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DRAFT••DO NOT QUOTE OR CITE • December, 1991 HEALTH EFFECTS OF PASSIVE SMOKING: • ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN Steven P Bayard, Ph.D. Project Manager, U.S. EPA NOTICE THIS REPORT IS A PRELIMINARY DRAFT SUBMITIED TO THE U. S. ENVTRONMEIYT'AL PROTECTION AGENCY FOR REVIEW AND SHOULD NOT BE CONSTRUED AS REPRESENTING THE AGENCY'S POSITION. This report has been supported by the Office of Health and Environmental Assessment, Office of Research and Development, and the Indoor Air Division, Office of Atmospheric and Indoor

DRAFT--DO NOT QUOTE OR CITE CONTENTS Tables ................................................................. viii Figures ............................................................... Preface .................................... :............................. uiv Authors and Reviewers ...................................................... xv 1. EXECUTTVE SUMMARY .............................................. 2. INTRODUCTION ..................................... k................... 3. ESTIMATION OF EIr'VIRONMENTAL TOBACCO SMOKE EXPOSURE ............. 3.1.ITTRODUCTION . ................................................. 3.2. PHYSICAL AND CHEMICAL PROPERTIES ............................... 3.3. ASSESSING E'I'S EXPOSURE ........................................... 3.3.1. Markers for Environmental Tobacco Smoke ............................ 3.3.2. Measured Exposures to ETS-Associated Nicotine and RSP ................ 3,3.2.1. Personal Monitors ....................................... 3.3.2.2. Measurements Using Stationary Monitors ..................... 3.3.3. Biomarkers of ETS Exposure ....................................... 3.3,4. Questionnaires for Assessing ETS Fxposures ........................... 3.4. MODELS FOR ASSESSING ETS EXPOSURE ................ . ............. 3.3.SUMMARY .......................................................... 4. HAZARD IDENTTFICATION I. LUNG CANCER IN ACTNE SMOKERS AND LONG-TERM ANIMAL S'NDIES ...................................... ..... 4.1.IwTRODUCTTON ................................................ 4.2. DIRECT EVIDENCE FROM HUMAN STUDIES ............................ 4.2.1. Tiune Trends ..................................................... 4.2.2. Dose-response Relationships ....................................... 4.2.3. Histological Types of Lung Cancer and Associations with Smoking ....................................... 4.2.4. Proportion of Risk Attributable to Active Smoking ....................... ~ 0 ~ c*~ ~ iu ~ ~ ~ ~ 0

DRAF'I'--DO NOT QUOTE OR CrIE CONTENTS (continued) 4.3. LIFETIME ANIMA,L SNDIES 4.3.1. Inhalation Studies .......................................... 4.3.2. Intrapulmonary Implantations of Cigarette Smoke Condensates ............................................ 4.3.3. Mouse Skin Painting of Cigarette Smoke Condensates ............... 4.4. GENOTOXICITY ................................................ 4,5. SUMMARY AND CONCLUSIONS ................ .................. 5. HAZARD rDENTIFICATION IT. INTERPRETATION OF EPIDEMIOLOGIC STUDIES ON ETS AND LUNG CANCER ...................................... 5.1. INTRODUCTION ..................................................... 5.2. RELATIVE RISKS USED IN STATISTICAL INF'ERE.NCE ..................... 5.2.1. Selection of Relative Risks ................................... 5.2.2. Downward Adjustment to Relative Risk for Smoker Misclassification Bias .................................... 5.3. STATISTICAL INFERENCE ............................................. 5.3 1. Introduction .................................................. 5.3.2. Outcomes by Study and Country ................................... 5.3.2.1. Tests for Association ................................... 5.3.2.2, Confidence Intervals .................................... 5.3.2.3.TestsforTrend ........................................ 5.3.2.4. Statistical Conclusions .................................. 5.4, EXTENDED DATA INTERPRETATION .................................. •5.4.1. Introduction ............. . ......... . . . . . . . . ..................... 5.4.2. Potential Confounders ............................................ v 5.4.2.1. History of Lung Disease ................................... 5.4.2.2. Family History of Lung Disease ............................. 5.4.2.3. Heat Sources for Cooking or Heating ......................... ~ 5.4.2.4. Cooking with Oil ....................................... 5.4.2.5. Occupation ............................................. ~ 5.4.2.6. Dietary Factors .......... ........ .,.~.~,. ., dso'...... ..• 3.y. 2.t , 5~.~«.~..xy or+ ?o+Cr~+i~.l ~~~.. 5.4,3. Potential Sources of Bias and Other Uncertainty .................... r ..---~" 5.4.4. Potential Effects on Individual Studies ................................ .4.5. Impact on Statistical Conclusions .................................. - S5 ~ 6. i. 6. Conclusions for Hazard Identification ................................. iv

