Document jmD97N19XoEmn5OG31ZyRv1wQ

Int. J. Cancer: 109, 125-131 (2004) 2003 Wiley-Liss, Inc. Publication of the International Union Against Cancer SECONDHAND SMOKE EXPOSURE IN ADULTHOOD AND RISK OF LUNG CANCER AMONG NEVER SMOKERS: A POOLED ANALYSIS OF TWO LARGE STUDIES Paul Brennan1*, Patricia A. Buffler2, Peggy Reynolds3, Anna H. Wu4, H. Erich Wichmann5, Antonio Agudo6, Goran Pershagen7, Karl-Heinz JOckel8, Simone Benhamou9, Raymond S. Greenberg10, Franco Merletti11, Carlos Winck12, Elizabeth T.H. Fontham13, Michaela Kreuzer5, Sarah C. Darby14, Francesco Forastiere15, Lorenzo Simonato16 and Paolo Boffetta1 1International Agency for Research on Cancer, Lyon, France 2University of California School of Public Health, Berkeley, CA, USA 3California Department of Health Services, Emeryville, CA, USA 4University of Southern California Keck School of Medicine, Los Angeles, CA, USA 5GSF Institute for Epidemiology, Munich, Germany 6Catalan Institute of Oncology, Barcelona, Spain 1Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden 8Institute for Medical Informatics, Biometry and Epidemiology, Essen, Germany 9National Institute of Health and Medical Research, Paris, France 10Medical University of South Carolina, Charleston, SC, USA 11Unit of Cancer Epidemiology, CeRMS and Center for Oncologic Prevention, University of Turin, Turin, Italy 12Hospital Vianna do Castelo, Vianna do Castelo, Portugal 13Department of Pathology, Louisiana State University Medical Center, New Orleans, LA, USA 14Imperial Cancer Research Fund, Oxford, United Kingdom 15Epidemiology Unit Latium Region, Rome, Italy 16Venetian Cancer Registry, Padua, Italy The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case-control studies was used. Subjects in cluded 1,263 never smoking lung cancer patients and 2,740 population and hospital controls recruited during 1985-1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01-1.37) and for long-term exposure was 1.23 (95% CI = 1.01-1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99 1.36) and for long-term exposure was 1.27 (95% CI = 1.03 1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A doseresponse relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10--1.79) for the long-term exposure from all sources. There was no evidence of confounding by em ployment in high-risk occupations, education or low vegeta ble intake. Sensitivity analysis for the effects of misclassifica tion (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear doseresponse relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the develop ment of lung cancer among never smokers. 2003 Wiley-Liss, Inc. lung cancer of the order of 24% in nonsmokers who lived with a smoker, which could not be explained by chance, potential biases or confounding.1-2 Although heterogeneity exists in the study- Grant sponsor: the National Cancer Institute; Grant number: CA40095; Grant sponsor: the Louisiana Cancer and Lung Trust Board and the Stanley S. Scott Cancer Center; Grant sponsor: European Commission DG-XII; Grant number: EV5V-CT94-0555; Grant sponsor: Association pour la Recherche sur le Cancer; Grant sponsor: European Commission; Grant number: 90CVV01018; Grant sponsor: Caisse Nationale d'Assurance Maladie des Travailleurs Sociaux; Grant sponsor: the Federal Ministry for Education, Science, Research and Technology; Grant number: 01 HK 546; Grant sponsor: the Federal Ministry of Work and Social Affairs; Grant number: IIIb 7-27/13; Grant sponsor: the Federal Office of Radiation Protection, Salzgitter; Grant number: St Sch 1066, 4047, 4074/1; Grant sponsor: the Federal Office of Radiation Protection, Salzgitter; Grant number: St Sch 4006, 4112; Grant sponsor: Italian Ministry of Research (MURST); Grant sponsor: the Italian Association for Cancer Research (AIRC); Grant sponsor: Regione Piemonte-Ricerca Finalizzata and Special Project "Oncology" Compagnia San Paolo/International Foundation of Research in Experimental Medicine (FIRMS); Grant sponsor: the National Research Council; Grant number: 91.00327.CT04; Grant sponsor: the Italian Association for Cancer Research; Grant sponsor: Comissao de Fomento de Investigacao em Cuidados de Saiide; Grant sponsor: the Spanish Ministry of Health; Grant number: 89002300; Grant sponsor: the Swedish Match; Grant number: 8913/9004/9109/9217; Grant sponsor: the Swedish Environmental Protection Agency; Grant number: 5330071-1; Grant sponsor: the Imperial Cancer Research Fund; Grant sponsor: the Department of