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RESIDENTIAL RADON EXPOSURE AND LUNG CANCER IN SWEDEN

GÖRAN PERSHAGEN, M.D., GUSTAV ÅKERBLOM, M.SC., OLAV AXELSON, M.D., BERTIL CLAVENSJÖ, M.SC., LENA DAMBER, PH.D., GUNILLA DESAI, B.A., ANITA ENFLO, PH.D., FRÉDÉRIC LAGARDE, B.SC., HANS MELLANDER, M.SC., MAGNUS SVARTENGREN, M.D., AND GUN ASTRI SWEDJEMARK, PH.D.

Abstract Background. Residential radon is the principal source of exposure to ionizing radiation in most countries. To determine the implications for the risk of lung cancer, we performed a nationwide case-control study in Sweden.

Methods. The study included 586 women and 774 men 35 to 74 years of age with lung cancer that was diagnosed between 1980 and 1984. For comparison, 1380 female and 1467 male controls were studied. Radon was measured in 8992 dwellings occupied by the study subjects at some time since 1947. Information on smoking habits and other risk factors for lung cancer was obtained from questionnaires.

Results. Radon levels followed a log-normal distribution, with geometric and arithmetic means of 1.6 and 2.9 pCi per liter (60.5 and 106.5 Bq per cubic meter), respectively. The risk of lung cancer increased in relation to both estimated cumulative and time-weighted exposure to radon. In comparison with time-weighted average radon concentrations up to 1.4 pCi per liter (50 Bq per cubic meter), the relative risk was 1.3 (95 percent confidence interval, 1.1 to 1.6) for average radon concentrations of 3.8 to 10.8 pCi per liter (140 to 400 Bq per cubic meter), and it was 1.8 (95 percent confidence interval, 1.1 to 2.9) at concentrations exceeding 10.8 pCi per liter. The estimates of risk were in the same range as those projected from data in miners. The interaction between radon exposure and smoking with regard to lung cancer exceeded additivity and was closer to a multiplicative effect.

Conclusions. Residential exposure to radon is an important cause of lung cancer in the general population. The risks appear consistent with earlier estimates based on data in miners. (N Engl J Med 1994;330:159–64.)

RADON-222 in dwellings is the dominant source of exposure to ionizing radiation in most countries.1 Nationwide measurement programs suggest that the average radon concentration in Sweden is about 2.7 pCi per liter (100 Bq per cubic meter), a level that appears higher than those in many other countries. Current standards in Sweden correspond to about 3.8 pCi per liter (140 Bq per cubic meter) for new houses and 10.8 pCi per liter (400 Bq per cubic meter) for existing houses, whereas in the United States the recommended level at which action should be taken is 4 pCi per liter (148 Bq per cubic meter).2

Underground miners exposed to high levels of radon progeny (also known as radon daughters because they are decay products that follow radon-222 in the uranium series that begins with uranium-238)3 have an increased risk of lung cancer.4 Studies in laboratory animals confirm that the inhalation of radon progeny can induce lung cancer. Quantitative assessments of risks to the population based on data in miners have considered the role of differences in age, sex, cigarette smoking, the size distribution of aerosol particles, the unattached fraction of radon progeny, breathing rate, and route,46 but the value for many of these indexes is uncertain, as is their influence on estimates of risk.

The risk of lung cancer posed by residential exposure to radon has been studied in epidemiologic investigations using ecologic, cohort, and case-control designs.713 Positive trends were observed in some studies but not in others, and there has been no consistent pattern to the interaction between radon exposure and smoking in relation to lung cancer.

The primary aim of this study was to narrow the uncertainty in the estimation of the risk of residential exposure to radon, which necessitated a study considerably larger than any of the earlier investigations. A further aim was to assess the interactions between residential radon exposure and other factors, primarily smoking.

METHODS
Study Subjects

The study base included all subjects 35 to 74 years of age who had lived in 1 of 109 municipalities in Sweden at some time from January 1, 1980, through December 31, 1984, and who had been living in Sweden on January 1, 1947. Fifty-six of the municipalities were selected as areas where there was a high risk of radon in dwellings according to earlier measurements, geologic information, and data on the use of uranium-rich alum shale concrete as a building material. This concrete is an important source of indoor radon in Sweden and was widely used until 1975.3 The remaining municipalities were areas where there was a low risk of radon in dwellings. Municipalities with mining activity and the large cities of Stockholm, Göteborg, and Malmö were not included.

