk models and a 5-year lag time. The post-55 sub-cohort includes 3377 miners, contributing 89,405 person-years, followed up through the end of 1999 with a mean follow-up of 26.5 years. Mean cumulative exposure was 17.8 WLM for radon, 54.7 mSv for γ rays, and 1,632 Bq.m(-3).h for LLR. Among the 611 deaths observed, 66 were due to lung cancer. Annual individual exposures were significantly correlated. Increased mortality was observed for lung cancer (SMR = 1.30; 95% CI: 1.01, 1.65) and for brain and central nervous system (CNS) cancer (SMR = 2.00; 95% CI: 1.09, 3.35). Cumulative exposure to radon, γ rays and LLR was associated only with a significant risk of lung cancer. These new results could suggest an association between lung cancer and exposure to γ rays and LLR. They must nonetheless be interpreted with caution because of the correlation between the types of exposure. The calculation of organ doses received by each of these exposures would reduce the collinearity.     

Lung Cancer Mortality (1950-1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models

Lung cancer mortality after exposure to radon decay products (RDP) among 16,236 male Eldorado uranium workers was analyzed. Male workers from the Beaverlodge and Port Radium uranium mines and the Port Hope radium and uranium refinery and processing facility who were first employed between 1932 and 1980 were followed up from 1950 to 1999. A total of 618 lung cancer deaths were observed. The analysis compared the results of the biologically-based two-stage clonal expansion (TSCE) model to the empirical excess risk model. The spontaneous clonal expansion rate of pre-malignant cells was reduced at older ages under the assumptions of the TSCE model. Exposure to RDP was associated with increase in the clonal expansion rate during exposure but not afterwards. The increase was stronger for lower exposure rates. A radiation-induced bystander effect could be a possible explanation for such an exposure response. Results on excess risks were compared to a linear dose-response parametric excess risk model with attained age, time since exposure and dose rate as effect modifiers. In all models the excess relative risk decreased with increasing attained age, increasing time since exposure and increasing exposure rate. Large model uncertainties were found in particular for small exposure rates.     

Effects of 500-year mercury mining and milling on cancer incidence in the region of Idrija, Slovenia

The aim of the study was to determine whether the 500-year of mercury mining and milling in the Idrija region in Slovenia and the resulting environmental pollution with mercury and smelting wastes containing radon, has caused an increased cancer risk of the inhabitants. The polluted and the non-polluted parts of the region were defined. Cancer incidence from the two regions was compared. Cancer incidence among miners was investigated separately. In the polluted area male and female cancer incidence was higher than in the non-polluted area. Miners had an excess of incidence of total cancer, of oral and pharyngeal cancers and of lung cancer. As indicated by multivariate analysis the increased risk of miners could be assigned to their smoking and alcohol drinking habits. Higher estimated cumulative exposure to inorganic mercury seems to contribute to their risk as well. Most of the excess cancer incidence of the population from the polluted area could be explained by an unhealthy life style. In the case of lung cancer radon exposure contributes to the increased risk as well. Therefore, a well planed health promotion program and further sanitation of old houses is proposed.     

Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.     

Case-control study of lung cancer and combined home and work radon exposure in the town of Lermontov

Relation between the risk of lung cancer and combined home and work indoor radon exposure was studied on the example of the population of Lermontov town (Stavropol Region, Russia). The town is situated in the former uranium mining area. Case (121 lung cancer cases) and control (196 individuals free of lung cancer diagnosis) groups of the study included both ex-miners and individuals that were not involved in the uranium industry. Home and work radon exposures were estimated using archive data as well as contemporary indoor measurements. The results of our study support the conclusion about the effect of radon exposure on the lung cancer morbidity.     