DRAFT--DO NOT QUOTE OR CITE COIVTENTS (continued) 5, 5 . j . i.4i,t. Criteria for Causality ..................................... 5.S.Z. i.bie3, Assessment of Causality ................................... Conclusion for Hazard Identification ................................. 6, POPUL.ATION RISK OF LUNG CANCER FROM PASSIVE SMOKING .............. 6.1. INTRODUCITON ...................................................... 6.2. PRIOR APPROACHES TO ESTIMATION OF POPULATION RISK ............. 6.2.1. Fxamples Using Epidemiologic Data ........................ 6.2.2. Examples Based on Cigarette Equivalents .................... 6.3. LUNG CANCER MORTALITY ATFRIBUTABLE TO ETS IN THE U.S. 6.3.1, Introduction and Background .............................. 6.3.2. Parameters and Formulas for Attributable Risk ......................... 6.33. U. S. Lung Cancer Mortality Estimates Based on Results of Combined Estimates from ' siaaM~t 4 lv`: A ........ 6,3.4. U. S. Lung Cancer Mortality Estimates Based on Results ~.S. ko* ............. of the VOW P~t .~0. 6.3.5. Sensitivity to Parameter Values ..................................... 6.4 SUMMARY AND CONCLUSIONS ON POPULATION RISK ................. 7. PASSIVE SMOKING AND RESPIRATORY DISORDERS OTfER TKAN CANCER .... 7.1, INTRODUCTION ........................................ 7.2, BIOLOGICAL MECHANISMS....................... .... .... 7.2.1. Plausibility ................................................ . . . . . 7.2.2. Effects of Exposure In-utero and During the First Monthsof Life................................................ 7.2.3. Long Term Significance of Early Etfects on Airway Function ............................................... 7.2.4. Exposure to ETS and Bronchial Hyperresponsiveneas .................... 7.2.5. ETS Exposure and Atopy .......................................... 7.3. EFFEC,'T OF PASSIVE SMOKING ON ACUTE RESPIRATORY ILLNESSES IN CHILDREN ...................................................... 1 7.3.1. Recent Studies on Acute Lower Respiratory Itlnesses ..................... 7.3.2. Summary and Discussion on Acute Respiratory Illnesses .................. Nl~ 7.4. PASSIVE SMOKING AND ACUTE CHRONIC MIDDLE EAR DISEASES ........ p ~ ~ c.R v ..__. ~ ~ ~ ~

DRAFL'--DO NOT QUOTE OR CITE CONTENTS (continued) 7.4.1. Recent Studies on Acute and Chronic Middle Ear Diseases ................ 7.4.2. Summary and Discussion on Middle Ear Diseases ....................... 7S. EFFECT OF PASSIVE SMOKING ON COUGH, PHLEGM, AND WHEEZING .. 7.5.1. Recent Studies on the Effect of Passive Smoking on Cough, Phlegm, Bronchitis, and Wheezing ................................. 7.5.2. Summary and Discussion on Cough, Phlegm, Bronchitis, and Wheezing ................................................ 7.6. EFFECT OF PASSIVE SMOKING ON ASTHMA .................. , ......... 7.6.1. Recent Studies on the Effect of Passive Smoking on Asthma in Ch.ddren .......................................... 7.6.2. Summary and Discussion on Asthma ............................... 7,7, ETS EXPOSURE AND THE SUDDEN INFANT DEATH SYNDROME ..... .. 7.8. PASSIYE SMOKING AND LUNG FUNCTION IN CHILDREN ............. 7.8.1. Recent Studies on Passive Smoking and Lung Function in Chlldren ................................................ 7.8.2. Summary and Conclusions on Pulmonary Function in Children .............................................. 7.9. PASSIVE SMOKING AND RESPIRATORY SYMPTOMS AND LL'NG FUNCTION IN ADULTS ........................................... 7.9.1. Recent Studies on Passive Smoking and Adult Respiratory . . . . . . Symptoms and Lung' Function ............................. 7.9.2, Summary and Discussion on Respiratory Symptoms and Lung Function in Adults ....................................... 8. ASSESSMENT OF INCREASED RISK FOR RESPIRATORY ILLNESSES IN CHILDREN FROM ENVIRO.'vMENTAL TOBACCO SMOKE ..................... 8.1. POSSIBLE ROLE OF CONFOUNDING ................................... 8.2. MISCLASSIFICATION OF EXPOSED AND UNEXPOSED SUBJECTS .......... 8.2.1. Effect of Active Smoking in Children ................................. 8.2.2. Misreporting and Background Exposure ................................ 8.3. ADJUSTMENT FOR BACKGROUND EXPOSURE .......................... 8.4. ASSESSMENT OF RISK ............. . .................................. REFERENCES ................,....................,..................... R-1 vi