A total of 1500 subjects 35 to 74 years of age with primary cancer of the bronchus or lung (“lung cancer,” as defined in the International Classification of Diseases, 7th Revision, code 162.1) diagnosed from January 1, 1980, through December 31, 1984, were selected from the Swedish Cancer Registry. This included all 650 women and a random sample of 850 men that corresponded to about 40 percent of the men with lung cancer in the study base. Twelve subjects were excluded because the medical records revealed that nine did not have primary lung cancer and that three had nonepithelial tumors. After the further exclusion of 128 subjects not residing in Sweden on January 1, 1947, 586 women and 774 men remained (Table 1). Nearly half the cases of lung cancer appeared in the group 65 to 74 years of age, and the men with the disease tended to be older than the women.

Histologic confirmation of lung cancer was available for 84.2 percent of the subjects, cytologic confirmation was available for 14.6 percent, and in 1.1 percent the diagnosis was based on other

   

From the Institute of Environmental Medicine, Karolinska Institute, Stockholm (G.P., F.L., M.S.); the Swedish Radiation Protection Institute, Stockholm (G.Å., A.E., H.M., G.A.S.); the Department of Occupational and Environmental Medicine, University Hospital, Linköping (O.A., G.D.); Bjerking Ingenjörsbyrå, Uppsala (B.C.); and the Department of Oncology, University Hospital, Umeå (L.D.)—all in Sweden. Address reprint requests to Dr. Pershagen at the Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden.

Supported by grants from the Swedish Radiation Protection Institute, the Swedish Cancer Society, the Swedish Council for Building Research, and the Swedish Council for Planning and Coordination of Research.