Health; Grant sponsor: the Department of the Environment; Grant sponsor: the European Commission. Correspondence to: Unit of Environmental Cancer Epidemiology, In ternational Agency for Research on Cancer, 69008 Lyon, France. Fax: +33-472-73-83-20. E-mail: brennan@iarc.fr Key words: lung cancer; secondhand smoke More than 50 studies based on over 7,300 nonsmoking lung cancer cases have examined the association between exposure to secondhand smoke and the risk of lung cancer in lifelong nonsmokers.1 Recent systematic reviews identified an excess risk of Received 3 June 2003; Revised 12 September 2003; Accepted 23 Sep tember 2003 DOI 10.1002/ijc.11682 126 BRENNAN ET AL. specific results, there is a marked consistency in the risk estimates for men and women and by study design, with both cohort and case-control studies yielding similar summary risk estimates. Moreover, a recent international working group of 29 experts convened by the IARC Monographs Program concluded that sec ondhand smoke is carcinogenic to humans.3 Despite the amount of evidence available, there is uncertainty regarding the actual level of the increased risk with increasing dose, as well as the level of the increased risk from other sources, including social and workplace settings. We have therefore under taken a pooled analysis of the data from the 2 largest studies to measure the relationship between secondhand smoke and lung cancer. The aims of this combined analysis were to obtain a more precise estimate of the role of secondhand smoke from spousal, workplace and social sources from individual level data, to esti mate the effect of potential confounders including dietary effects and workplace exposure to other lung carcinogens and to conduct a sensitivity analysis concerning the potential effect of exposure misclassification. MATERIAL AND METHODS The analysis included cases of lung cancer and controls enrolled in 2 case-control studies conducted in the United States and in Europe. The methods used in both studies have been previously described in detail4-5 and are briefly summarized here. U.S. study The U.S. study was a population-based case-control study car ried out in 5 metropolitan areas: Atlanta, Georgia (4 counties); New Orleans, Louisiana (3 parishes); Houston, Texas (2 counties); Los Angeles, California (1 county); and San Francisco Bay Area, California (6 counties). Cases were women resident of the study areas diagnosed with a microscopically confirmed primary lung cancer during 1985-1990 (1985-1988 in Atlanta and Houston), aged 20-79 at diagnosis, able to speak English, Spanish or Chi nese, with no history of previous cancer, who smoked less than 100 cigarettes in their lifetime. Controls were selected via random digit dialing, supplemented, for women aged 65-79, by random sampling from files of the Health Care Financing Administration. Two controls were frequency matched to each case on age group, ethnicity and study area. The selection criteria described above for cases were also applied to controls. The project was approved by an institutional review board within each center. Interviews were conducted with 665 out of 800 potential cases (including 241 interviews with next of kin; response rate, 83%) and 1,278 out of 1,826 potential controls (no interviews with next of kin; response rate, 70%). The questionnaire was primarily aimed at assessing exposure to secondhand smoke during child hood (up to age 18) and in adult life from spouses, other household members and occupational and social sources. For household members, information was sought on duration of exposure and the type of tobacco product. The daily amounts smoked by household members including spouses were also elicited. Only duration of exposure was elicited for occupational and social sources of ex posure. Information was also obtained on other potential causes of lung cancer, including dietary factors, family history of cancer and workplace exposure to occupational carcinogens. Urine samples were obtained from 53% of cases and 83% of controls and were analyzed for cotinine level. Two cases and 25 controls had a urinary cotinine/creatinine ratio above 99 ng/mg and were excluded. An additional 9 cases and 25 controls had levels in the 55-99 ng/mg range, compatible with high exposure to second hand smoke. A central pathology review was conducted on sam ples from 85% of cases; the diagnosis was confirmed for 98% of them, and the 10 cases with unconfirmed diagnosis were excluded. Previous