Combined Effect of Radon Exposure and Smoking and Their Interaction in Czech Studies of Lung Cancer

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1 Combined Effect of Radon Exposure and Smoking and Their Interaction in Czech Studies of Lung Cancer Ladislav Tomasek a*, Antonin Kubik b a National Radiation Protection Institute, Bartoskova 28,CZ14000 Prague,Czech Republic b University Hospital Na Bulovce, Budinova 2, CZ18081 Prague, Czech Republic. Abstract. The aim is to compare lung cancer risks from radon in smoking categories in Czech residential radon and uranium miners studies and to evaluate interactions between smoking and radon exposure. The residential and occupational studies are based on one hospital based case-control study and three case-control studies nested within cohort studies, two among uranium miners and one in the general population in a radon prone area. Controls in the nested studies are individually matched by sex, age and year of birth. Smoking data were collected in person or from relatives of deceased subjects. In the occupational studies, some smoking data were obtained from medical files. Radon exposures were based on measurements of radon in houses by open track detectors LR115 in the radon prone area and by closed detectors and electrets in the hospital based study. Exposures in uranium mines were based on extensive measurements and personal dosimetry. The analyses are based on conditional logistic regression with linear dependence of the risk on radon exposure adjusted for smoking. The study resulted in 300 cases and 1035 controls in the residential study and 672 cases and 1491 controls in the study of uranium miners. The dependence of lung cancer risk on radon exposure adjusted for smoking was not substantially different from analyses when smoking was ignored and reflected mainly the risk among smokers. However, the excess relative risk per unit exposure among non-smokers was 3-10 fold higher in comparison to that in smokers. The relative risk from radon among non-smokers was consistently higher in the occupational and residential studies, reflecting probably differences in lung morphometry, clearence and unattached fraction of radon progeny in houses of non-smokers. Risks from combined effects are substantially lower than the risk derived from the multiplicative model, but consistent with the additive model. KEYWORDS: Lung cancer, Uranium miners, Residential radon, Smoking. 1. Introduction According to the International Agency for Research on Cancer in Lyon, radon exposure is the second leading cause of lung cancer after cigarette smoking [1]. This conclusion is based mainly on studies of uranium miners. Because of the predominant role of cigarette smoking as a cause of lung cancer, an understanding of the joint effect of smoking and radon exposure is needed for the assessment of the risk from radon exposure. In most studies conducted among miners, individual smoking habits were not recorded. The exception of these are the studies of Colorado, New Mexico, Newfoundland, Sweden, and China [2]. In the Czech study, established in the early 1970s, individual smoking data could not be collected when the study was established [3]. However, as this information and analyses are substantial, a nested case-control study in the original cohort was initiated later, and smoking information was collected from medical files, from relatives and by personal interviews. Results from this occupational study are here compared to results from residential studies conducted in the Czech Republic recently. Earlier results summarized in the BEIR VI report [2] suggest higher relative risk coefficients among non-smokers, which can been explained by differences in lung morphometry or physical characteristics of the exposure. The aim of the present work is to verify these findings in the Czech cohort of uranium miners, together with results in the Czech residential studies. * Presenting author, ladislav.tomasek@suro.cz 1