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Environmental Medicine: Integrating a Missing Element into Medical Education RESIDENTIAL RADON EXPOSURE AND LUNG CANCER IN SWEDEN GÖRAN PERSHAGEN, M.D., GUSTAV ÅKERBLOM, M.SC., OLAV AXELSON, M.D., BERTIL CLAVENSJÖ, M.SC., LENA DAMBER, PH.D., GUNILLA DESAI, B.A., ANITA ENFLO, PH.D., FRÉDÉRIC LAGARDE, B.SC., HANS MELLANDER, M.SC., MAGNUS SVARTENGREN, M.D., AND GUN ASTRI SWEDJEMARK, PH.D. Abstract Background. Residential radon is the principal source of exposure to ionizing radiation in most countries. To determine the implications for the risk of lung cancer, we performed a nationwide case-control study in Sweden. Methods. The study included 586 women and 774 men 35 to 74 years of age with lung cancer that was diagnosed between 1980 and 1984. For comparison, 1380 female and 1467 male controls were studied. Radon was measured in 8992 dwellings occupied by the study subjects at some time since 1947. Information on smoking habits and other risk factors for lung cancer was obtained from questionnaires. Results. Radon levels followed a log-normal distribution, with geometric and arithmetic means of 1.6 and 2.9 pCi per liter (60.5 and 106.5 Bq per cubic meter), respectively. The risk of lung cancer increased in relation to both estimated cumulative and time-weighted exposure to radon. In comparison with time-weighted average radon concentrations up to 1.4 pCi per liter (50 Bq per cubic meter), the relative risk was 1.3 (95 percent confidence interval, 1.1 to 1.6) for average radon concentrations of 3.8 to 10.8 pCi per liter (140 to 400 Bq per cubic meter), and it was 1.8 (95 percent confidence interval, 1.1 to 2.9) at concentrations exceeding 10.8 pCi per liter. The estimates of risk were in the same range as those projected from data in miners. The interaction between radon exposure and smoking with regard to lung cancer exceeded additivity and was closer to a multiplicative effect. Conclusions. Residential exposure to radon is an important cause of lung cancer in the general population. The risks appear consistent with earlier estimates based on data in miners. (N Engl J Med 1994;330:159–64.) RADON-222 in dwellings is the dominant source of exposure to ionizing radiation in most countries.1 Nationwide measurement programs suggest that the average radon concentration in Sweden is about 2.7 pCi per liter (100 Bq per cubic meter), a level that appears higher than those in many other countries. Current standards in Sweden correspond to about 3.8 pCi per liter (140 Bq per cubic meter) for new houses and 10.8 pCi per liter (400 Bq per cubic meter) for existing houses, whereas in the United States the recommended level at which action should be taken is 4 pCi per liter (148 Bq per cubic meter).2 Underground miners exposed to high levels of radon progeny (also known as radon daughters because they are decay products that follow radon-222 in the uranium series that begins with uranium-238)3 have an increased risk of lung cancer.4 Studies in laboratory animals confirm that the inhalation of radon progeny can induce lung cancer. Quantitative assessments of risks to the population based on data in miners have considered the role of differences in age, sex, cigarette smoking, the size distribution of aerosol particles, the unattached fraction of radon progeny, breathing rate, and route,4–6 but the value for many of these indexes is uncertain, as is their influence on estimates of risk. The risk of lung cancer posed by residential exposure to radon has been studied in epidemiologic investigations using ecologic, cohort, and case-control designs.7–13 Positive trends were observed in some studies but not in others, and there has been no consistent pattern to the interaction between radon exposure and smoking in relation to lung cancer. The primary aim of this study was to narrow the uncertainty in the estimation of the risk of residential exposure to radon, which necessitated a study considerably larger than any of the earlier investigations. A further aim was to assess the interactions between residential radon exposure and other factors, primarily smoking. METHODS Study Subjects The study base included all subjects 35 to 74 years of age who had lived in 1 of 109 municipalities in Sweden at some time from January 1, 1980, through December 31, 1984, and who had been living in Sweden on January 1, 1947. Fifty-six of the municipalities were selected as areas where there was a high risk of radon in dwellings according to earlier measurements, geologic information, and data on the use of uranium-rich alum shale concrete as a building material. This concrete is an important source of indoor radon in Sweden and was widely used until 1975.3 The remaining municipalities were areas where there was a low risk of radon in dwellings. Municipalities with mining activity and the large cities of Stockholm, Göteborg, and Malmö were not included. A total of 1500 subjects 35 to 74 years of age with primary cancer of the bronchus or lung (“lung cancer,” as defined in the International Classification of Diseases, 7th Revision, code 162.1) diagnosed from January 1, 1980, through December 31, 1984, were selected from the Swedish Cancer Registry. This included all 650 women and a random sample of 850 men that corresponded to about 40 percent of the men with lung cancer in the study base. Twelve subjects were excluded because the medical records revealed that nine did not have primary lung cancer and that three had nonepithelial tumors. After the further exclusion of 128 subjects not residing in Sweden on January 1, 1947, 586 women and 774 men remained (Table 1). Nearly half the cases of lung cancer appeared in the group 65 to 74 years of age, and the men with the disease tended to be older than the women. Histologic confirmation of lung cancer was available for 84.2 percent of the subjects, cytologic confirmation was available for 14.6 percent, and in 1.1 percent the diagnosis was based on other     From the Institute of Environmental Medicine, Karolinska Institute, Stockholm (G.P., F.L., M.S.); the Swedish Radiation Protection Institute, Stockholm (G.Å., A.E., H.M., G.A.S.); the Department of Occupational and Environmental Medicine, University Hospital, Linköping (O.A., G.D.); Bjerking Ingenjörsbyrå, Uppsala (B.C.); and the Department of Oncology, University Hospital, Umeå (L.D.)—all in Sweden. Address reprint requests to Dr. Pershagen at the Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden. Supported by grants from the Swedish Radiation Protection Institute, the Swedish Cancer Society, the Swedish Council for Building Research, and the Swedish Council for Planning and Coordination of Research.

