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Indoor Radon and Lung Cancer in France

Baysson, Hélène*; Tirmarche, Margot*; Tymen, Georges; Gouva, Sylvie; Caillaud, Denis§; Artus, Jean-Claude; Vergnenegre, Alain; Ducloy, Françoise*; Laurier, Dominique*

doi: 10.1097/01.ede.0000142150.60556.b8
Original Article
Free

Background: Several case-control studies have indicated an increased risk of lung cancer linked to indoor radon exposure; others have not supported this hypothesis, partly because of a lack of statistical power. As part of a large European project, a hospital-based case-control study was carried out in 4 areas in France with relatively high radon levels.

Methods: Radon concentrations were measured in dwellings that had been occupied by the study subjects during the 5- to 30-year period before the interview. Measurements of radon concentrations were performed during a 6-month period using 2 Kodalpha LR 115 detectors (Dosirad, France), 1 in the living room and 1 in the bedroom. We examined lung cancer risk in relation to indoor radon exposure after adjustment for age, sex, region, cigarette smoking, and occupational exposure.

Results: We included in the analysis 486 cases and 984 controls with radon measures in at least 1 dwelling. When lung cancer risk was examined in relation to the time-weighted average radon concentration during the 5- to 30-year period, the estimated relative risks (with 95% confidence intervals) were: 0.85 (0.59–1.22), 1.19 (0.81–1.77), 1.04 (0.64–1.67), and 1.11 (0.59–2.09) for categories 50–100, 100–200, 200–400, and 400+ becquerels per cubic meter (Bq/m3), respectively (reference <50 Bq/m3). The estimated relative risk per 100 Bq/m3 was 1.04 (0.99–1.11) for all subjects and 1.07 (1.00–1.14) for subjects with complete measurements.

Conclusions: Our results support the presence of a small excess lung cancer risk associated with indoor radon exposure after precise adjustment on smoking. They are in agreement with results from some other indoor radon case-control studies and with extrapolations from studies of underground miners.

From the *Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Direction de la Radioprotection de l'Homme, Service de Radiobiologie et d'Epidémiologie, Fontenay-aux-Roses, France; †Faculté des sciences de Brest, Laboratoire de Recherches Appliqués Atmosphère-Hydrosphère, UFR Sciences et Techniques, Brest, France; ‡CHU de Brest, Brest, France; §CHU de Clermont-Ferrand, Clermont-Ferrand, France; ∥Faculté de Médecine, Université Montpellier 1, Montpellier, France; and ¶Registre des cancers du Limousin, Service de pathologie respiratoire, CHU de Limoges, Limoges, France.

Submitted 28 February 2003; final version accepted 12 July 2004.

This study was partly funded by ARC (Association pour la Recherche sur le Cancer) and by the European Commission.

Correspondence: Hélène Baysson, Institut de Radioprotection et de Sûreté Nucléaire, Direction de la Radioprotection de l'Homme, Service de Radiobiologie et d'Epidémiologie, BP n°17, 92262 Fontenay-aux-Roses Cedex, France. E-mail: helene.baysson@irsn.fr.

There is considerable information from epidemiologic cohort studies of miners exposed to high radon concentrations in uranium, iron, fluorspar, and tin mines, as well as from experimental studies in animals, showing that exposure to radon progeny increases the risk of lung cancer.1,2 The International Agency for Research on Cancer (IARC) concluded in 1988 that there is sufficient evidence to classify radon as a lung carcinogen in humans.3 Radon is not confined to underground mines, but may also accumulate in dwellings. A national survey aiming to describe the radon exposure of the French population was conducted using long-term measurements of radon concentrations in dwellings.4 It suggested that radon accounts for approximately one third of the average annual effective dose of ionizing radiation received by the French population. The average concentration of radon gas has been estimated to be close to 60 becquerels per cubic meter (Bq/m3) after adjustment for density of population in each department.4 There is, however, a wide range of values across the country, as reported in the national radon database, with the highest values occurring predominantly in Brittany and in the center of France.5,6

Extrapolation of the risk of lung cancer observed in cohort studies of underground miners suggests that residential radon could be responsible for 5% to 10% of lung cancer cases occurring in France.7 Such extrapolation depends, however, on several assumptions and must be considered with caution. Direct epidemiologic investigations of the general population have been conducted in New Jersey,8 China,9,10 Finland,11,12 Sweden,13–15 Canada,16 Finland nationwide,17,18 Missouri,19,20 Iowa,21 southwest England,22 Germany,23,24 and Spain.25 Some of these studies have suggested that residential radon is a risk factor for lung cancer, with risk estimates consistent with those derived from studies on miners. However, not all results are consistent, and the statistical power of many studies is limited. Ecologic studies had also been conducted, but as a result of methodologic limitations, such studies cannot provide precise risk coefficients.