2 2. Methods 2.1 Study populations The present study is based on four different studies, two residential and two occupational. The residential studies include one nested case-control study selected within a cohort study conducted in in a radon prone area [4]. The other study was conducted within a large case-control study [5,6] in the University Hospital Na Bulovce with the catchment area covering north-eastern sectors of Prague and the adjacent central Bohemia region. Cases in this study were patients with confirmed lung cancer admitted to the Department of Pneumology in Controls were spouses, relatives or friends of other patients of hospital departments, with conditions unrelated to smoking. The controls were matched by sex and age (within 5 years). Informed consent was obtained from all interviewed subjects. In the residential study of Middle Bohemia Pluton, four controls were selected at random from the cohort members who were alive at the time of death of the case and were matched by sex, year of birth (within 5 years), and age. Smoking data were collected in person and from the relatives of deceased subjects. The occupational study includes two cohorts of uranium miners, one located in West Bohemia mines (Jachymov, exposure ) and the other in Pribram mines in central Bohemia (exposure ). Details of these cohort studies are given elsewhere [7]. In the nested occupational studies, for each case of lung cancer with smoking data up to three controls were selected from all cohort members similarly as the controls in the residential cohort matched by year of birth, age, and the study. Information on cases in the cohorts was based on death certificates. Data on smoking in the occupational study were collected from subjects by personal interview (40%), from medical records (26%), and from relatives (34%). The project was approved by the Ethical Committee of the Hospital Na Bulovce and registered by the Czech Office of Personal Data Protection and was conducted in accordance with epidemiological good practice standards. 2.2 Exposure estimates and radon measurements Exposure estimates in the residential studies were based on one year measurements of radon progeny in all houses in the study area using open alpha track detectors (LR115), missing data were replaced by appropriate municipality means according to national radon survey [4]. Exposures in houses in the hospital based study were measured using electret ionization chambers exposed for 3 months and by closed passive alpha track detectors (LR-115, type Karlsruhe) exposed for 4 months in the current home. In the occupational study, exposure estimates were based on extensive measurements of radon that were conducted since 1949 in the mines. There were about 200 measurements per year and shaft. Missing values (4%) were extrapolated. For comparison to earlier results, occupational exposures are given in working level months (WLM). One WLM is exposure for 1 month (170h) at 1 WL (working level) corresponding to MeV of potential alpha energy released by the short-lived progeny in equilibrium with radon in one litre of air (3.7 kbq/m 3 ). For comparison to residential exposure, occupational exposures are converted to cumulated intake in MBq assuming breathing rate 1.2 m 2 /h, which results in equation 1 WLM = MBq. On the other hand, residential exposures within previous 5-34 years are converted in time integrated exposure in the same units, assuming an equilibrium ratio F=0.4 between concentrations of radon and radon progeny, mean occupancy 80% (7000 hours annually) and breathing rate of 0.6 m 2 /h (corresponding to predominant activity in homes rest and sleeping). Mean concentration of 100 Bq/m 3 then corresponds to cumulated intake of 5.04 MBq. 2

3 2.3 Statistical assessment The statistical assessment of the study was based on conditional logistic regression with linear dependence of estimated relative risk (odds ratio) on radon exposure (X). RR = exp(α) exp (γ Z) ( 1 + β X), where exp(α) is baseline risk when X=0 and β describes the linear trend between the risk and radon exposure (X). In the residential study, the exposure was considered in terms of mean radon concentration during previous 5-34 years before the index year. This period was chosen because exposures before more than 34 years were found to have little effect (see for instance Tomasek et al [7]) and exposure in recent 5 years before diagnosis is ignored because of the minimum latency period that is commonly used in studies of lung cancer and radon. In controls individually matched to each case, exposure were ignored 5 years before corresponding index year of the case. In the occupational study, the exposure was considered in terms of time integrated cumulated exposure in WLM and lagged correspondingly by 5 years. Allowance was always made for potential confounders through stratification and by including categorical smoking covariates Z in the model. 3. Results A total of 300 cases and 1035 controls were included in the residential study and 672 cases and 1491 controls in the study of uranium miners (Table 1). The earlier study in the radon prone area, where only 7% of subjects had exposures below 200 Bq/m 3, was complemented by the hospital based study with most of subjects' exposure below 200 Bq/m 3. In both the studies, the mean exposures among cases were significantly higher in comparison to controls. In the residential study, there were 14% of women. The age in the residential study ranged from 37 to 98 years with the mean of 66 and the standard deviation of 10. In the occupational study of uranium miners, a total of 672 cases of lung cancer and 1491 controls were observed reflecting higher risk in the original cohort of 9979 miners. The age in this study ranged from 28 to 90 years with the mean of 59 and the standard deviation of 10, which reflects the substantial effect of radon exposure in addition to smoking. Table 1: Summary of the studies, numbers of cases and controls and their exposure Study Cases Controls Exposure in cases Exposure in controls Middle Bohemia Pluton Bq/m Bq/m 3 University Hospital Na Bulovce Bq/m 3 81 Bq/m 3 both residential Bq/m Bq/m 3 Jachymov U miners WLM 146 WLM Pribram U miners WLM 8 WLM both occupational WLM 118 WLM In the residential study, there were 46 (15%) never-smokers and 69 (23%) ex-smokers among cases (Table 2). In the occupational study, the proportion of never-smokers was lower 8% (54 cases). The risks from smoking in both the studies were substantially lower in subjects who quitted smoking before more than 10 years, but the risks in ex-smokers who quitted before less than 10 years were comparable to the risk in current smokers. In the next analyses, the latter two groups of smokers are combined. Because of similar risks in the remaining two groups of ex-smokers, we consider only one category of ex-smokers quitting before 10 years or more. The current and ex-smokers who quitted before less than 10 years are further divided according to mean number of cigarettes per day in three categories 1-14, 15-24, and 25+ cigarettes per day. Lower relative risks from smoking among uranium miners (Table 2) reflect the substantial effect of radon exposure, mainly among neversmokers, which is analyzed further. 3