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Environmental Medicine: Integrating a Missing Element into Medical Education Table 1. Age Distribution of the Case Subjects with Lung Cancer and the Subjects in the Two Control Groups, According to Sex. AGE (YR) CASE GROUP FIRST CONTROL GROUP SECOND CONTROL GROUP   WOMEN MEN WOMEN MEN WOMEN MEN   number of subjects (percent)   35–44 46 (7.9) 22 (2.8) 33 (4.5) 36 (5.2) 29 (4.5) 33 (4.3) 45–54 81 (13.8) 75 (9.7) 82 (11.2) 97 (14.0) 96 (14.8) 88 (11.4) 55–64 200 (34.1) 277 (35.8) 256 (35.1) 232 (33.4) 232 (35.7) 286 (37.0) 65–74 259 (44.2) 400 (51.7) 359 (49.2) 329 (47.4) 293 (45.0) 366 (47.3) All 586 (100.0) 774 (100.0) 730 (100.0) 694 (100.0) 650 (100.0) 773 (100.0) evidence (e.g., autopsy findings or operation without histologic analysis). Histopathological typing of the tumors was based on the classification of the World Health Organization (WHO).14 The reports from the pathology departments were reviewed and used to code the cancer in 1264 subjects (92.9 percent). For the remaining subjects, the coding was based on information from the Swedish Cancer Registry. This registry used a classification that was compatible with the WHO system for squamous-cell carcinomas and adenocarcinomas but did not differentiate between small-cell and large-cell carcinomas. Two control groups representing the study base were selected from the population registers of Statistics Sweden. Each group included 1500 subjects. The first control group was frequency-matched for age (in five-year intervals) and calendar year of residence with the case group, and it originally included 775 women and 725 men. Immigrants to Sweden after January 1, 1947, were excluded, leaving 730 women and 694 men for the subsequent analyses (Table 1). The slight differences in age distribution between the case subjects and the controls resulted from the exclusion of immigrants. The second control group was selected according to the same criteria used to select the first group, except that in addition it was frequency-matched for vital status, with use of the Swedish Cause of Death Registry. Matching for vital status was performed to reduce potential bias in obtaining information on exposure. Subjects who had died of smoking-related causes were excluded from the second control group to avoid overrepresentation of smoking.15 On the basis of evidence from Swedish studies,16,17 the following diagnoses were regarded as related to smoking: cancer of the mouth, esophagus, liver, pancreas, larynx, uterine cervix, or bladder; ischemic heart disease; aortic aneurysm; cirrhosis of the liver; chronic bronchitis and emphysema; gastric ulcer; death from violent causes; and intoxication. The second control group originally included 683 women and 817 men, but after the exclusion of those who did not reside in Sweden on January 1, 1947, a total of 650 women and 773 men remained. When the study subjects were selected (on December 31, 1986), 518 women (88.4 percent) and 706 men (91.2 percent) in the case group had died. In the first control group, 55 women (7.5 percent) and 68 men (9.8 percent) had died, and in the second control group, 572 women (88.0 percent) and 707 men (91.5 percent) had died. Information on Radon Exposure All the study subjects or their next of kin were mailed a standardized questionnaire inquiring about the smoking habits of the subjects and their spouses and parents. The subjects’ lifetime occupational history and their residential addresses since 1947 were also investigated. Questions were asked about the type of house, the building material used, the heating system, the amount of time spent at home, and the like. In the event of an incomplete questionnaire or a failure to respond, supplementary information was obtained in telephone interviews. Those collecting the data did so without knowing whether the subject under study was a case subject or a control. Questionnaires were returned for 1118 case subjects, as well as for 1192 and 1135 subjects in the two control groups, yielding response rates of 82.2, 83.7, and 79.8 percent, respectively. In the first control group the respondents to the questionnaire were primarily the study subjects (81.7 percent), whereas in the case group and the second