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I I I I- I I I I I I I I I i I I I I Caapter 7 Main Results 7.1 Deaths from Lung Cancer and H.istological Dam in Death Certificates 7.2 Potential confounders age, gender, schooling, race, prexisting lung disease, occupational exposure to lung carcinogens, consumption of foods containing carotenoids, and fat as nutrient index. A~ Gender Race Schooling ~ Asbestos Prexisting chronic lung disease Diet Other 7.3.a. Self reported ETS 7.3.b. Dose-response of S,elf reported ETS 7.3.c. Spousal ETS 7.4 Joint effects of'ETS and asbestos exposure 7.5 Leading causes of death in the cohort Chapter 8 Discussion and Conclusions ... 8.1 Consistency 8.2 Study Power 8.3 Misclassification 8.4 Confounding 8.5 Misclassification of smoking status 8.6 Causal Inference : 8.7 Conclusions References Appendices 85 86 86 87 88 89 90 92 94 94 97 97 107 123 128 129 133 134 138 139 141 143 146 158 o 0~ 0~ o

List of figures Page I. RR of lung cancer for ETS from 36 epidemiologic studies ......................... 18 2. Funnel plot of RR fro ETS from 36 studies .......................................... 19 3. Hypothetical cohort study: effect of misclassification of active smoking on lung cancer risk ............................... 22 4. Exclusions for dose-response analyses ............................................... 36 5. Outline of analytical approach .......................................................... 46 6. Self-reported ETS of spouses and cigarette smoked by their husbands ........... 73 7. Rates of lung cancer among nonsmokers by age ..................................... 86 8. Rates of lung cancer among nonsmokers by ETS exposure ........................ 104 9. Rates of lung cancer among nonsmokers by ETS from spousal smoking ...................................................................................... 110 10. Log-log (S) curves for ETS .......................................................... 126 List of Tables ............................................................................ Page 1. Extent of ETS Exposure in the USA ................................................ 9 2 Metanalysis from 36 published studies ............................................. 17 3. Smoking habits at time of enrollment ............................................... 34 4 Analytic cohorts ........................................................................ 35 5 Comparison of age- men US,CPS 17, and analytic cohorts ..................... 55 6. Comparison of age : women US, CPS 17, and analytic cohorts ................. 56 7. Comparison of occupations of employed US, CPS II, and analytic cohorts .............................................................................. 57 8. Comparison of college graduates US,CPS II, and analytic cohorts ............ 58 9. Comparison of married whites in the US, CPS lr, and analytic cohorts ................................................. : ............................ 59 10. Comparison residence US, CPS II participants .................................... 61 11. Age-adjusted prevalence smoking, CPS 1-[ and NI-~S-83 ......................... 62 12. CPS 17 on reported hours of ETS exposure at different settings .................. 65 13. Patterns of answers given by CPS II participants to seE-assessment ............ 66 14. Nonsmokers reportedly exposed to ETS at home CPS 17 and NHIS ........... 69 15. Characteristics of CPS II nonsmokers in analytic cohort for self- reported ETS analysis by completeness of information on ETS ....................... 70 16. Comparison of self-reported exposure to ETS at home by CPS rr nonsmoking women and the number of current smokers among cohabitees, and spouses .................................................................... 71 17. Distribution of reported hours of exposure to ETS at home by nonsmoking women, according to number of cigarettes smoked by their husbands ............................................................................... 74 18. Hours of exposure to ETS reported by nonsmoking CPS participants at differente settings, 1982 ................................................................. 76 I I I I I I ! I I I i I