4 Table 2: Summary smoking data in the studies, numbers of cases and relative risks (OR) residential study occupational study Smoking cases OR 90%CI cases OR 90%CI never quitted 20y quitted 10-19y quitted <10y current Combined risk in the residential study The combined risks from smoking and radon in the residential study are given in Table 3, where the risks are in terms of odds ratios (OR) and odds ratios adjusted for smoking and radon exposure. For radon exposure, we estimate the excess relative risk per unit exposure (100 Bq/m 3 ), both and smoking adjusted. Estimates of the risk coefficients are somewhat higher when adjusted, which reflects some negative correlation between smoking and radon exposure. The interaction between smoking and radon exposure is given in terms of separate estimates of risk coefficients in non-smokers (never- and ex-smokers for 10 years or more) and smokers (current and ex-smokers for less than 10 years). The excess relative risk per 100 Bq/m 3 in non-smokers (never-smokers and ex-smokers for more than 10 years) is higher, but the overall attributable risk in smokers is higher because of substantially higher risks from smoking. Separate estimates for all the three smoking categories could not been obtained because of small numbers of cases in never- and ex- smokers. Table 3: Relative risks from smoking and radon exposure in the residential study, estimates of excess relative risk per unit exposure (ERR/100Bq m -3 ) cases OR 90%CI adjusted a OR 90%CI Smoking never quitted 10y other b <15c/d other b 15-24c/d other b 25c/d Radon exposure <100 Bq m Bq m Bq m Bq m Bq m Risk coefficients ERR/100Bq m -3 90%CI smoking adjusted ERR/100Bq m -3 90%CI overall non-smoking c other b p d a adjusted for radon exposure or smoking b other = current + quitted <10 years c non-smoking = never smoking + quitted 10 years d test of homogeneity 4

5 3.2 Combined risk from radon and smoking in the occupational study In the occupational study, where the numbers of cases were more than doubled, the pattern of risk are more pronounced than in the residential study (Table 4), but the patterns are similar. In these analyses, the risk from radon exposure is somewhat reduced when adjusted for smoking which reflects a positive correlation between smoking and radon exposure in miners. In this study, the excess relative risks per 1WLM could be estimated for all the three categories of smoking. Although the three estimates are not significantly different as a whole, the risk coefficients are more than 3 fold higher among never smokers in comparison to current smokers (1-sided p=0.087). The estimated risks from smoking in the occupational study are lower than those in the residential study. However, when interactions are included in the model (in terms of smoking specific estimates of ERR/WLM), the OR in ex-smokers for 10 years or more is 2.9 and ORs are in the range for current and ex-smokers who quitted before 10 year or less. Table 4: Relative risks from smoking and radon exposure in the occupational study, estimates of excess relative risk per unit exposure (ERR/WLM) Cases OR 90%CI adjusted a OR 90%CI Smoking never quitted 10y other b <15c/d other b 15-24c/d other b 25c/d Radon exposure 0-49 WLM WLM WLM WLM Risk coefficients ERR/WLM 90%CI smoking adjusted ERR/WLM 90%CI Overall non-smoking c other b p d never smoking > >0.5 quitted 10y other b p d a adjusted for radon exposure or smoking b other = current + quitted <10 years c non-smoking = never smoking + quitted 10 years d test of homogeneity 3.3 Risk from radon and smoking in the entire study In order to increase the statistical power to detect the interaction, we combined both the studies. Because exposures in the residential study are limited to exposure window 5-34 years, the following results are presented in relation to this window. As expected, general trends of the risk in smoking and radon exposure categories are strengthened in the combined study. The most important result in this analysis are significant differences in risk coefficients observed mainly among never-smokers and ever-smokers. The substantially higher excess relative risk per unit exposure among never-smokers confirms the earlier observations among uranium miners. 5