control group next of kin predominated (91.8 and 90.7 percent). Among next-of-kin respondents, spouses were the most common (47.8 percent in the case group and 43.8 percent in the second control group), followed by children (39.0 and 37.9 percent in the case group and the second control group, respectively). The assessment of each subject’s exposure to radon was based on a residential history and on radon measurements. In the compilation of the residential history, data from parish registers were supplemented with information from the questionnaires, so that a complete record of residential addresses from 1947 on was made available. The radon measurements were intended to include all dwellings in which the subject had lived during a “residential period,” defined as a period of two years or more from 1947 to three years before the end of follow-up. The year of diagnosis constituted the end of follow-up for the case subjects, whereas the frequency-matched year of selection was used for the controls. A total of 13,392 residential periods were identified (Table 2), but for 7.5 percent the address could not be identified because the subject resided in an unknown place, abroad, in a hospital, on a ship, or the like. Information on addresses was available for 12,394 dwellings, or an average of 3.1, 2.9, and 2.8 dwellings per subject in the case group and the first and second control groups, respectively. Radon measurements could not be made in 3402 dwellings (27.4 percent), usually because the house no longer existed or was being used only as a summer house. Radon was measured over a period of three months during the heating season—i.e., a time between October 1 and April 30. In each dwelling one detector was placed in a bedroom and another in the living room, mostly by personnel from the local board of public health. Radon was measured by solid-state alpha track detectors processed at the Swedish Radiation Protection Institute. The system includes an alpha track detector, a holder, a chemical etching process, and an automatic readout by an image system.18 For a measurement period of 90 days, the total error resulting from uncertainty in calibration, film sensitivity, readout, counting statistics, and background is 10 percent at radon concentrations of 1.6 pCi per liter (60 Bq per cubic meter), 7 percent at concentrations of 3.1 pCi per liter (115 Bq per cubic meter), and 5 percent at concentrations of 10 pCi per liter (370 Bq per cubic meter). The detectors were calibrated at the Radiation Protection Institute, which has taken part in international comparisons since the 1970s with good results.19,20 Cumulative radon exposure since 1947 was estimated for each subject by adding the products of the measured radon level and the length of time the subject lived in each residence. Time-weighted mean radon concentrations were calculated by dividing the cumulative radon exposure by the total time spent living in residences for which radon measurements were available. In some analyses of cumulative exposure to radon, missing measurements were replaced by the median radon level for all study subjects. In other analyses, these replacements were based on information about the characteristics of the residence (the building material and type of house) obtained from the questionnaire and the characteristics of the municipality (high, medium, or low risk of radon in dwellings). Information on whether the subjects slept in a room with an open window, which may have an influence on radon exposure, was used in some analyses. Cutoff points in the analyses using time-weighted mean radon concentrations were based partly on current Swedish standards. Smoking habits were classified according to the time-weighted mean consumption of tobacco during the subject’s lifetime. Daily consumption was expressed in cigarette equivalents, with one pack (50 g) of pipe tobacco a week corresponding to 7.1 cigarettes a day. Conversions were also made for cigarillos and cigars, which were rarely used. Subjects who stopped smoking two or more years before the end of the follow-up period were classified as ex-smokers. Each job held by a study subject was classified in one of four categories based on earlier evidence of occupational risks of lung

