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.     

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.     

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.     

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.     

Indoor radon and lung cancer. Estimating the risks.

Radon is ubiquitous in indoor environments. Epidemiologic studies of underground miners with exposure to radon and experimental evidence have established that radon causes lung cancer. The finding that this naturally occurring carcinogen is present in the air of homes and other buildings has raised concern about the lung cancer risk to the general population from radon. I review current approaches for assessing the risk of indoor radon, emphasizing the extrapolation of the risks for miners to the general population. Although uncertainties are inherent in this risk assessment, the present evidence warrants identifying homes that have unacceptably high concentrations.     

Quantitative health impact of indoor radon in France

Radon is the second leading cause of lung cancer after smoking. Since the previous quantitative risk assessment of indoor radon conducted in France, input data have changed such as, estimates of indoor radon concentrations, lung cancer rates and the prevalence of tobacco consumption. The aim of this work was to update the risk assessment of lung cancer mortality attributable to indoor radon in France using recent risk models and data, improving the consideration of smoking, and providing results at a fine geographical scale. The data used were population data (2012), vital statistics on death from lung cancer (2008–2012), domestic radon exposure from a recent database that combines measurement results of indoor radon concentration and the geogenic radon potential map for France (2015), and smoking prevalence (2010). The risk model used was derived from a European epidemiological study, considering that lung cancer risk increased by 16% per 100 becquerels per cubic meter (Bq/m³) indoor radon concentration. The estimated number of lung cancer deaths attributable to indoor radon exposure is about 3000 (1000; 5000), which corresponds to about 10% of all lung cancer deaths each year in France. About 33% of lung cancer deaths attributable to radon are due to exposure levels above 100 Bq/m³. Considering the combined effect of tobacco and radon, the study shows that 75% of estimated radon-attributable lung cancer deaths occur among current smokers, 20% among ex-smokers and 5% among never-smokers. It is concluded that the results of this study, which are based on precise estimates of indoor radon concentrations at finest geographical scale, can serve as a basis for defining French policy against radon risk.     

Analysis of a historical cohort of Chinese tin miners with arsenic, radon, cigarette smoke, and pipe smoke exposures using the biologically based two-stage clonal expansion model.

Hazelton, W. D., Luebeck, E. G., Heidenreich, W. F. and Moolgavkar, S. H. Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model. Radiat. Res. 156, 78-94 (2001).The two-stage clonal expansion model is used to analyze lung cancer mortality in a cohort of Yunnan tin miners based on individual histories with multiple exposures to arsenic, radon, cigarette smoke, and pipe smoke. Advances in methodology include the use of nested dose-response models for the parameters of the two-stage clonal expansion model, calculation of attributable risks for all exposure combinations, use of both a fixed lag and a gamma distribution to represent the time between generation of the first malignant cell and death from lung cancer, and scaling of biological parameters allowed by parameter identifiability. The cohort consists of 12,011 males working for the Yunnan Tin Corporation, with complete exposure records, who were initially surveyed in 1976 and followed through 1988. Tobacco and arsenic dominate the attributable risk for lung cancer. Of 842 lung cancer deaths, 21.4% are attributable to tobacco alone, 19.7% to a combination of tobacco and arsenic, 15.8% to arsenic alone, 11% to a combination of arsenic and radon, 9.2% to a combination of tobacco and radon, 8.7% to combination of arsenic, tobacco and radon, 5.5% to radon alone, and 8.7% to background. The models indicate that arsenic, radon and tobacco increase cell division, death and malignant conversion of initiated cells, but with significant differences in net cell proliferation rates in response to the different exposures. Smoking a bamboo water pipe or a Chinese long-stem pipe appears to confer less risk than cigarette use, given equivalent tobacco consumption.     

Lung cancer incidence attributable to residential radon exposure in Finland

This study aimed to estimate (1) the number of avoidable lung cancer cases attributable to residential radon in Finland in 2017, separately by age, sex, dwelling type and smoking status, (2) the impact of residential radon alone and the joint effect of residential radon and smoking on the number of lung cancers and (3) the potential decrease in the number of radon-attributable lung cancers if radon concentrations exceeding specified action levels (100, 200 and 300 Bq m^?3) would have been mitigated to those levels. Population-based surveys of radon concentrations and smoking patterns were used. Observed radon levels were contrasted with 25 Bq m^?3 representing a realistic minimum level of exposure. Lung cancer risk estimates for radon and smoking were derived from literature. Lastly, the uncertainty due to the estimation of exposure and risk was quantified using a computationally derived uncertainty interval. At least 3% and at most 8% of all lung cancers were estimated as being attributable to residential radon. For small cell carcinoma, the proportion of cases attributable to radon was 8–13%. Among smokers, the majority of the radon-related cases were attributable to the joint effect of radon and smoking. Reduction of radon exposure to 100 Bq m^?3 action level would eliminate approximately 30% of radon-attributable cases. Estimates were low compared with the literature, given the (relatively high) radon levels in Finland. This was mainly due to the lower radon levels and higher smoking prevalence in flats than in houses and a more realistic point of comparison, factors which have been ignored in previous studies. The results can guide actions in radon protection and in prevention of lung cancers.