results have been based on the analysis of data from 653 cases and 1,253 controls. European study The European study was conducted as a population-based casecontrol study in Germany (3 areas: Bremen and Frankfurt; Thuringia and Saxony; parts of North Rhine-Westphalia, Eifel and Saarland), Italy (2 areas: Turin; parts of Veneto) and Sweden (Stockholm) and as a hospital-based case-control study in Italy (1 hospital in Rome), Spain (10 hospitals in Barcelona), France (12 hospitals, mainly in Paris) and Portugal (2 areas: 3 hospitals in Lisbon; 1 hospital in Porto). The center in the United Kingdom (Devon and Cornwall) included both hospital and population con trols. Cases were men and women either resident of the study areas or referred to the participating hospitals who were diagnosed with a primary lung cancer during 1988 -1994, aged up to 75, and who smoked less than 400 cigarettes in their lifetime. Population-based controls were selected via random sampling from population reg istries and hospital-based controls were selected among patients admitted to the same hospitals as the cases, excluding those with tobacco-related diseases. Controls were frequency matched to cases for age, sex and region of residence. There were differences among centers regarding restriction to microscopically confirmed cases, list of eligible diseases of hospital controls and inclusion of subjects above age 75. The project was approved by an institu tional review board within each center. No interviews were conducted with next of kin. The question naire on secondhand smoke was very similar to the one used in the American study. Information comparable to that of the American study was also collected on occupational exposures and diet (the latter in 8 centers). No validation of nonsmoking status was con ducted via urinary cotinine measurement. In 3 centers, cross interviews were conducted with next of kin for a subset of cases and controls in order to validate both the nonsmoking status of the index subjects and their exposure to secondhand smoke from the spouse. Nonsmoking status was not confirmed for 1/175 cases and 4/233 controls. No central pathology review was conducted. Pre vious results have been based on the analysis of data from 650 cases and 1,542 controls. Pooled analysis The data included in this pooled analysis differ slightly from those that previous published results were based on. First, the data from the area in Lisbon were excluded (54 cases and 47 controls) because the local investigator was unable to participate in this analysis. Second, a common cut-point for the definition of never smokers in the 2 studies was adopted, of 100 cigarettes or equiv alent amount from other tobacco products, resulting in the exclu sion of 27 cases and 90 controls from the European study who had reported smoking between 101 and 400 cigarettes. Third, a com mon upper age limit of 79 was adopted, resulting in the inclusion of 34 cases and 69 controls from the European study aged 76 -79. The final data set included 1,263 cases (653 from the American study, 610 from the European study) and 2,740 controls (1,253 and 1,487, respectively). Further differences between the studies were evaluated by con ducting sensitivity analyses after excluding 241 cases from the American study with next-of-kin interview; excluding 229 cases and 564 controls from European centers with hospital-based re cruitment; and restricting analysis to women by excluding 121 male cases and 498 male controls from the European study. The following variables were obtained from the original studies: age at diagnosis for cases or interview for controls (classified in 10-year groups), study center, sex, ever employment in high-risk occupations, education level (low, intermediate, high and un known, based on country-specific classifications), vegetable in take, type of respondent (study subject and next of kin), type of subject recruitment (population- and hospital-based) and histologic type of lung cancer (adenocarcinoma, small and squamous cell carcinoma, other types). Tertiles of vegetable intake included a predefined list of common vegetables, fruits and vitamin supple- SECONDHAND SMOKE AND LUNG CANCER 127 ments in the American study, and a predefined list of common vegetables in the European study. High-risk occupations in the European study included a predefined list of occupations known to be associated with lung cancer.6 The U.S. list involved those working for 5 years or more in 12 