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Environmental Medicine: Integrating a Missing Element into Medical Education Table 2. Assessment of Radon Levels in Dwellings Where the Study Subjects Lived for at Least Two Years during the Period Studied.* VARIABLE CASE SUBJECTS WITH LUNG CANCER FIRST CONTROL GROUP SECOND CONTROL GROUP   number (percent)   Residential periods 4581 4437 4374 Addresses identified 4246 (100.0) 4138 (100.0) 4010 (100.0) Dwellings assessed 3078 (72.5) 3030 (73.2) 2884 (71.9) Dwellings not assessed   House nonexistent 483 (11.4) 405 (9.8) 447 (11.1) House used only in summer 229 (5.4) 221 (5.3) 227 (5.7) House not used as residence 86 (2.0) 71 (1.7) 106 (2.6) Permission for assessment withheld 141 (3.3) 198 (4.8) 168 (4.2) House not able to be located 192 (4.5) 175 (4.2) 154 (3.8) Other 37 (0.9) 38 (0.9) 24 (0.6) *The assessment of residential exposure to radon is explained in greater detail in the Methods section. Percentages may not total 100 because of founding. cancer, including data from some Swedish studies.21–23 Subjects working for two years or more in a job assigned to either of the two highest-risk categories were considered to have a high risk, those working only in jobs assigned to the category with lowest risk were considered to have a low risk, and the remaining subjects were considered to have a medium risk. Subjects who lived for 10 years or more in one of the three largest cities in Sweden (Stockholm, Göteborg, or Malmö) at some time between 1947 and the end of the follow-up were classified as urban dwellers. Excess risks of lung cancer have been reported in these cities after adjustment for smoking.24 Statistical Analysis The data were analyzed with the Epicure package.25 Associations between different measures of exposure to radon and the risk of lung cancer were described with maximum-likelihood estimates of relative risk and 95 percent confidence intervals based on logistic-regression analyses.26 The indicator variables were categories of exposure to radon, age (in five-year intervals), smoking status, urbanization, and occupational exposure. Cross-classification of these variables constituted the strata in a conditional logistic regression. Analyses of trends with a continuous variable for exposure to radon were based on a linear model of relative risk,27 in accordance with most current analyses of studies of miners.4 The coefficient for the linear increase in relative risk was adjusted to improve the convergence of the iterative estimation procedure,28 and the confidence intervals were based on the likelihood-ratio criterion. The interaction between smoking and radon was assessed through a geometric combination of additive and multiplicative effects.29 The data presented combine both control groups, because the results of analyses with each group were similar. RESULTS The radon levels in the 8992 homes where measurements were made followed an approximately log-normal distribution, with geometric and arithmetic means of 1.6 and 2.9 pCi per liter (60.5 and 106.5 Bq per cubic meter), respectively. The cutoff points for quartiles of radon levels were 0.8, 1.5, and 3.1 pCi per liter (30, 57, and 116.5 Bq per cubic meter), and the highest measured concentration was 183 pCi per liter (6784 Bq per cubic meter). Radon measurements were available for an average period of 23.5 and 23.0 years in the case and control groups, respectively, or 72.4 and 71.1 percent of the period intended for measurement. No measurements could be made for 79 case subjects (5.8 percent) and 271 controls (9.5 percent), and these subjects were excluded from the subsequent analyses. Table 3 shows the relative risk of lung cancer in relation to the estimated level of residential exposure to radon, according to histologic type of cancer. When all types were considered together, there was a positive trend, with an excess relative risk of 0.10 (95 percent confidence interval, 0.01 to 0.22) per 2.7 pCi per liter. The relative risks in subjects exposed to average time-weighted radon levels of 3.8 to 10.8 pCi per liter and to levels exceeding 10.8 pCi per liter were 1.3 (95 percent confidence interval, 1.1 to 1.6) and 1.8 (95 percent confidence interval, 1.1 to 2.9), respectively. The Table 3. Relative Risk of Lung Cancer in Sweden, 1980–1984, According to Time-Weighted Mean Residential Exposure to Radon since 1947 and Histologic Type. HISTOLOGIC TYPE OF LUNG CANCER RADON EXPOSURE (Bq PER CUBIC METER)* EXCESS RELATIVE RISK PER UNIT OF RADON (95% CI)†   ≤50 >50 TO 80 >80 TO 140 >140 TO 400 >400     No. of Case Subjects No. of Case Subjects Relative Risk (CI) No. of Case Subjects Relative Risk (CI) No. of Case Subjects Relative Risk (CI) No. of Case Relative Risk (CI)   All 452 268 1.1 272 1.0 246 1.3 43 1.8 0.10   (0.9–1.3)   (0.8–1.3)   (1.1–1.6)   (1.1–2.9) (0.01–0.22) Squamous cell 144 89 1.2 99 1.3 82 1.5 11 1.7 0.09   (0.9–1.7)   (0.9–1.8)   (1.1–2.1)   (0.8–3.7) (0.31)‡ Small cell 110 56 0.9 64 1.1 51 1.2 15 2.8 0.15   (0.6–1.4)   (0.7–1.6)   (0.8–1.8)   (1.3–5.9) (0.43)‡ Adenocarcinoma 121 77 1.1 68 1.0 67 1.4 12 2.3 0.17   (0.8–1.6)   (0.7–1.5)   (1.0–1.9)   (1.1–4.6) (0.01–0.42) Other or not determined 47 46 1.0 41 0.9 46 1.4 5 1.3 0.06   (0.6–1.5)   (0.6–1.3)   (0.9–2.1)   (0.5–3.5) (0.34)‡ *To convert becquerels per cubic meter to picocuries per liter, divide by 37. There were 952, 561, 568, 436, and 59 controls, respectively, in the five exposure categories. Relative risks and 95 percent confidence intervals (CI) are shown after adjustment for age, occupation, sex, smoking status, and urban as compared with nonurban living. †Values shown are per unit increase in the radon concentration (1 unit=2.7 pCi per liter, or 100 Bq per cubic meter). ‡The trend is not statistically significant (P≥0.05). Only the upper limit of the confidence interval is shown because the lower limit cannot be calculated with the method used when the confidence interval includes 0.