6 Table 5: Estimates of excess relative risk per unit exposure (ERR/MBq) in the combined study of residential and occupational exposure in relation to cumulated radon intake (MBq) in exposure window 5-34 years Risk coefficients ERR/MBq smoking adjusted ERR/MBq overall non-smoking a other b p c never smoking ever smoking p c <0.001 <0.001 never smoking quitted 10y other b p c <0.001 <0.001 a non-smoking = never smoking + quitted 10 years b other = current + quitted <10 years c test of homogeneity 3.4 Relative risks according to additive and multiplicative models The relative risks of smoking and radon and their interaction is further evaluated for the present combined study. The relative risks (OR) are estimated at 4 categories of exposure for smokers and never-smokers with cut points approximately corresponding to quartiles among cases. The resulting risks are given in Table 6 together with projections corresponding to the additive and multiplicative models. Based on lowest exposure category (0-15 MBq), the relative risk of smoking alone is estimated as RR(0,S)=16.0. In the additive model, the combined risk from radon and smoking is obtained as RR a (Rn,S) = RR(Rn,0) + RR(0,S) 1, in the multiplicative model RR m (Rn,S) = RR(Rn,0) * RR(0,S), Where RR(Rn,0) is the relative risk from radon alone (in never-smokers). Table 6: Relative risk in combined categories of smoking and radon exposure and comparison to additive and multiplicative models never- smokers smokers a additive mutiplicative Exposure model model (MBq) cases OR 90%CI cases OR 90%CI RR a RR m a current and short-term ex-smokers Although the combined risks from radon and smoking are between the multiplicative and additive model, the observed relative risk is closer to the additive model. In the highest category, the relative risk from radon and smoking exceeds the additive model by 40%, whereas the combined risk is lower 6

7 by 85% than the risk corresponding to the multiplicative model. Considering the confidence intervals, we can conclude that the observed combined risk is consistent with the additive model. 4. Discussion 4.1 The effect of adjustment for smoking After adjustment for smoking in the present residential study, a steeper trend in the risk from radon (and higher risk coefficients) in comparison to estimates was observed. This is usual in residential studies as smoking is negatively correlated with radon levels. For instance, there are 40% never smokers among controls below 600 Bq/m 3 in comparison to 48% never smokers above 600 Bq/m 3 in the present study. The explanations include higher socio-economic levels among owners of family houses with usually higher levels of radon and also a higher level of ventilation in homes of smokers. In the occupational study, the adjustment for smoking leads to a certain decrease of the relative risk in exposure categories and the risk coefficient. This is because smoking was positively correlated with exposure to radon. There were 33% never smokers among controls below 99WLM in comparison to 28% in WLM and 23% over 200WLM. Relative risks from smoking in the present study of uranium miners are lower than the risks in the population study, when the multiplicative model is assumed. Similar low risks were reported by L'Abbe et al [8] (OR=2.52) or Leuraud et al [9], where OR from smoking was 3.32 and OR was 4.83 in the multiplicative model. However, it should be noted that the RR=1 in the multiplicative model corresponds to non-smoking and low exposed subjects. Because the never-smoking group includes also cases from higher exposure categories, the baseline risk in this group is elevated in comparison to the general population. For the entire combined study, the risks from smoking are estimated better with OR=9.7 for current and short-term ex-smokers. In the present Czech study, however, smoking related risks are higher in the model with interactions. 4.2 Comparison of the risk in the present residential and occupational studies When the excess relative risk from radon in the present two studies were related to the same unit cumulated exposure (MBq), the smoking adjusted estimate of ERR/MBq in the residential study (90%CI: ) was somewhat different than the estimate obtained from the occupational study (90%CI: ). These two estimates, however, are not statistically different (p=0.779). Therefore, the combined analysis of the two studies is justified. Generally, the assessment of interactions between risk factors requires studies of higher statistical power than the evaluation of single risk factors. The study power depends on number of cases and, mainly, on the levels of exposure. In the studies of the lung cancer risk from radon and smoking, the substantial issue is the level of radon exposure. The exposures in the present studies belong to highest in comparison to other studies both in miners and the general population. 4.3 Comparison to other occupational studies The interactions between exposure to radon and smoking in six studies of miners were investigated by Lubin et al [10]. Most of this studies were consistent with a model intermediate between additive and multiplicative. Additive interactions were reported in a Swedish study of iron miners [11] or in a Czech study of shale-clay miners [3], whereas a multiplicative interaction was reported in the New Mexico study of uranium miners [12] and in the Newfoundland study of fluorspar miners [13]. An intermediate interaction between additive and multiplicative was observed in the Colorado Plateau study of uranium miners [14] and in the Chinese study of tin miners [15]. Six of the above studies were jointly analyzed in the BEIR VI report [2] and resulted in a sub-multiplicative model. The ratio of ERR/WLM in non-smokers and smokers was 2.1 (95%CI: ). The confidence interval of this ratio is relatively wide and reflects mainly small numbers of lung cancers among non-smokers - 64 cases in the joint study of BEIR VI. 7