industries likely to involve exposure to lung carcinogens. Spousal exposure to secondhand smoke was defined as ever having a spouse who smoked any tobacco product while they lived together, while smoke-years of exposure was defined as the num ber of years that the subject's spouse smoked while they were living together. Similarly, years of workplace exposure was de fined as the total number of years in which the subject reported working in an environment where others were smoking, and smoke-years of social exposure was defined as the total number of years of exposure to tobacco smoke in places other than the home and the workplace (at least 2 hr per week in the U.S. study). Finally, in order to obtain a cumulative estimate of exposure to secondhand smoke, the sum of smoke-years from the 3 sources was calculated. The statistical analysis was based on unconditional logistic regression modeling, resulting in the estimate of odds ratios (ORs) and 95% confidence intervals (CIs). For each source of second hand smoke, individuals unexposed from that source formed the reference group. Tertiles for secondhand smoke exposure were calculated according to the distribution of the exposed control group for each exposure source separately (although this resulted in tertiles of exposure that are different for the 3 exposure sources). Information from each form of exposure was incomplete for a small number of subjects, although this was not imputed. Regres sion models included center, age and gender. In addition, models including also education level, exposure to occupational carcino gens and vegetable intake were fitted to test for their potential confounding effect. Linear trends were tested by fitting regression models with an ordinal exposure variable. Selected analyses were repeated after stratification for histologic type. RESULTS The distribution of the cases and controls by study center, age, sex and other demographic and study design variables is shown in Table I. The number of subjects included from the U.S. study is identical to the previous published analysis, whereas the number of subjects from the European study differs slightly due to the exclu sion of one center and the more stringent criteria of a never smoker, and also by including cases and controls only up to 79 years of age. The U.S. subjects were generally older than the Study center Sweden Germany 1 Germany 2 Germany 3 United Kingdom France Portugal 2 Spain Italy 1 Italy 2 Italy 3 Atlanta Houston Los Angeles Louisiana San Francisco Bay Area Age, years < 50 50-59 60-69 70-79 Gender Male Female High-risk occupations Nonexposed Ever exposed Education level Low Intermediate High Unknown Respondent Study subject Next of kin Type of recruitment Population-based Hospital-based Histological type Adenocarcinoma Small and squamous cell Other types TABLE I - SELECTED CHARACTERISTICS OF CASE AND CONTROL SUBJECTS European study Controls (n = 1487) Cases (n = 610) n %n% American study Controls (n = 1253) Cases (n = 653) n % n% Combined study Controls (n = 2,740) Cases (n = 1,263) n % n% 116 7.8% 77 12.6% 228 15.3% 76 12.5% 159 10.7% 141 23.1% 52 3.5% 30 4.9% 140 9.4% 26 4.3% 139 9.3% 69 11.3% 55 3.7% 35 5.7% 182 12.2% 81 13.3% 202 13.6% 40 6.6% 166 11.2% 17 2.8% 48 3.2% 18 3.0% 76 6.1% 46 7.0% 42 3.4% 41 6.3% 512 40.9% 264 40.4% 57 4.5% 34 5.2% 566 45.2% 268 41.0% 116 4.2% 228 8.3% 159 5.8% 52 1.9% 140 5.1% 139 5.1% 55 2.0% 182 6.6% 202 7.4% 166 6.1% 48 1.8% 76 2.8% 42 1.5% 512 18.7% 57 2.1% 566 20.7% 77 6.1% 76 6.0% 141 11.2% 30 2.4% 26 2.1% 69 5.5% 35 2.8% 81 6.4% 40 3.2% 17 1.3% 18 1.4% 46 3.6% 41 3.2% 264 20.9% 34 2.7% 268 21.2% 162 10.9% 70 11.5% 396 26.6% 158 25.9% 558 37.5% 218 35.7% 371 24.9% 164 26.9% 165 13.2% 70 10.7% 154 12.3% 110 16.8% 398 31.8% 213 32.6% 536 42.8% 260 39.8% 327 11.9% 550 20.1% 956 34.9% 907 33.1% 140 11.1% 268 21.2% 431 34.1% 424 33.6% 498 33.5% 121 19.8% 498 18.2% 121 9.6% 989 66.5% 489 80.2% 1,253 100.0% 653 100.0% 2,242 81.8% 1,142 90.4% 1,419 68 95.4% 588 4.6% 22 96.4% 1,216 3.6% 37 97.0% 629 96.3% 2,635 3.0% 24 3.7% 105 96.2% 1,217 96.4% 3.8% 46 3.6% 252 16.9% 55 9.0% 299 20.1% 96 15.7% 648 43.6% 309 50.7% 288 19.4% 150 24.6% 270 21.5% 108 16.5% 522 19.1% 315 25.1% 99 15.2% 614 22.4% 659 52.6% 433 66.3% 1,307 47.7% 9 0.7% 13 2.0% 297 10.8% 163 12.9% 195 15.4% 742 58.7% 163 12.9% 1,487 100.0% 610 100.0% 1,253 100.0% 412 63.1% 2,740 100.0% 1,022 80.9% 241 36.9% 241 19.1% 923 62.1% 381 62.5% 1,253 100.0% 653 100.0% 2,176 79.4% 1,034 81.9% 564 37.9% 229 