This article presents the results of a case-control study of radon and lung cancer in France with a focus on precise reconstruction of indoor radon exposure over the 30 years preceding lung cancer diagnosis.

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METHODS

Study Design

The investigation took place from 1992 to 1998 in several areas of France. The definition of the study areas was based on a selection of administrative districts with relatively high radon concentrations. According to data from the French national radon survey in dwellings conducted in the 1980s and the 1990s,4 the regions of Auvergne, Brittany, and Limousin are 3 main radon-prone areas, which can be characterized as granitic and rural regions. The area of Languedoc-Roussillon was added because of the presence of a smaller but rich radon-prone area.

Cases were recruited in 5 main university hospitals of the selected regions. All subjects with incident primary lung cancer and age less than 75 years at the date of diagnosis were interviewed within 6 months after the diagnosis. Subjects were eligible for the study if they had lived in the study area for at least 25 of the last 35 years. There were no exclusion criteria based on sex, occupation, or nationality. The diagnosis of primary lung tumor was confirmed histologically or cytologically by the hospital's pathologist. Histologic confirmation of lung cancer was available for 85% of the cases, cytologic confirmation was available for 2%, and for 13% the diagnosis was based on other clinical evidence. The following subtypes were considered: small-cell carcinoma, squamous cell carcinoma, adenocarcinoma, and other lung cancers.

For each subject interviewed with confirmed lung cancer, we identified 2 individually matched controls (by sex and age ± 5 years) from the pool of hospital patients of the same region. Each control had to satisfy the study residence requirements. In each region, attempts were made to include patients with a wide variety of diseases in the hospital control group (orthopedics, rheumatism, injury, and so on). Patients whose current hospital admission was for a disease closely associated with smoking were excluded to avoid an overrepresentation of smokers in the hospital control group compared with the general population of the region.22

Physicians invited eligible patients to participate with an estimated response rate above 90%. Face-to-face interviews were conducted in hospitals by interviewers especially trained for this study. The same interviewer collected data for both cases and controls. A standardized questionnaire was used to ascertain demographic characteristics, information on active and passive smoking, occupational exposure and medical history, as well as extensive details on residential history. Mean duration of interviews was 40 minutes.

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Radon Exposure

For all subjects interviewed, full residential histories covering the previous 30 years were obtained. For each dwelling occupied for more than 1 year, information was collected on the precise address, the duration of occupation, and housing characteristics known to have the greatest bearing on residential radon concentrations (type of building, floor levels of living area and of bedroom, building materials of houses, and period of construction).

Radon was measured in current and former dwellings during a 6-month period allocated throughout the year. In each dwelling, 2 Kodalpha LR 115 detectors (Dosirad, France) were installed, one in the living room and one in the bedroom. The accuracy of measurements was tested every 6 months, and stringent quality assurance procedures were applied.4 A series of intercomparison exercises was also organized under controlled conditions.26 Detectors were placed and later collected by trained assistants who asked current occupants to fill in a questionnaire about housing characteristics and their way of life (eg, ventilation habits, heating). For each address, the radon concentration was estimated by the average of the measured radon concentrations in the bedroom and the living room. Radon gas concentrations were expressed in Becquerels per cubic meter.

The time-weighted average (TWA) radon concentration for a subject during the 5- to 30-year period before interview was based on radon concentrations over all addresses occupied by the subject during the period, weighting concentrations proportionally to the number of years spent at each address. We did not consider the 0- to 5-year period before interview; this was done to take into account a minimum latency period of 5 years between exposure and lung cancer diagnosis. For the time intervals without available measurements, we imputed the region-specific arithmetic average of radon concentrations for measured addresses of control subjects.27

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Other Risk Factors

By far the most important lung cancer risk factor is tobacco use.28 Other important risk factors we considered are exposure to occupational carcinogens such as asbestos, chromates, nickel, arsenic, tar products, or underground mining activities.28

We defined subjects as smokers if they had ever smoked regularly (at least 1 cigarette per day, or 4 cigarillos per week, or 3 cigars or 3 pipes per week) for a period of at least 1 year. For each distinctive smoking periods (based on changes in either quantity or type of tobacco product), dates of start and end and quantity and type of tobacco (cigars, cigarettes, pipes) were ascertained. Exsmokers were formerly smokers who had stopped smoking at least 2 years before the interview. Passive smoking information was collected during never-smokers’ interviews, but as a result of the small number of never-smokers, we did not consider this information in the analysis.