8 4.4 Comparison to other residential studies The interaction between radon exposure and smoking was investigated in pooled analyses of European, North American, and Chinese residential studies. The ratio in ERR/100Bq m -3 between never- and ever-smokers in the European combined study [16] was 1.5 with an approximate 95%CI and this ratio was 2.2 (95%CI ) after a correction for uncertainties in exposures. A similar ratio was observed in the North American study [17,18] with an approximate 95%CI (p=0.64). In the pooled China study [18] for complete coverage of exposure in time window (5-30 years) the ratio was 2.6, approximate 95%CI (p=0.42) In spite of large numbers in these pooled studies, there is a low statistical power to detect interactions between radon exposure and smoking. Mean radon concentrations in these studies were 105 Bq/m 3, 67 Bq/m 3, and 199 Bq/m 3, respectively. In the present Czech residential study, the mean exposure was substantially higher Bq/m Interpretation of interactions The differences between all three main categories of smokers (never-, ex- and current smokers) could not been tested in the residential study alone because of its lower power given by numbers of cases and mainly because of substantially lower exposures (mean residential exposure 21 MBq in comparison to 79 MBq among uranium miners). In the residential study, only excess relative risks per unit exposure in combined smoking categories (never + quitted 10 years) could be estimated and compared. In the combined study, however, the estimates in all three smoking categories were possible and resulted in large differences mainly between never and other smokers. In the BEIR VI report [2], potential reasons for interactions of smoking and radon exposure are given. Some of them include the impact on exposure, others - exposure-dose relation and others - doseresponse relation in smokers and non-smokers. Although the study does not provide evidence relevant to each of the reasons, the likely explanations include differences in lung morphometry of target cells, thickness of the mucous layer [20] and clearence between smokers and non-smokers. In the residential study, the difference in the relative risk may be influenced in addition by a higher proportion of unattached fraction in homes of non-smokers where aerosol particle concentrations are generally lower. According to the BEIR VI report [2], unattached decay products have much higher mobility in the air and can more effectively deposit in the respiratory tract. The latter conditions are not typical in the occupational study because smoking was not allowed in underground workplaces and underground aerosol particle concentrations were much higher in comparison to homes. In the occupational study, the increase of ERR/WLM in never smokers was about 3 fold in comparison to 10 fold increase in the combined study. 5. Conclusions The relative risk from radon among non-smokers was consistently higher in the present occupational and residential studies. These differences are likely to reflect differences in lung morphometry and clearence among smokers and non-smokers. The differences may be also influenced by different proportion of unattached fraction of radon progeny in houses of smokers and non-smokers. Risks from combined effects are substantially lower than the risk derived from the multiplicative model, but consistent with the additive model. Acknowledgements The research on the residential study was supported by the Internal Grant Agency of the Czech Ministry of Health (Reg. No. NR ) and the nested occupational study was partially supported by European Commission (Reg. No FI6R). The authors wish to thank Dana Struplova, Milada Jelinkova and Milana Rendlova for the collection of data and Josef Holecek for the evaluation of radon track detectors. 8

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