37.5% 564 20.6% 229 18.1% 311 51.0% 162 26.6% 137 22.5% 497 76.1% 64 9.8% 92 14.1% 808 64.0% 226 17.9% 229 18.1% 128 BRENNAN ET AL. European subjects; the proportion of subjects who reported work ing in high-risk occupations was less than 5% in both studies. Histologic type also differed between the 2 regions with a higher proportion of adenocarcinomas in the United States. The OR of lung cancer associated with ever exposure to spousal tobacco smoke was 1.18 (95% CI = 1.01-1.37) (Table II). There was some evidence of a dose-response relationship with duration of exposure (p = 0.07), with highest risk being observed in the upper tertile of exposure, corresponding to more than 30.9 years (OR = 1.23; 95% CI = 1.01-1.51). The risk in the high-exposure group was similar for adenocarcinoma (OR = 1.24; 95% CI = 0.98-1.57) and small and squamous cell carcinoma (OR = 1.26; 95% CI = 0.84-1.90). Results were similar when proxy inter views were excluded from the analysis, although the exclusion of data from hospital-based centers resulted in a more statistically significant dose-response relationship (p = 0.04) and increased risk in the upper tertile of exposure (OR = 1.30; 95% CI = 1.04 -1.63). An excess risk was observed for ever exposure to secondhand smoke in the workplace (OR = 1.13; 95% CI = 0.97-1.31) and, when analyzed by duration of exposure, a dose-response effect was observed (p = 0.01) with a significant increased risk in the upper tertile, corresponding to more than 21 years of exposure (OR = 1.25; 95% CI = 1.03-1.51; Table III). When proxy cases were excluded from the analysis, the overall increased risk was 1.16 (95% CI = 0.99-1.36), and in the upper tertile it was 1.27 (95% CI = 1.03-1.57). An increase in risk was observed for those who reported ever exposure to secondhand smoke in social settings (OR = 1.17; 95% CI = 1.00-1.36), and a dose-response effect was detected with duration of exposure (p = 0.02), with the largest increase in risk in the highest exposed group corresponding to more than 20 years of exposure (OR = 1.26; 95% CI = 1.01-1.58; Table IV). When stratified by histologic type, the increased risk in the highest exposed group was more apparent for small and squamous cell carcinoma (OR = 1.54; 95% CI = 1.01-2.34) than for adenocar cinoma (OR = 1.26; 95% CI = 0.97-1.64). A similar pattern was observed for an analysis of any exposure to secondhand smoke from spousal, workplace or social sources combined (OR = 1.22; 95% CI = 0.99-1.51), along with a dose-response effect (p = 0.01) with the greatest risk in the highest exposure category (OR = 1.32; 95% CI = 1.04-1.66; Table V). Restricting the analysis to study subject interviews made little difference, although a more marked overall effect was observed when hospital controls were excluded (OR = 1.31; 95% CI = 1.03-1.67). Results of the analysis restricted to women are practically iden tical to those reported in Tables II to V and are not presented in detail. The results reported in Tables II to V were subsequently controlled for employment in high-risk occupations in addition to education level and vegetable consumption. However, results were similar when the potential confounders were either included or excluded from the regression models. For example, the OR for ever exposure from any of the 3 sources combined was exactly the same at 1.22 (95% CI = 0.99-1.51) when potential confounders were included or excluded, confirming the lack of any apparent confounding. DISCUSSION This pooled analysis of 2 large studies of secondhand smoke and lung cancer provides firm evidence for a dose-response relation ship between lung cancer risk and duration of exposure to second hand smoke for the 3 main sources of exposure: spousal, work place and social. The estimate of the increased risk is 18% (95% CI = 1-37) in those ever exposed to spousal secondhand smoke and is 23% (95% CI = 1-51) in the long-term exposed. Increased risks for long-term exposure to secondhand smoke were also observed for workplace exposure (OR = 1.25; 95% CI = 1.03 1.51) and social exposure (OR = 1.26; 95% CI = 1.01-1.58). Metaanalyses of lung cancer and secondhand smoke have been criticized for the potential lack of standardization in defining exposure and the potential for publication bias.7 Our pooled anal ysis also offers several advantages over previous metaanalyses, and in particular we have been able to ensure a similar definition of nonsmoker for all subjects. We have also been able to conduct an