Two binary variables were constructed. One variable (list A) distinguished subjects who, for a year or more during their entire occupational history, held occupations recognized to present lung cancer risk, whereas the other variable (list B) distinguished subjects who held occupations suspected to present lung cancer risk. Classification relied on a list of jobs, branches, and industries recently published by Ahrens and Merletti29 in which a risk for lung cancer has been recognized or suspected. We also considered exposure to asbestos (ever/never).

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Statistical Analysis

Relative risks (RR) and 95% confidence intervals (CIs) were calculated using logistic regression with adjustment for sex, age, region, cigarette smoking, and occupational exposure. We included in the model only variables showing an association with lung cancer or, alternatively, a confounding effect on the association between radon exposure and lung cancer. Exposure to domestic radon was defined as a categorical variable with a priori defined cutpoints at 50, 100, 200, and 400 Bq/m3. When treating radon exposure as a continuous variable, we tested a linear exposure-risk relationship and estimated the relative risk per additional exposure of 100 Bq/m3. Cigarette smoking was taken into account both continuously by log(pack-years + 1) and by smoking status in 4 categories (lifelong nonsmoker, current smoker, exsmoker <10 years, exsmoker >10 years). Occupational exposure was taken into account through 2 binary variables: ever/never exposed to asbestos and ever/never exposed in an occupation included in list A. Risk estimates did not change when we used different smoking variables such as average number of cigarettes smoked per day and duration of smoking (years) or after further adjustment for additional occupational exposure (list B) and social status (educational level). The analysis was carried out considering the time-weighted average radon concentration during the 5- to 30-year period before the interview. It was then repeated considering only the radon concentration in the home occupied at the time of the interview. In a sensitivity analysis, several methods for handling missing data were also tested.27 First, the region-specific arithmetic average of radon concentrations for measured addresses of control subjects was used. The second method considered a stratum-specific average of radon concentrations in which data were stratified by type of house, period of construction, and building materials. In this method, radon measurements performed in controls’ homes were supplemented with those made as part of the national radon database.30 Finally, the analysis was repeated including only those subjects for whom all dwellings were measured.

Heterogeneity tests for subject and tumor characteristics were based on the likelihood ratio.

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RESULTS

Study Population

Of the 1655 study subjects enrolled (552 cases and 1103 controls), we included in the risk analyses 1470 subjects (486 cases, 984 controls) with at least 1 address that was occupied during the 5- to 30-year period and assessed for radon concentration.

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Sociodemographic Characteristics

Sociodemographic characteristics of the 1470 study subjects are outlined in Table 1. Almost 90% of the cases and controls were men. Mean age was 59 years for both cases and controls. Cases and controls were also similar in their educational levels.

TABLE 1

TABLE 1

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Smoking and Occupational Exposure

Table 1 shows the distributions of cases and controls by smoking status and occupational exposure. Cigarette smoking was strongly associated with lung cancer risk. After adjusting for age, sex, and region, relative risks were 15.6 (CI = 9.3–24.5) for current smokers, 9.2 (CI = 5.6–15.2) for exsmokers who stopped smoking within the previous 10 years, and 2.9 (CI = 1.8–4.8) for exsmokers who stopped smoking at least 10 years earlier. Daily number of cigarettes, duration of smoking, and pack-years were associated with lung cancer risk. After adjusting for sex, age, and region, there was a positive association between risk of lung cancer and occupational asbestos exposure (RR = 1.4; CI = 1.0–2.1). No clear association between lung cancer and exposure to other occupational carcinogens was observed (RR = 1.2; CI = 0.9–1.5).

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Residential History and Outcome of Radon Monitoring

The number of homes occupied during the previous 5 to 30 years was similar for cases and controls. Current homes were occupied for an average of 24 years among cases and 26 years among controls. The mean period of residence for which direct measurements were available was 21 years among cases and 22 years among controls.

The arithmetic mean of measured radon concentrations in the 2195 addresses was 141 Bq/m3. Regional means ranged from 53 Bq/m3 in Languedoc-Roussillon to 187 Bq/m3 in Limousin. In the entire study area, the median concentration was 79 Bq/m3 for cases and 77 Bq/m3 for controls.

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Radon Exposure (5- to 30-Year Period)

The distribution of time-weighted average radon concentrations during the previous 5 to 30 years among cases was shifted slightly toward higher values compared with controls (Table 2). The contrast between cases and controls with respect to the distribution of time-weighted average radon concentrations was unaffected when gaps in the exposure history were imputed with the average radon concentrations over controls. After imputation for missing values, the arithmetic mean of time-weighted average radon concentrations during the previous 5 to 30 years was 146 Bq/m3 for cases and 140 Bq/m3 for controls (Table 2).