I I I I I I I I I I I I I I I I I 19. t'ropomon of nonsmo~tng ~.PS Lt pamcipants m analytic cohorts who reported any ETS exposure by age at interview, 1982 ........................... 78 20. Age of nonsmoking participants by ETS from spousal smoking ................ 78 21. Characteristics of nonsmoking participants according to self-reported ETS .............................................................................. 80 22. Characteristics of nonsmoking participants according to ETS from spousal smoking ..........~ ............................................................ 81 23. Intensity and duration of spousal cigarette smoking by spouses ................. 84 24. Distribution of hystological types in 115 deaths from lung cancer .............. 85 25. Rates of Lung Cancer among Nonsmokers by Age and Gender ................. 87 26. Rates of Lung Cancer among Nonsmokers by Age and Race .................... 88 27. Rates of Lung Cancer among Nonsmokers by Age and Schooling .............. 89 28. Rates of Lung Cancer amohg Nonsmokers by Asbestos exposure at work .............................................................................. 90 29. Rates of Lung Cancer among Nonsmokers by years of exposure to asbestos .............................................................................. 93 30. Rates of Lung Cancer among Nonsmokers by non ETS risk factors ............ 96 3 I. Lung cancer mortality and risk estimates by self-reported exposure to ETS (any versus none) .........!. ........................................................... 99 32. Lung cancer mortality and risk estimates by self-reported exposure to ETS (by tertiles) ............................................................................. I00 33. Multivariate risk estimates of lung cancer by self-reported exposure to ETS .............................................................................. I06 34. Lung cancer rate ratios among nonsmokers by smoking status of their husbands (current cigarettds vs. never) ................................................... 109 35. Lung cancer rate ratios among nonsmoking wives by smoking status of their husbands (current pipe/cigar vs. never) ......................................... 1 I2 36. Lung cancer multivariate rate ratios by type of smoking of spouses ............. 113 37. Lung cancer multivariate rate ratios by amount of cigarette smoking ............ 115 38. Lung cancer multivariate rote ratios by amount of cigarette smoking (among spouses married once)! ........................................................... 117 39. Lung Cancer multivariate rate ratios by time in marriage with cigarette smoking spouses ........................................................................... 40. Lung Cancer multivariate rote ratios by pack-years of cigarette smoking spouses ............................................. ., .............................. 122 41. Rate ratios for lung cancer by ETS and asbestos exposure ....................... 124 42. Other causes of death .................................................................. 128 43. Power calculations ..................................................................... 134 44. Corrected RR by degree of misclassification of ETS exposure ................... 135 45. Rate ratios for lung cancer by ETS by approach to missing data ................. 136 46. ETS exposure by education ........................................................... 137 0 O~ O~ 0

i III I April 5, 1954. 1978 1977 1979-1980 1981 1982-1985 1985-1987 1987-1989 1989-1990 Vita Born, Mexico, D.F. M.D. National University, Mexico City Medical doctor at the EI DuPont de Nemours manufacturing plant in Mexico City. Researcher. Directorate of Occupational Health, Ministry of Labor. Degree of Epidemiologist School of Public Health of Mexico. Epidemiologist, Directorate of Epidemiology, Ministry of Health. Degree of Epidcmiologist Mexican Field Epidcmiology Training Program. Ministry of Health, School of Public Health of Mexico, and Centers for Disease Control. Associate P, csearchcr and Professor Center for Public Health Research and School of Public Health of Mexico. National Institute of Public Health. Master of Public Health Emory University. 0 O~ 0 I I I i I I I I I I I I / I