analysis with identical exposure categories for each of the exposure sources, and we have been able to adjust for similar potential confounding variables, including diet, occupation and educational level. The inclusion or exclusion of these potential confounding variables did not influence the results, indicating no confounding effect in any direction from these sources. Our results provide more conservative estimates of the increased risk of ex posure to secondhand smoke than a previous metaanalysis, which TABLE II -ODDS RATIOS OF LUNG CANCER FROM EXPOSURE TO SECONDHAND SMOKE FROM THE SPOUSE, ANY TYPE OF TOBACCO Cases Cases All subjects Controls OR 95% CI Study subjects interviews only Cases Controls OR 95% CI Cases Population controls only Controls OR 95% CI Ever exposed No Yes Duration of exposure (years) Nonexposed < 16 16-30.9 > 31.0 Trenda Adenocarcinoma Nonexposed < 16 16-30.9 > 31.0 Trend Small and squamous cell Nonexposed < 16 16-30.9 > 31.0 Trend 496 764 496 246 224 264 306 163 149 170 96 38 42 45 1,277 1.00 421 1,458 1.18 1.01- 1.37 600 1,277 457 480 491 1.00 1.18 0.97- 1.44 1.05 0.86- 1.29 1.23 1.01- 1.51 0.07 421 194 173 211 1,277 457 480 491 1.00 1.14 0.90- 1.43 1.08 0.85- 1.37 1.24 0.98- 1.57 0.10 259 129 109 134 1,277 457 480 491 1.00 1.22 0.80- 1.85 1.11 0.74- 1.67 1.26 0.84- 1.90 0.30 84 32 37 39 1,277 1.00 404 1,458 1.16 0.99-1.36 627 1,277 457 480 491 1.00 1.19 0.96-1.47 1.01 0.81-1.26 1.24 1.00-1.54 0.11 404 212 190 211 1,277 1.00 260 457 1.14 0.89-1.46 144 480 0.98 0.76-1.28 136 491 1.24 0.96-1.60 144 0.20 1,277 1.00 457 1.32 0.83-2.08 480 1.17 0.75-1.82 491 1.33 0.85-2.07 0.23 80 32 31 32 1,043 1.00 1,133 1.19 1.01-1.40 1,043 387 385 348 1.00 1.17 0.95-1.45 1.06 0.85-1.32 1.30 1.04-1.63 0.04 1,043 387 385 348 1.00 1.13 0.88-1.45 1.12 0.87-1.45 1.30 1.01-1.69 0.05 1,043 387 385 348 1.00 1.20 0.76-1.89 0.96 0.60-1.53 1.26 0.78-2.02 0.52 All ORs adjusted by age, center, gender.-ap-value for linear trend. SECONDHAND SMOKE AND LUNG CANCER 129 TABLE III - ODDS RATIOS OF LUNG CANCER FROM EXPOSURE TO SECONDHAND SMOKE FROM WORKPLACE Cases All subjects Controls OR 95% CI Study subjects interviews only Cases Controls OR 95% CI Cases Population controls only Controls OR 95% CI Ever exposed No Yes Duration of exposure (years) Nonexposed < 8.0 8.0-20.9 > 21.0 Trenda Adenocarcinoma Nonexposed < 8.0 8.0-20.9 > 21.0 Trend Small and squamous cell Nonexposed < 8.0 8.0-20.9 > 21.0 Trend 490 729 490 198 267 262 300 133 178 164 92 36 40 51 1174 1.00 410 1560 1.13 0.97-1.31 610 1174 472 544 543 1.00 410 0.94 0.76-1.15 169 1.17 0.97-1.42 220 1.25 1.03-1.51 219 0.01 1174 472 544 543 1.00 246 0.95 0.74-1.21 110 1.20 0.96-1.50 147 1.20 0.95-1.51 139 0.05 1174 472 544 543 1.00 0.96 0.62-1.47 0.98 0.65-1.48 1.36 0.92-2.00 0.19 82 33 35 46 1,174 1.00 363 1,560 1.16 0.99-1.36 627 1,174 472 544 543 1.00 1.00 0.80-1.26 1.19 0.97-1.46 1.27 1.03-1.57 0.01 363 179 220 228 1,174 1.00 236 472 0.99 0.76-1.29 126 544 1.24 0.97-1.58 150 543 1.27 0.99-1.62 150 0.03 1,174 1.00 472 1.04 0.66-1.63 544 1.02 0.66-1.58 543 1.41 0.93-2.13 0.16 64 31 35 40 857 1.00 1,313 1.11 0.94-1.31 857 1.00 406 0.95 0.75-1.18 454 1.11 0.89-1.37 453 1.29 1.04-1.59 0.02 857 1.00 406 0.99 0.77-1.29 454 1.13 0.88-1.45 453 1.27 0.99-1.63 0.05 857 1.00 406 0.95 0.59-1.53 454 1.03 0.65-1.63 453 1.31 0.84-2.05 0.28 All ORs adjusted by age, center, gender.-ap-value for linear trend. TABLE IV-ODDS RATIOS OF LUNG CANCER FROM EXPOSURE TO SECONDHAND SMOKE FROM SOCIAL EXPOSURE Cases All subjects Controls OR 95% CI Study subjects interviews only Cases Controls OR 95% CI Cases Population controls only Controls OR 95% CI Ever exposed No Yes Duration of exposure (years) Nonexposed < 8.0 8.0-19.9 > 20.0 Trenda Adenocarcinoma Nonexposed < 8.0 8.0-19.9 > 20.0 Trend Small and squamous cell Nonexposed < 8.0 8.0-19.9 > 20.0 Trend 818 407 818 123 128 154 530 70 85 95 139 28 23 33 1,827 1.00 666 904 1.17 1.00-1.36 349 1,827 1.00 666 287 1.04 0.84-1.32 105 290 1.20 0.95-1.52 114 320 1.26 1.01-1.58 128 0.02 1,827 1.00 427 287 0.92 0.69-1.24 60 290 1.30 0.99-1.72 74 320 1.26 0.97-1.64 79 0.03 1,827 1.00 120 287 1.33 0.85-2.08 25 290 1.04 0.64-1.70 22 320 1.54 1.01-2.34 29 0.07 1,827 1.00 669 904 1.17 0.99-1.37 327 1,827 287 290 320 1.00 1.05 0.82-1.35 1.21 0.95-1.56 1.24 0.98-1.58 0.03 669 101 104 121 1,827 287 290 320 1.00 0.94 0.69-1.29 1.31 0.98-1.76 1.28 0.96-1.69 0.04 454 59 72 81 1,827 287 290 320 1.00 1.38 0.86-2.22 1.09 0.66-1.80 1.52 0.97-2.38 0.08 110 24 17 22 1,476 1.00 691 1.22 1.03-1.45 1,476 221 217 248 1.00 1.08 0.83-1.41 1.30 0.99-1.70 1.30 1.01-1.67 0.01 1,476 221 217 248 1.00 0.93 0.67-1.28 1.38 1.02-1.88 1.30 0.97-1.73 0.03 1,476 221 217 248 1.00 1.50 0.92-2.47 1.02 0.58-1.80 1.39 0.83-2.30 0.23 All ORs adjusted by age, center, gender.