TABLE 2

TABLE 2

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Relative Risk of Lung Cancer

Crude RR per 100 Bq/m3 based on time-weighted average radon concentration during the previous 5 to 30 years was 1.01 (CI = 0.96–1.07). After adjusting for age, sex, region, smoking, and occupational exposure, the RRs in comparison with <50 Bq/m3 were 0.85 (CI = 0.59–1.22), 1.19 (CI = 0.81–1.77), 1.04 (CI = 0.64–1.67), and 1.11 (CI = 0.59–2.09) for categories 50–100, 100–200, 200–400, and 400+ Bq/m3, respectively. Considering time-weighted average radon concentration as a continuous variable, the estimated RR per 100 Bq/m3 was 1.04 (CI = 0.99–1.11) (Table 3 and Fig. 1). Using only radon measurements of current homes with respect to study subjects’ actual living habits did not change the results (Table 3). We also assessed the impact of several different methods for handling radon missing values. Using stratum-specific averages of radon concentrations increased the RR per 100 Bq/m3 from 1.04 to 1.05 (CI = 0.99–1.11). When the analysis was limited to the 850 subjects for whom all dwellings were measured, the RR per 100 Bq/m3 increased to 1.07 (CI = 1.00–1.14). This subgroup was characterized by a low residential mobility, with mostly 1 dwelling occupied during the studied period.

TABLE 3

TABLE 3

FIGURE 1.

FIGURE 1.

To test for any evidence that the effect of radon differed according to known characteristics of the subject, we estimated the RRs per 100 Bq/m3 separately by sex, by age, by smoking status, by histologic type of tumor, and according to the habit of sleeping with an open window. Among these characteristics, notable heterogeneity was found only for the habit of sleeping with an open window; the relative risk per 100 Bq/m3 was higher among subjects who slept with closed window (RR = 1.07; CI = 1.00–1.15) than among the others (RR = 0.87; CI = 0.74–1.01).

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DISCUSSION

The design of the present study is basically the same as in previous studies,22,23 and consistent with international recommendations.31,32

Considering the 5- to 30-year period and after adjustment for sex, age, region, smoking, and past occupational exposure, the estimated RR per 100 Bq/m3 was 1.04 (CI = 0.99–1.11). It increased to 1.07 (CI = 1.00–1.14) when the analysis was limited to the 850 subjects for whom all dwellings were measured.

Our results are consistent with the findings from other studies. In 1997, the metaanalysis of 8 case-control studies resulted in a RR of 1.09 per 100 Bq/m3 (CI = 1.00–1.20).33 Since then, 9 additional case-control studies, based on large numbers of subjects and adjusted for several potential confounders, have been published.10,15,20–25,34 Most of these studies had inadequate power to detect a risk on their own, although a weighted average of some published results showed a RR of 1.06 per 100 Bq/m3 (CI = 1.01–1.10).35 The estimated RR in the present study is also consistent with those derived from cohort studies of underground miners (Fig. 1). A pooled analysis of 11 cohort studies of miners36 showed a RR of 1.005 per working-level month and the recently published RR in the French uranium miners cohort is 1.008 per working-level month.37 Assuming that 25 working-level month would result in the same bronchial dose as living in a house with a radon concentration of 230 Bq/m3 for 25 years,2 RRs of 1.05 to 1.09 per 100 Bq/m3 can be inferred from these 2 studies.

Present results are based on observed radon concentrations, ignoring uncertainties in the assessment of radon exposure. Previous studies suggested that risks are likely to be underestimated owing to random error in exposure estimates. In Swedish studies, underestimation by nearly a factor of 2 is probable38; and a comparably large impact on the risk estimates has been shown in the southwest England case-control study22 and in the Chinese case-control study.10 In reviewing the findings from indoor case-control studies, the studies with more complete and accurate radon measurement data have demonstrated an association between indoor radon exposure and lung cancer. Thus, the inability to detect an association in some studies may have been the result of poor retrospective radon exposure assessment.39

Heterogeneity tests for subject characteristics suggested an elevated risk only for those sleeping with a closed window. A similar effect was described in the Swedish nationwide study.14 Because the occupants at the time of measurement usually were not the subjects themselves, there may have been some exposure misclassification resulting from this factor. However, when the present analysis was repeated using only radon measurements in the current homes with respect to study subjects’ actual living habits, the RR per 100 Bq/m3 was also higher among those who slept with closed windows (RR = 1.08; CI = 1.01–1.16) than among the others (RR = 0.90; CI = 0.77–1.06). This may be a chance finding or it could reflect other differences in individual living habits.