     

A retrospective mortality study of workers exposed to radon in a Brazilian underground coal mine

Recently a high radon concentration was detected in the underground coal mine of Figueira, located in the south of Brazil. This coal mine has been operating since 1942 without taking cognizance of the high radon environment. In order to assess possible radon-related health effects on the workers, a retrospective (1979-2002) mortality study of 2,856 Brazilian coal miners was conducted, with 2,024 underground workers potentially exposed to radon daughters. Standard mortality ratio (SMR) analysis hints at lower mortality from all causes for both underground (SMR = 88, 95% CI = 78-98) and surface workers (SMR = 96, 95% CI = 80-114). A high statistically significant SMR for lung cancer mortality was observed only in the underground miners (SMR = 173, 95% CI = 102-292), with a statistically significant trend reflecting the duration of underground work. High statistically significant SMRs were observed for pneumonia as a cause of death between both surface (SMR = 304, 95% CI = 126-730) and underground miners (SMR = 253, 95% CI = 140-457). Because mortality from smoking-related cancers other than lung cancer was not found elevated in underground workers and because diesel equipments were not used in this mine, it can be concluded that the enhanced lung cancer mortality observed for underground miners is associated with exposure to radon and radon daughters, rather than other confounding risk factors.     

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.     

Radon-associated lung cancer risk among French uranium miners: modifying factors of the exposure–risk relationship

Radon is classified as a known pulmonary carcinogen in humans. A better understanding of the effects of low exposure and time-dependent factors, modifying the lung cancer risk is of continued interest. We present analyses of the exposure–risk relationship in the French cohort of uranium miners updated until 1999 and including five additional years of follow-up. These new analyses provide a better opportunity to look at low radon exposures with longer follow-up intervals, and allow consideration of new modifying factors, such as physical activity, mine location and job type. The cohort includes 5,086 miners, and 159 lung cancer deaths have been observed among these over a follow-up of more than 30 years. The exposure–risk relationship was estimated using excess relative risk models, which allow investigation of several modifying factors such as period of exposure, time since exposure, age at exposure, duration of exposure, exposure rate, job type, mine type and physical activity. The analysis confirms the association between radon exposure and lung cancer risk (ERR per 100 WLM = 0.58, P < 0.01). Period of exposure and physical activity appear as major modifying factors. Higher risks are observed for hard physical activity works. The effect of hard physical activity persists when the period of exposure is taken into account (ERR per 100 WLM = 2.95, P < 0.01).     

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 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.     

Biologically Based Prediction of Empirical Nonlinearity in Lung Cancer Risk vs. Residential/ Occupational Radon Exposure

Ecologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM) that are inconsistent with clearly positive ones revealed by individual data on underground miners. If this inconsistency is due to competing effects of induced cell killing vs. mutations in alpha-radiation exposed bronchial epithelium, then linear extrapolation from miner data may overestimate typical residential radon risks. To investigate the plausibility of this hypothesis, a biologically based “cytodynamic 2-stage” (CD2) cancer-risk model was fit to combined 1950 to 1954 age-specific person-year data on white females of age 40+ y in 2821 U.S. counties (～90% never-smokers), and on five cohorts of underground miners who never smoked, conditional on a realistic rate of alpha-radiation-induced killing of human lung cells, and on linear-no-threshold dose-response relations for both processes assumed to affect cancer risk (alpha-induced mutations and cell killing). As summarized previously (Bogen, K.T., Hum. Exper. Toxicol. 17:691-6, 1998), a good CD2 fit was obtained that involved biologically plausible parameter values and (without further optimization) also predicted inverse dose-rate effects observed in the nonsmoking miners. The present paper reports mathematical details of the CD2 model used, as well as additional modeling results involving the same combined data set. The results obtained are consistent with the hypotheses that low-level radon exposure is nonlinearly related to LCM risk, and that current linear no-threshold extrapolation models overestimate LCM risk associated with relatively low residential radon concentrations (<～200?Bq m^?3). Testing this hypothesis would require more extensive individual-level epidemiological data relating residential radon exposures to LCM than are currently available.     

Lung cancer and indoor radon exposure in the north of Portugal--an ecological study

BackgroundIndoor radon exposure is a well documented environmental factor as a leading cause of lung cancer. Objectives: The aim of this study was to assess the risk of lung cancer and estimate the number of deaths due to indoor radon exposure in the north of Portugal, between 1995 and 2004. Methods: The sixth Biological Effects of Ionizing Radiation Committee (BEIR VI) preferred models were applied to estimate the risk of developing lung cancer induced by indoor radon exposure, by age and level of exposure, and calculated the number of lung cancer deaths attributable to this exposure. Lung cancer mortality data were granted by the North Regional Health Administration and indoor radon concentrations resulted from a national survey conducted by the Portuguese Environmental Agency. The smoking habit was accounted with two methods. A submultiplicative interaction between smoking and indoor radon exposure was considered. Results: Depending on the model applied and the method used to account for the smoking habit, the estimated number of lung cancer deaths attributed to indoor radon exposure, in northern Portugal, ranges from 1565 to 2406, for the period between 1995 and 2004. This indicates that of the 8514 lung cancer deaths observed, from 18 to 28% could be associated with indoor radon exposure.ConclusionsThis was the first study realized in Portugal on the impact of indoor radon exposure in lung cancer mortality. The application of the BEIR VI models led to a high number of lung cancer deaths due to indoor radon exposure.