-ap-value for linear trend. reported an overall increase of 24% (95% CI = 13-36) for spousal exposure and 39% (95% CI = 15-68) for occupational expo sure.2-8 The confidence intervals from the pooled analysis do, however, include the higher odds ratios obtained from previous metaanalyses, indicating that the results are broadly consistent with each other. Misclassification of exposure to secondhand smoke is inevitable and, assuming that it is nondifferential with respect to case/control status, will dilute the estimate of the effect. The substantial pro portion of U.S. cases for whom information was obtained from their next of kin is a potential source of differential misclassification. When these cases are removed from the analysis, it is of interest that the odds ratio for ever exposure does not change substantially for any of the sources of exposure. Concerning historical exposure to secondhand smoke, some exposure is likely to be inevitable, resulting in an unexposed group who will have been exposed to some extent. A previous validity study found that over 60% of nonsmokers who reported no expo sure to secondhand smoke from spousal or workplace sources had detectable levels of urinary cotinine.9 One approach to estimating the risk of exposure to secondhand smoke when compared to a true never-exposed group, which was adopted in a recent metaanalysis,2 was based on the observation of 3 times higher cotinine levels in nonsmokers living with a smoker as opposed to nonsmokers living with a nonsmoker. Assuming that the observed relative risk is equal to (1 + 3x)/(1 + x), where x is the background exposure level of secondhand smoke for nonexposed subjects, and adopting test-based confidence intervals, this results in an estimate of ad justed true OR of 1.30 (95% CI = 1.11-1.51) for ever exposure to spousal smoking. The other form of misclassification, that of previous smokers classifying themselves as nonsmokers, may work in the opposite fashion to increase the risk estimate artificially. The proportion of reported never smokers with cotinine levels consistent with current 130 BRENNAN ETAL. TABLE V-ODDS RATIOS OF LUNG CANCER FROM EXPOSURE TO SECONDHAND SMOKE FROM SPOUSE, WORKPLACE AND SOCIAL EXPOSURE Cases All subjects Controls OR 95% CI Study subjects interviews only Cases Controls OR 95% CI Population controls only Cases Controls OR 95% CI Ever exposed No Yes Duration of exposure (in years) Nonexposed < 20.0 20.0-38.9 > 39.0 Trenda Adenocarcinoma Nonexposed < 20.0 20.0-38.9 > 39.0 Trend Small and squamous cell Nonexposed < 20.0 20.0-38.9 > 39.0 Trend 146 1,102 146 329 348 413 91 210 222 269 26 57 65 75 383 2,351 383 752 768 817 383 752 768 817 383 752 768 817 1.00 1.22 0.99-1.51 1.00 1.09 0.86-1.39 1.21 0.96-1.54 1.32 1.04-1.66 0.01 1.00 1.03 0.77-1.37 1.18 0.89-1.57 1.30 0.98-1.71 0.02 1.00 1.26 0.76-2.08 1.48 0.90-2.42 1.52 0.93-2.47 0.08 125 896 125 262 299 327 77 164 192 208 22 50 57 66 383 1.00 108 2,351 1.18 0.94-1.48 911 383 1.00 108 752 1.03 0.80-1.33 281 768 1.24 0.96-1.59 275 817 1.25 0.97-1.60 349 0.02 383 1.00 71 752 0.96 0.70-1.31 183 768 1.22 0.90-1.65 186 817 1.22 0.90-1.65 241 0.05 383 1.00 752 1.38 0.80-2.38 768 1.60 0.94-2.74 817 1.63 0.96-2.77 0.07 21 48 52 54 298 1.00 1,874 1.31 1.03-1.67 298 1.00 629 1.16 0.88-1.52 612 1.25 0.95-1.64 623 1.50 1.15-1.96 0.00 298 1.00 629 1.09 0.79-1.50 612 1.25 0.91-1.71 623 1.50 1.10-2.05 0.00 298 1.00 629 1.20 0.68-2.11 612 1.41 0.81-2.47 623 1.38 0.79-2.40 0.23 All ORs adjusted by age, center, gender.-ap-value for linear trend. smoking has consistently been found to be approximately 2%,9-15 although this figure is likely to be lower in the current study given the cotinine analysis conducted on the majority of cases and controls in the American study and the next-of-kin verification conducted on a sample of subjects in the European study. The proportion of former smokers classifying themselves as never smokers is harder to estimate. Overall, such misclassified cases are likely to consist of light smokers and long-term quitters and have a correspondingly low relative risk of lung cancer when compared to current smokers. The likely relative risk for misclassified never smokers has been estimated to be approximately 