I I I I- I I I I I I I I I I I I I I ! iv Fublicadons 1) C~denas-Ayala, VM.,I Montesano-Castellanos R, Morales-Marfn, R Villegas-Espinosa, A mad Flores-Salinas, E: Prevalence and incidence estimates of paralytic poliomyelitis by means of lanmess surveys in Tecom~n, Colima. Sal Ptib M~x 1985, 27 (2): 52-59. (Published in Spanish). 2) C~denas-Ayala, VM, Koopman James S, Guerrero-Reyes P: Tuberculosis mortality by birth cohorts, b, lexico. Bol. Mensual Epiderniologia del Sector Salud 1986; I: 137-141. (Pdblished in Spanish). 3) Dfaz-Ortega JL, Valdespino-G6mez JL, ZArate-Aquino ML, Ruiz-Mams C, C~denas-Ayala, VM and Solache G: Sero-immune response to measles vaccine in children 8 -18 months of age. Bol M~d Hosp Infant (M6x) 1986; 43: 526-532. (Published in Spa~.ish). 4) C~denas-Ayala, VM: Factors contributing to ARI mortality. ARI News 1987; 1 (7): 5. (Published in English). Also in Noticias sobre IRA: 1987, p.19-20. (Published in Spanish). 5) Ruiz-Mams C, .K.oopman)James S, Cgrdenas-Ayala VM, Herrera-Bastos E and I-Iinojosa-Martmez M: 'Diarrhoeal disease after the 1985 earthquakes in Mexico City. Sal Ptib Mdx 1987; 29: 399-405. (Published in Spanish). 6) C~denas-Ayala VM, Vilchis-Lic6n H, Stetler Harrison C, Koopman James S, Cabrera-Coello L, Valdespino-G6mez JL, Vega G and Muro Amador M: Risk factors for wild poliov~rus transmission in Sinaloa, Mexico, 1984-1986. Bol Of Sanit Panam 1988; 105(1): 1-12. English version of the same paper in: PAHO Bull 1988; 22 (3): 227-239. Also reprinted in Infectologia 1988; 8 (11): 571-580. 7) C~rdenas-Ayala VM, Bemal-P6rez J, Stetler Harrison C, Guerrero-Reyes P: Tuberculin skin surveys in Guerrero and new estimates for tuberculous infection frequency in Mexico. Sal INb Mdx 1988; 30: 152-157. (published in Spanish). 8) Pefia Corona MP, C~denas-Ayala VM, Ruiz Mares C, Stetler HC, L6pez Ortiz O, Ibarra Rosales J, Sapiafn L6pez LA and VillafLn FS: Whooping cough outbreak in San Bartotom6 Quialana, 1988. Report of the field investigation. Bol. Mensual Epidemiologia del Sector Salud 1989; 4 (8): 112- 118. (Published in Spanish). 9) Cgtrdenas-Ayala VM, Ruiz-Matus C, Montesano-Castellanos R, Cabrera- Coello L, Garrido-Lozada T, OIvera-Castillo, R and Diaz-Ortega JL: Cost- benefit analysis of measles vaccination program in Mexico. Sal Ptib M6x 1989; 31 (6): 735-44. (Published in Spanish). 0

v it)) (2arctenas-Ayaia VM anct bancttez, ~2: 5octal impact or measles vaccination programs in Mexico. Bol. M6d Hosp IMantil (M6xico) 1990; 47 (7) • 500-505. (Published in Spanish). i 1) Stem C, Tolbert K, Nufiez R_M, Goodwin M, Cg.rdenas VM: Changing conditions of child survival in M6xico and strategies for the furore. S~1 M6x 1990; 32 (5): 532-542. (Published in Spanish). 12) Garrido F, Borgues GG, C~irttenas VM, Ibarra JM, Borgues GG: Po.stneonatal mortality from diarrheal diseases: a case-control study. S~fl Mex 1990; 32 (3): 261:-268. (Published in Spanish). 13) C~denas-Ayala VM, Koopman James S, Garrido-Latorre F, Bazxia Luis F and Ibarra-Rosales, Alag6n J and Stetler, Harrison C.: Protective effect of antibiotics on mortality from acute respiratory infections. PAHO Bull 1992 26 (2): 109-120. Also published in Spanish in Bol Of Sanit Panam 1993; 114 (3); 202-212. 14) Flanders DW, C~denas VM, Austin H: Confounding by time since hire in internal comparisons of cumulative exposure in occupational cohort studies. Epidemiology 1992; 4:336-341. 15) Cgrdenas VM, Saad C, Varona M, and Linero M: Waterborne cholera in Riohacha, 1992. PAHO Bull 1993; 27 (4): 313-336. 16) C,'frdenas VM, Smith TE, Nufiez RM, Brogan DN, Gatica N, Ibarra JM, Galv~fn S, Flores ME, and Escobar A: Neonatal tetanus mortality in Veracruz 1989. PAHO Bull (accepted). 0 I I I I I I I I I I I /