Radon sources and impacts: a review of mining and non-mining issues

Radon is a ubiquitous natural carcinogen derived from the three primordial radionuclides of the uranium series (²³⁸U and ²³⁵U) and thorium series (²³²Th). In general, it is present at very low concentrations in the outdoor or indoor environment, but a number of scenarios can give rise to significant radiological exposures. Historically, these scenarios were not recognised, and took many centuries to understand the links between the complex behaviour of radon and progeny decay and health risks such as lung cancer. However, in concert with the rapid evolution in the related sciences of nuclear physics and radiological health in the first half of the twentieth century, a more comprehensive understanding of the links between radon, its progeny and health impacts such as lung cancer has evolved. It is clear from uranium miner studies that acute occupational exposures lead to significant increases in cancer risk, but chronic or sub-chronic exposures, such as indoor residential settings, while suggestive of health risks, still entails various uncertainties. At present, prominent groups such as the BEIR or UNSCEAR committees argue that the ‘linear no threshold’ (LNT) model is the most appropriate model for radiation exposure management, based on their detailed review and analysis of uranium miner, residential, cellular or molecular studies. The LNT model implies that any additional or excess exposure to radon and progeny increases overall risks such as lung cancer. A variety of engineering approaches are available to address radon exposure problems. Where high radon scenarios are encountered, such as uranium mining, the most cost effective approach is well-engineered ventilation systems. For residential radon problems, various options can be assessed, including building design and passive or active ventilation systems. This paper presents a very broad but thorough review of radon sources, its behaviour (especially the importance of its radioactive decay progeny), common mining and non-mining scenarios which can give rise to significant radon and progeny exposures, followed by a review of associated health impacts, culminating in typical engineering approaches to reduce exposures and rehabilitate wastes.     

Risk of lung cancer mortality in relation to lung doses among French uranium miners: follow-up 1956-1999

The aim of this study was to assess the risk of lung cancer death associated with cumulative lung doses from exposure to α-particle emitters, including radon gas, radon short-lived progeny, and long-lived radionuclides, and to external γ rays among French uranium miners. The French "post-55" sub-cohort included 3,377 uranium miners hired from 1956, followed up through the end of 1999, and contributing to 89,405 person-years. Lung doses were calculated with the ICRP Human Respiratory Tract Model (Publication 66) for 3,271 exposed miners. The mean "absorbed lung dose" due to α-particle radiation was 78 mGy, and that due to the contribution from other types of radiation (γ and β-particle radiation) was 56 mGy. Radon short-lived progeny accounted for 97% of the α-particle absorbed dose. Out of the 627 deaths, the cause of death was identified for 97.4%, and 66 cases were due to lung cancer. A significant excess relative risk (ERR) of lung cancer death was associated with the total absorbed lung dose (ERR/Gy = 2.94, 95% CI 0.80, 7.53) and the α-particle absorbed dose (4.48, 95% CI 1.27, 10.89). Assuming a value of 20 for the relative biological effectiveness (RBE) of α particles for lung cancer induction, the ERR/Gy-Eq for the total weighted lung dose was 0.22 (95% CI: 0.06, 0.53).     

Coronary heart disease mortality and radon exposure in the Newfoundland fluorspar miners’ cohort, 1950–2001

Kreuzer and coworkers recently reported no association between cumulative exposure to radiation and death from cardiovascular disease in a cohort of German uranium miners. Here, we report on the relationship between cumulative exposure to radon progeny and coronary heart disease among Newfoundland fluorspar miners. Previous analyses in this cohort found elevated death rates from coronary heart disease among those with higher cumulative radon exposure. However, this finding was based on a relatively small number of deaths and was not statistically significant. Since then, the follow-up of this cohort has been extended by 10 years until the end of 2001. Among the 2,070 miners in our study, 267 died from coronary heart disease. There was no trend evident between cumulative exposure to radon and the relative risk of death from coronary heart disease (P = 0.63). This finding was unchanged after adjusting for the lifetime smoking status that was available for approximately 54% of the cohort. Similarly, the cumulative radon exposure was found to be unrelated to deaths of the circulatory system, acute myocardial infarction, and cerebrovascular disease. These findings are consistent with those recently reported by Kreuzer and colleagues. We share their view that uncontrolled confounding for other coronary heart disease risk factors hinders the interpretation of the risk estimates.     

Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.     

NOTCH1, HIF1A and Other Cancer-Related Proteins in Lung Tissue from Uranium Miners—Variation by Occupational Exposure and Subtype of Lung Cancer

Background

Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners.

Methodology/Principal Findings

Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r_s). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r_s = 0.18, 95% CI 0.02–0.33; arsenic: r_s = 0.23, 95% CI 0.07–0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%.

Conclusions/Significance

These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.