3-fold when compared to true never smokers.2 Even if we assume that in the current study, in addition to 2% of the subjects being true current smokers, there are an extra 5% being true ex-smokers, and that smokers are 3 times more likely to marry other smokers, the effect on the reported odds ratio for ever exposure to spousal secondhand smoke will not be large. Adopting the method by Hackshaw et al.,2 the effect will be to reduce our adjusted OR from 1.30 (95% CI = 1.11-1.51) to 1.24 (95% CI = 1.06-1.44), still above the observed OR for ever spousal exposure of 1.18 (95% CI = 1.01-1.37). Therefore, the increase in the odds ratio potentially caused by this type of misclassification is likely to be outweighed by the attenu ation caused by exposure to secondhand smoke from subjects classified as nonexposed. Other forms of bias that may influence the results of our pooled analysis are the inclusion of hospital-based controls and the col lection of exposure information from next-of-kin interviews. How ever, we have conducted subgroup analyses to address these po tential sources of bias. Results were generally higher when proxy interviews were excluded, especially for workplace exposure, and also for social exposure when analysis was restricted to population controls. It is therefore likely that there is some attenuation in the risk estimates for the main analysis, which incorporates cases with proxy interviews and data from hospital-based centers. Our results according to histologic type of lung cancer suggest an increased risk of both adenocarcinoma and squamous/small cell carcinomas from all 3 sources of exposure. For example, when all 3 sources are combined, a consistent dose response with duration of exposure is seen for both histologic types with a higher risk for squamous and small cell carcinomas apparent for each tertile. Although these results should be interpreted with caution, given the lack of a central pathologic review in the European study and the inconsistency of this finding when just restricted to centers that recruited population controls, they are broadly compatible with the stronger association between active smoking and small and squa mous cell carcinomas as opposed to adenocarcinoma.16 In conclusion, our pooled analysis provides more precise esti mates of the effect of secondhand smoke on lung cancer risk in nonsmokers from all sources than those previously obtained in individual studies and emphasizes the importance of protecting nonsmokers from secondhand smoke. The implications of reduc ing exposure to secondhand smoke, however, go beyond the pre vention of lung cancer in nonsmokers, since such measures to reduce exposure to secondhand smoke also result in a decreased opportunity for smoking among active smokers and a subsequent reduction in active smoking levels.17 ACKNOWLEDGEMENTS The U.S. study was supported by grant CA40095 from the National Cancer Institute (Bethesda, MD) with additional support from the Louisiana Cancer and Lung Trust Board and the Stanley S. Scott Cancer Center (New Orleans, LA). The European study was partially supported by the following grants: European Com mission dG-XII (EV5V-CT94-0555) for the coordination; in France, Association pour la Recherche sur le Cancer, European Commission (90CVV01018) and Caisse Nationale d'Assurance Maladie des Travailleurs Sociaux; in Germany 1, the Federal Ministry for Education, Science, Research and Technology (grant 01 HK 546) and the Federal Ministry of Work and Social Affairs (IIIb 7-27/13); in Germany 2, the Federal Office of Radiation Protection, Salzgitter (St Sch 1066, 4047, 4074/1); in Germany 3, the Federal Office of Radiation Protection, Salzgitter (St Sch 4006, 4112); in Italy 1, MURST, the Italian Association for Cancer Research (AIRC), Regione Piemonte-Ricerca Finalizzata and Spe cial Project "Oncology" Compagnia San Paolo/FIRMS; in Italy 2, the National Research Council (91.00327.CT04) and the Italian Association for Cancer Research; in Portugal 2, Comissao de Fomento de Investigacao em Cuidados de Sattde; in Spain, the Spanish Ministry of Health (reference 89002300); in Sweden, the Swedish Match (8913/9004/9109/9217) and the Swedish Environ mental Protection Agency (5330071-1); and in the United King dom, the Imperial Cancer Research Fund, the Department of Health, the Department of the Environment and the European Commission. SECONDHAND SMOKE AND LUNG CANCER 131 REFERENCES 1. 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