DRAFT--DO NOT QUOTE OR C1TE CONTENTS (continued) APPENDIX A: REVIEWS OF EPIDEMIOLOGIC STUDIES ON ETS AND LUNGCANCER............................................. A-i APPENDIX B: METHOD FOR CORREC,'ITNG RELATIVE RISK FOR SMOKER MISCLASSIFTCATION ........................................ B•1 APPENDIX C: REVIEW FORMAT FOR CASE-CONTROL STUDIES .............. C-1 APPENDIX D: LUNG CANCER MORTALITY RATES DUE TO SPOUSAL ETS IN INDIVIDUAL EPIDEMIOLOGIC STUDIES ...................... D-1 ~ C ~ ~ ~rr vii o~ ~ ~

DRAFT'--DO NOT QUOTE OR CITE TABLES 3-1 Distribution of Constituents in Fresh, Undiluted Mainstream Smoke and Diluted Sidestrearn Smoke from Nonfilter Cigarettes ..................... . . . . . . 3-2 Personat Exposures to Nicotine in The Work Setting ............................ 3-3 Studies of Personal Exposure to Particle Matter Associated with ETS for Non-Smokers ..........................,...........,.............:. 3-4 Range of Nicotine and RSP Levels Measured in Various Indoor Envirotunents and Associated with Smoking Occupancy (From Figures 2 and 4) ................. 3-5 Approximate Relations of Nicotine as Parameter Between Nonsmokers, Passive Srnokers, and Active Srnokers ........................................... 4-1 Main Characteristics of Major Cohort Studies on the Relationship Between Smoking and Cancer .................................................... 4-2 Lung Cancer Mortality Ratios--Prospective Studies .............................. 4-3 Lung Cancer Mortality Ratios for Men and Women, By Current Number of Cigarettes Smoked Per Day-Prospective Studies ............................... 4-4 Relationship Between Risk of Lung Cancer and Duration of Smoking in Men, Based on Available Information from Cohort Studies ......................... 4-S Lung Cancer Mortality Ratios for Males, By Age Began Smoking-- Prospective Studies ..................................................... 4-6 Relationship Between Risk of Lung Cancer and Number of Years Since Stopping Smoking, in Men, Based on Available Information from Cohort Studies ............. 4-'1 Relative Risks of Lung Cancer in Some Large Cohort Studies Among Men Smoking Cigarettes and Other Types of Tobacco ...................................... 4-8 Age-adjusted Lung Cancer MortaUty Ratios for Males and Femaks, by Tar and Nicotine in Cigarettes Smoked ............................................. 4-9 Relative Risk for Lung Cancer By Type of Cigarette Smoked (Filter vs. Nonfilter), in Men, Based on Cohort and Gse-Control Studies . . .......................... ~ O 4-10 Main Results of Studies Dealing writh the Relationship Between Smoking and Different ''" Histological Types of Lung Cancer ......................................... cn 4-11 Lung Cancer Deaths Attributable to Tobacco Smoking in Certain Countries .......... o0 ~ 5.1 Epidemiologic Studies on ETS and Lung Cancer in this Report . . . . . .............. ~% UP viu

D RAFT-DO NOT QL;O'IE O R CITE TABLES (continued) 5-2 Studies by Location, Time, Size, and ETS Exposure ........................... 5-3 Case-Control Studies of ETS: Characteristics ................................. 5-4 Prevalences and Estimates of Lung Cancer Risk Associated with Active and Passive Stnoking ....................................................... 5-5 Effect of Adjustments on Risk Estimates For Passive Smoking .................... 5-6 Alternative Estinmates of Lung Cancer Relative Risks Associated with Active and Passive Smoking ..................................................... 5-7 Estimated Correction for Smoker Misclassification ............................. . . . . . . . . 5-8 Statistical Measures by Study and Country ........................... 5•9 Case-Control and Cobort Studies: Exposure Response Trends for Females .......... 5-10 Summary of Trend Tests for ETS Exposure Measures ........ 11, ......... 5-11 Summary of Test Results .......................................... 5-12 Other Risk-Related Factors for Lung Cancer Evaluated in Selected Studies ..... 5-14A Study Limitations and Sources of Uncertainty .............................. 5-14B Study Limitations and Sources of Uncertainty ............................... 5-15 Diagnosis, Confirmation, and Exclusion of Lung Cancer Cases .................. . 5-16 Classification of Studies by Tier ............................................ 3.17 Summary Data Interpretation by Country .................................... 6-1 Female Lung Cancer Mortality by Attributable Sources for United States, 1985,UsingStudiesfromTiersland2 .................••••.••••••••... 6•2 Female and Male Lung Cancer Mortality by Attributable Sources for United States, 1985, Using Studies from Tiers I and 2(Never-staokers and Former Smokers Who Have Quit for 5+ Years ............................................ 6-3 "- Female Lung Cancer Mortaliry by Attributable Sources for United States, 1985, Using Study from Tier 1 Only ......................................... 6-4 Female and Male Lung Cancer Mortality by Attributable Sources for United Stares, 1985, Using Study from Tier 1 Only (Never-smokers and Former Smokers Who Have Quit S+ Yeas's ........................................................ ix