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Environmental Medicine: Integrating a Missing Element into Medical Education strongest association was suggested for small-cell carcinoma and adenocarcinoma. It should be noted that 20 tumors, which probably included mostly small-cell carcinomas, were classified as “other or not determined” because the codes in the Swedish Cancer Registry did not differentiate small-cell and large-cell carcinomas. Interactions between estimated exposure to radon and smoking are shown in Table 4. The subjects who never smoked and were assigned to the lowest category of radon exposure were used as the reference group. In comparison, current smokers exposed to an average of more than 10.8 pCi per liter had relative risks of 25 to 30. Stronger trends in relation to radon exposure were suggested for current smokers than for subjects in the other categories of smoking habits. The interaction between residential exposure to radon and smoking exceeded an additive effect when both radon and smoking were used as continuous variables (P=0.02). The combined effect appeared particularly strong in the category with the highest degree of exposure to radon. For subjects who slept near an open window, there was no apparent trend in risk with increasing estimated radon exposure (Table 5). These subjects slept near an open window during an average of 81.6 percent of the residential period for which measurements were available. When these subjects were excluded from the analysis, the excess relative risk per 2.7 pCi of radon per liter was 0.18 (95 percent confidence interval, 0.06 to 0.37). No clear differences in the risk of lung cancer were apparent between the subjects who slept near an open window and the remaining subjects, other than differences related to radon exposure. In general, the pattern of excess risk per unit of exposure in different subcategories was similar when the subjects who slept near an open window were excluded from the analysis, but the magnitude of risk tended to be higher than that for the group as a whole (data not shown). The trend seen in the analyses using time-weighted mean exposure was confirmed when the risk of lung cancer was related to cumulative exposure to radon and the two measures were found to be highly correlated. When the unit of exposure was defined as a combination of the average period for which exposures were estimated (32.5 years) and a radon level of 2.7 pCi per liter, the excess risk per unit of exposure was 0.11 (95 percent confidence interval, 0.01 to 0.28) when missing measurements were replaced by median levels and 0.10 (95 percent confidence interval, 0.00 to 0.36) when they were replaced by information about the house and the municipality. These values were quite similar to the risk estimated without the use of replacements for missing values (Table 3). After the exclusion of subjects who slept near an open window, the corresponding estimates of risk were 0.23 (95 percent confidence interval, 0.07 to 0.51) and 0.21 (95 percent confidence interval, 0.05 to 0.45) per unit of exposure. DISCUSSION Our results indicate that residential exposure to radon is an important risk factor for lung cancer in the general population. The observed excess risk of 11 percent per 2.7 pCi of radon per liter over a 32.5-year period corresponds to an excess relative risk of lung cancer of 3.4 percent per 27 pCi per liter (1000 Bq per cubic meter) per year. The exclusion of subjects who slept near an open window increased the excess risk to 22 percent per 2.7 pCi per liter over a 32.5-year period, or 6.7 percent per 27 pCi per liter per year. In miners, excess risk ranges from about 0.5 to 3 percent Table 4. Relative Risk of Lung Cancer in Sweden, 1980–1984, According to Time-Weighted Mean Residential Radon Exposure since 1947 and Smoking Status. SMOKING STATUS RADON EXPOSURE (Bq PER CUBIC METER)* EXCESS RELATIVE RISK PER UNIT OF RADON (95% CI)†   ≤50 >50 TO 80 >80 TO 140 >140 TO 400 >400     Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI)   Never smoked 64 1 36 1.1 35 1.0 38 1.5 5 1.2 0.07   443 — 240 (0.7–1.7) 252 (0.6–1.5) 198 (1.0–2.3) 31 (0.4–3.1) (0.35)‡ Exsmoker 35 2.6 21 2.4 24 3.2 27 4.5 1 1.1 0.01   105 (1.6–4.2) 69 (1.3–4.3) 63 (1.8–5.6) 48 (2.6–8.0) 8 (0.1–9.0) (0.66)‡ Current smoker (cigarettes/day)   <10 103 6.2 60 6.0 62 6.1 53 7.3 12 25.1 0.16   128 (4.2–9.2) 79 (3.8–9.4) 79 (3.9–9.5) 59 (4.5–11.7) 4 (7.7–82.4) (0.54)‡ ≥10 168 12.6 85 11.6 94 11.8 83 15.0 16 32.5 0.19   102 (8.7–18.4) 63 (7.4–18.0) 71 (7.7–18.2) 42 (9.4–24.0) 4 (10.3–102.1) (0.61)‡ Unknown 82 4.7 66 5.9 57 5.3 45 5.4 9 8.8 0.02   174 (2.9–7.7) 110 (3.5–10.0) 103 (3.1–9.2) 89 (3.1–9.5) 12 (3.3–23.7) (0.26)‡ *To convert becquerels per cubic meter to picocuries per liter, divide by 37. For each category, the number that appears on the first line under the heading Subjects is the number of case subjects and the number on the second line is the number of controls. Relative risks and 95 percent confidence intervals (CI) are shown after adjustment for age, occupation, sex, and urban as compared with nonurban living. †Values shown are per unit increase in the radon concentration within each stratum of smoking habits (1 unit=2.7 pCi per liter, or 100 Bq per cubic meter). ‡The trend is not statistically significant (P≥0.05). Only the upper limit of the confidence interval is shown because the lower limit cannot be calculated with the method used when the confidence interval includes 0.