I I I I I I I I I I I I I I ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER MORTALITY IN TIlE AMERICAN CANCER SOCIATY'S CANCER PREVENTION STUDY II by Victor M. Cardenas, M.D., National Autonomous University of Mexico, 1978 Epidemiologist, School of Public Health of Mexico, 1981 M.P.H, Emory University, 1990 Adviser: Harland D. Austin, D. Sc., An Abstract of A dissertation submitted to the Faculty of the Graduat~ School of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Division of Epidemiology 1994 I

I In presenting this dissertation as a partial fulfillment of the requirements for an advanced degree from Emory University, I agree that the Library of the University shall made it available for inspection and circulation in accordance with its regulations governing materials of this type. I agree that permission to copy from, or to publish, this dissertation may be granted by the professor under whose direction it was written or, in his/her absence, by the Dean of the Graduate School when such copying or publication is solely for scholarly purposes and does not involve potential financial gain. It is understood that any copying from, or publication of, this dissertation which involves potential financial gain will not be allowed without written permission. Vfctor M. Cardenas 0 0~ 0.~ O~ 0 I I I I i I I I I I I I i I I

I I I I- I I I I I I I I I I I I I I I vii Abstract Background Evidence from epidemiologic studies and animal and genotoxicity assays leads to the conclusion that environmental tobacco smoke (ETS) causes lung cancer. Objectives The hypothesis of a causal relationship between exposure to ETS during adulthood and risk of death from lung cancer was tested using seven years of follow-up data of the American Cancer Society's Cancer Prevention Study II. Methods Three analytic cohorts of life-time nonsmokers were assembled for ETS analyses based upon: i) self-reported current hours of exposure to ETS, 2) exposure from spousal smoking, and 3) dose of exposure to ETS from cigarette smoking of spouses. These cohorts included 362, 265, and 127 lung cancer deaths, respectively. Mantel-Haenszel rate ratio analyses by ETS exposure variables, followed by Cox regression modeling controlled for age, gender, race, education, intake of vegetables, fruits and fat, occupational exposure to asbestos and history of chronic lung diseases. Results Lung cancer risk among nonsmokers was not associated with current self-reported number of hours of exposure to ETS. Nonsmokers reportedly exposed to ETS for 6+ hours a day had a 20% statistically not significant increased risk: the multivariate rate ratio (RR) was 1.2, [95% Confidence Interval (CI)=0.8-1.7]. Nonsmoking women married to current smokers had also a statistically not significant 30 percent greater risk of developing lung cancer (multivariate RR=I.3, 95% CI=0.8-l.9). Women married to current cigar/pipe smokers had a 50% increased risk, but again the finding was not statistically significant (multivariate RR= 1.5, 95% CI=0.8-2.7). After adjusting for all covariates, we found among nonsmoking women an increasing risk of lung cancer with increasing pack-years of cigarettes smoked by their husbands which was not statistically significant (p=0.14). Discussion Missing data on self-reported ETS could have resulted in considerable misclassification and thus biased the study findings towards an absent of an effect. Self-reported hours of ETS exposure does not measure intensity of exposure and referred only to current, rather than lifelong ETS exposure. Assessment of exposure to ETS using spousal smoking habits is better, but still has considerable limitations and at best is an imperfect measurement. 2"he study also has limited statistical power and its generally null findings are still consistent with the positive association reported from other

oo. i studies. Conclusions This study found no evidence of an association between self-reported ETS and lung cancer risk among nonsmokers. However, using spousal smoking habits to assess exposure, we found ETS is only weakly, and not statistically significantly, related to lung cancer risk among nonsmoking women in seven years of follow-up of the CPS II cohort. I I I I I i I f I I I I I I I I I