DRAFT-DO NOT QUOTE OR CITE TABLES (continued) 6-5 Effects of Single Parameter Changes on Lung Cancer Mortaiity Due to ETS in Never-smokers and Former Smokers Who Have Quit 5+ Years . . . . . . . . . . . . . . . . . . . 7.1 Studies on Chronic Respiratory Symptoms Referenced in the U.S. Surgeon General's and National Research Council's Reports of 1986 ...................... 7-2 Epidemiologic Studies of Effects of Passive Smoking on Acute Lower Respiratory Tract Illnesses (LRIS) ........................................... 7-3 Studies on Middle Ear Diseases Referenced in the U.S. Surgeon General's Reportof1986 ......................................................... 74 Epidemiologic Studies of Effects of Passive Smoking on Acute and Chronic Middle Ear Diseases .................................................... 7-5 Studies on Respiratory Illness Referenced in the U.S. Surgeon General's and National Research Council's Reports of 1986 .............................. 7-6 Epidemiologic Studies of Effects of Passive Smoking on Cough, Pb.legm and Wheezing ............................................................. 7-7 Epidemiologic Studies of Effects of Passive Smoking on Asthma in Childhood ........ 7-8 Epidemiologic Studies of Effects of Passive Smoking on Incidence of Sudden Infant Death Syndrome (SIDS) ..................................... 7-9 Studies on Pulmonary Function Referenced in the U.S. Surgeon General's . . . . . and National Research Council's Reports of 1986 ......................... 7-10 Epidemiologic Studies on the Effects of Passive Smoking on Lung Function 7-11 B-1 B-2 B-3 ; B-4 B.5 in Children .................................................... Epidemiologic Studies on the Effects of Passive Smoking on Adult Respiratory Symptoms and Lung Function ...................................... to Current Smokers i l S k d R i f O Ob ccas ona ers mo serve at os o (Based on Cotinine Studies) ....................................... Misclassification of Female Current Smokers .......................... Misclassification of Female Former Smokers Reported as Never-Smokers Based on Discordant Answers ...... ...... . ....................... Misclassification of Female Lung Cancer Cases ........................ .,.....~ Propor:ionate Distribution of Reported Female Lung Cancer Cases and O ~a Controls by Husband's Smoking Status ...................................... ~ ~ x Gn ~ ~ -Q

DRAFT--DO NOT QUOTE OR CITE TABLES (continued) B-6 Conditional Probability Notation for Observed Smoking Status Given True Smoking Status .................................................... B-? Observed Lung Cancer Relative Risks for Exposed and Non-Exposed Wives by the Wives' Smoking Status Using Average Never-Smoking Wives as the Reference Category ................................................ B-8 Prevalences and Estimates of Lung Cancer Risk Associated With Active and Passive Smoking .................................................... B-9 Observed Smoking Prevalence Among the Controls ............................. B-10 Observed Relative Risks ................................................. B-11 Crude Case Table--Prevalence of Cases by Smoking Status ....................... B-12 Normalized Case Table-Prevalence of Cases by Smoking Status ................... B-13 Conditional Probabilities (Of Misclassification) for Wives ........................ B-14 Deletions from the Never Columns in Tables B-9 and B-12 ....................... B•1S Ratios of Female Former Smokers to Ever Smokers Populations Observed in the USA, U.K, and Sweden or Controls (Numbers or %) ...................... B-16 Observed Ratios of Current Smoker Lung Cancer Risk to Ever Smoker . . . . . . . . . . . . . . . . . . . . . . . Risk for Females ................................. D-1 Female Lung Cancer Mortaliry from All Causes ............................... D-2 Parameter Values used to Partition Female Lung Cancer Mortaiity into ComponentSourcat ................................................. D-3 Female Lung Cancer Mortality Rates by Attributable Source ..................... D-4 Lung Cancer Rates of Female Ever-Smokers (E.S.) and Never-Smokers (N.S.) by Fxposure Status ...................................................... , zi