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Environmental Medicine: Integrating a Missing Element into Medical Education Table 5. Relative Risk of Lung Cancer in Sweden, 1980–1984, According to Time-Weighted Mean Residential Radon Exposure since 1947 and the Habit of Sleeping near an Open Window. SLEEPING NEAR OPEN WINDOW RADON EXPOSURE (Bq PER CUBIC METER)* EXCESS RELATIVE RISK PER UNIT OF RADON (95% CI)†   ≤50 >50 TO 80 >80 TO 140 >140 TO 400 >400     Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI) Subjects Relative Risk (CI)   No or unknown 330 1 214 1.2 204 1.2 195 1.5 37 2.6 0.18 716 — 418 (0.9–1.5) 386 (1.0–1.6) 315 (1.1–1.9) 41 (1.5–4.4) (0.06–0.37) Yes 122 1.2 54 0.9 68 0.8 51 1.1 6 0.8 −0.03   236 (0.9–1.6) 143 (0.6–1.8) 182 (0.6–1.1) 121 (0.7–1.7) 18 (0.3–2.1) (0.05)‡ *To convert becquerels per cubic meter to picocuries per liter, divide by 37. For each category, the number that appears on the first line under the heading Subjects is the number of case subjects, and the number on the second line is the number of controls. Relative risks and 95 percent confidence intervals (CI) are shown after adjustment for age, occupation, sex, smoking status, and urban as compared with nonurban living. †Values shown are per unit increase in radon concentration (1 unit=2.7 pCi per liter, or 100 Bq per cubic meter). ‡The trend is not statistically significant (P≥0.05). Only the upper limit of the confidence interval is shown because the lower limit cannot be calculated with the method used when the confidence interval includes 0. per “working-level month,”7 which may be converted to a range of 3 to 17 percent per 27 pCi per liter per year, assuming an equilibrium factor between the concentrations of radon progeny and radon of 0.5 and an occupancy factor of 0.8 for time spent in the home. An equilibrium factor of 0.4 may be more representative of Swedish dwellings,3 and only about 60 percent of the time is spent in the home.30,31 When these circumstances are taken into consideration, the excess risk in miners corresponds to 2 to 10 percent per 27 pCi per liter per year. Additional downward adjustment in the conversion of risk estimates in miners to risk estimates for residential exposures may be necessary—for example, to control for differences in breathing patterns.6 Assuming that we have included an exposure period appropriate for the induction of lung cancer, it seems that our risk estimates correspond well to extrapolations based on studies in miners. Three recent studies suggested risk estimates within the same range as those based on projections in miners,8,11,13 although two other studies found no effect of radon.10,12 All five studies were small, and there were many differences among them—for example, in relation to sex, radon levels, type of measurements, effect of smoking, and indoor air pollution, all of which are potentially important for the compatibility of the results. The interaction between residential radon and smoking with regard to lung cancer exceeded additivity and was more consistent with a multiplicative effect. This implies that the number of radon-related lung cancers in a population depends heavily on rates of smoking and that the reverse is also true—i.e., the number of smoking-related cancers also depends on the level of radon exposure in the population. A stronger association between residential exposure to radon and lung cancer was suggested for small-cell carcinoma and adenocarcinoma than for other histologic types. In miners the picture is not fully consistent, but some studies indicate an excess risk, particularly for small-cell carcinoma.32–34 Bias in the selection of controls in our study was unlikely, since both control groups were population-based, the response rates were relatively high, and the results were consistent in the two control groups. Several Swedish studies show that information of high quality about a deceased subject’s occupation, residential history, and history of smoking can be obtained from a next of kin with the methods used in this study.35–37 Confounding by known risk factors for lung cancer, such as smoking, certain occupations, and urban living, was controlled for in the analysis, and no strong confounding of the association between radon exposure and lung cancer by these risk factors was indicated. If anything, the confounding was negative. It is not likely that confounding would explain relative risks on the order of 1.5 to 2, which were encountered in the highest category of exposure to radon. There is substantial uncertainty in the estimation of exposure to radon in the study subjects, which will primarily dilute the association with lung cancer. This uncertainty depends on several factors, including errors in radon measurements, duration of measurements, number of rooms measured, occupancy, the measurement of radon instead of unattached and attached radon progeny, and measurement made recently to estimate exposure decades ago. Measurement was avoided during the summer, when many Swedes leave their homes for several weeks. It is probable that the mean radon level is about 10 percent higher during the heating season than during the year as a whole.3,38–41 Factors affecting the accuracy of estimation of exposures decades ago based on current measurements have been studied with data from Sweden.42 The most important sources of uncertainty appear to be measurement errors and extrapolation from a rather short-term measurement to exposure over a long period. Measurements of Swedish residences today probably overestimate earlier levels of exposure.43,44 Using this information and data from other studies,45,46 we believe there has been an average increase of 10 to 20 percent in the radon concentration, weighted for

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Environmental Medicine: Integrating a Missing Element into Medical Education changes in the housing stock, from the time the study subjects lived in the dwellings until the time the measurements were carried out. As a rule, the radon concentration decreases when a window is kept open. A window ajar can provide an exchange of 10 to 30 cubic meters of air per hour at a wind velocity of 3 m per second.47 This may be two to three times the normal rate of air exchange and thus may reduce the radon concentration by 50 to 70 percent.3,41 No data on sleeping near an open window were obtained at the time of radon measurements, however. There may have been a degree of exposure misclassification due to this factor. 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