Considering the histologic type of the tumor, the present study provides no evidence of a preponderance of small-cell lung cancers as has been suggested by previous indoor radon case-control studies.22–24

The combined effect of smoking and indoor radon exposure has not yet been clarified fully.10 Main information from interaction between smoking and radon exposure comes from uranium miners studies in which a multiplicative or submultiplicative effect is suggested.1 Epidemiologic studies of lung cancer and indoor radon exposure have produced contrasting results. In the nationwide study in Sweden, Pershagen et al.14 found a combined effect particularly strong for current smokers (>10 cigarettes per day) in the category with the highest exposure to radon (>400 Bq/m3). However, such a synergistic effect has not been confirmed in other studies.20,22 These findings were generally limited by small sample size in the various smoking categories. Similarly, we could not test the interaction between smoking and indoor radon exposure because the number of cases among never-smokers was very small.

In the present study, we attempted to perform measurements in each dwelling occupied by study subjects for at least 1 year during the 5- to 30-year period of interest. For each region except Languedoc-Roussillon, radon measurements covered at least 70% of the exposure window, which compares favorably with other indoor radon studies for which the exposure window covers approximately 30 years. Although strenuous attempts were made to measure radon concentrations in all addresses occupied during the 5- to 30-year period, such a radon measurement program faces several challenges, including feasibility of placing dosimeters in individual houses and difficulty in gaining access to all houses where a subject had lived during the relevant period of exposure. In Languedoc-Roussillon, the program was interrupted because the local assistant resigned before the end of the study, and there were inevitably gaps in the measurement histories. However, various estimates using validated methodologies for handling missing data27 gave similar results; in our study, the choice of the methodology for handling missing data had a minor influence on the results. However, when the present analysis was limited to subjects for whom it was possible to obtain radon measurements for the entire 5- to 30-year period of interest, the estimated relative risks were slightly higher than for the entire group. This difference may be the result of the fact that more accurate information is available regarding the exposure histories in this subgroup, which is characterized by low residential mobility.

Indoor radon concentrations are subject to seasonal variation, with a minimum in summer and a maximum in winter. However, because of the poor prognosis of lung cancer and to increase acceptability of current occupants, radon detectors were in place for 6 months. To take into account the seasonal variation, correction factors were calculated.40 The correction effect was reduced (less than 20%), and seasonal adjustment was considered unnecessary.

Another source of imprecision could have been introduced by considering the contemporary measurements of radon concentrations as representative of concentrations as long as several decades. To minimize imprecision in radon exposure estimates, the analysis was carried out using only radon measurements of current homes. Current homes were occupied for 25 years on average, which is similar to other studies in Europe.14,17,23 Current homes therefore cover a large proportion of lifetime residential exposure. In addition, radon gas is measured with respect to study subjects’ actual living habits directly, which increases precision of individual exposure assessment.

In some case-control studies of lung cancer risk associated with radon,13–15,17–21 cases were recruited through cancer registries. With this approach, complete coverage of cases in the study area is possible, but most information depends on cases’ next of kin; because of the poor prognosis of lung cancer, most cases have already died by the time interviews and radon measurements are conducted.23 In contrast, we conducted face-to-face interviews at the hospital with the study subjects themselves, close to the date of diagnosis. In addition, hospital-based controls were selected rather than population-based controls to collect information in the same conditions for both cases and controls.

In the absence of an overall cancer registry in France, the representativeness of our case subjects is not measurable. The relatively low proportion of women among our cases is in agreement with previous studies showing that, in the past, lung cancer mortality rates in women were low in France compared with other industrialized countries.41

The present study will be part of pooled analyses from European and North American studies, with the goal of more precisely estimating the lung cancer risk associated with indoor radon exposure, while considering the interaction between radon and smoking.

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ACKNOWLEDGMENTS

We are indebted to the pneumologists who supported this study by opening their clinical departments to our interviewers, mainly Pr. Clavier and Dr. Larzul (Brittany), and Pr. Catanzano (Limousin). We thank all collaborators who organized and performed the field work. Special thanks to all interviewers in the participating hospitals, and especially to Joëlle Coutelle, Fabienne Jayoux, Anne Fort, and Jacqueline Foissac. We are also grateful to Florence Jourdain who made valuable contributions to data management and statistical analysis and to Pr. Lothar Kreienbrock for his helpful remarks, which served to improve the manuscript.

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