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DRAFT••DO NOT QUOTE OR CITE • December, 1991 HEALTH EFFECTS OF PASSIVE SMOKING: • ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN Steven P Bayard, Ph.D.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DRAFT--DO NOT QUOTE OR CITE CONTENTS Tables .................................................................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

DRAFT--DO NOT QUOTE OR CITE FIGURES 3-1 Cumulative frequency distributions of RS concentrations from central site ambient and personal monitoring of smoke-exposed and nonsmoke-exgosed individuals .............................................. 3-2 Mean, standard deviation, maximum and minimum nicotine values measured in different indoor environments with smoking occupancy ................. 3-3 Week-long RSP and vapor-phase nicotine measurements in 96 residences with a mixture of sources. Numbers 1-9 refer to the number of ' observations at the same concentration ............................... 3-4 Mean, standard deviation, maximum and minimum of resprable suspended ~ particle levels for different indoor environments for smoking and . nonsmoking occupancy. Also shown are outdoor concxntrations .................. 3.5 Cumulative frequency distribution and arithmetic means of respirable suspended particle mass levels by vapor-phase nicotine levels, measured over a 1-week period in the main living area in residences in Onondaga and Suffolk Counties in New York State between Yanuary and Apri1,1986 ................................................. 3-6 Monthly mean RSP concentrations in six U.S. cities ............... 3-7 Average cotinine to by age groups ............................ 3-8 Distribution of individual concentration of urinary cotinine by degree of self-reported exposure to ETS. Horizontal bars indicate median values .............................................. 3-9 Urinary cotinine concentrations by number of reported exposures to tobacco smoke in the past 4 days among 663 nonsmokers, Buffalo, New York,1986 ............................................. 3-10 Average cotiaine/creatinine levels (ng/rng) for subgroups of non- smoking women defined either by sampling categories of exposure or by se3f•reporting exposure to ETS from different sources during the 4 days preceding collection of the urine sample ........... 3-11 Diagram for calculating the RPS mass from ETS emitted into any ~ occupied space as a function of the smoking rage and removal rate (N) ........ . .... 3-12 Diagram to calculate the ETS RSP concentration in a space as a ~ function of total mass of ETS RSP emitted (determined from Figure 11) c and the volume of a space (diagonal lines) ................................... '~ 01: W-ilb csz cn ~ xu t~

DRAFT-DO NOT QUOTE OR CITE J 4-1 4-2 4-3 5-1 5-a 5-3 5-4 5-5 Age-adjusted cancer death tates for selected sites, males, United States, 1930-1986 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age-adjusted cancer death rates for selected sites, females, United States, 1930-1986 ................................................. Relative risks of lung cancar in ex-smokers, by number of years quit,women ........................................................... Test statistics for hypothesis RR - 1. all countries ............................. Test statistics for hypothesis RR • 1, USA only ............................... Test statistics for hypothesis RR = 1, by country ............................... Test statistics for hypothesis RR = 1, China without WUWI & LStJ ................ 90% Confidence Intervals, by country ........................................ 5-6 90% Confidence Intervals, China without WUWI dt LIU ........................ z

AL I M DRAFT--DO NOT QUOTE C)R CITE 1. SUMMARY AND CONCLUSIONS . In 1986, the National Research Council (NRC) and the U.S. Surgeon General (U.S. SG) assessed the health effects of exposure to environmental tobacco smoke (ETS). Both of the 1986 reports conclude that ETS exposure is causally associated with lung cancer and that children of parents who smoke have increased frequency of respiratory symptoms and acute respiratory illnesses and evidence of reduced lung function. The two reports were developed and edited by different processes, which strengthens the validity of the conclusions common to both reports. The NRC repor: is the product of a committee of experts; the U.S. SO report is a composite of contributions from individual experts that was edited, based on the review of other knowledgeable individuals, and ther, cleared through the U.S. Public Health Service. This document extends the analyses of those reports to include more recent extensive evidence on the potential associations between ETS and ()) lung cancer in nonsmoking adults and (d) respiratory disease and pulmonary effects, mainly in children. It also develops the evidence alor.g the lines suggested by EPA's 1986 Guidelines for Carcinogen Risk Assessment. Inclusion of these recent studies more than doubles the size of the database available for analysis from that of the 1986 reports. This report concludes that: 1. Passive smoking is causally associated with lung cancer in adults and that ETS by the weight-of-evidence belongs in the category of compounds classified by EPA as Group A (known human) carcinogens. It also estimates that approximately 3,000 lung cancer deaths per year among nonsmokers (never-smokers and former smokers) of both sexes are attributable to ETS in the United States. 2. Exposure to ETS from parental smoking causes in children: a. increased prevalence of respiratory symptoms of irritation (cough, sputum and wheeze), b. increased prevalence or middle ear effusions (a sign of middle ear disease), and c. a small but significant reduction in lung function. 3. ETS exposure of young children and particularly infants from parental (and especially mother's) smoking is causally associated with lower respiratory tract infections (bronchitis and pneumonia). This report estimates that this exposure to parental smoking causes more than 210,000 lower respiratory tract infections in infants and children less than eighteen months, resulting in more than 10,000

DRAFT--DO NOT QUOTE OR CITE hosp'stalizations annually. These effects continue at a decreasing rate for children up until about age three. 4. Exposure to ETS is causally associated with increased incidence, prevalence, and severity of asthma. Data suggest that levels of exposure required to induce asthma in children are high. This report estimates that exposure of children to ETS from heavily smoking mothers resuits in approximately 13,000 to 25,000 additionat cases of asthma annually. 5. Infants whose mothers smoke are at an increased risk of dying from sudden infant death syndrome (SIDS). This relationship is consistent across studies and is independent of all other known risk factors for SIDS, including low birth-weight and low gestational age (both associated with active smoking during pregnancy). However, since the cause of SIDS is still unknown, this report does not conclude that the association is causal. The U.S. Centers for Disease Control estimates that over 700 SIDS deaths annually are attributable to smoking parents. This report concurs with those estimates. While the EPA cannot determine whether and to what extent the risk can be attributed to ETS exposure vs. in utero or lactational exposure to tobacco smoke products, prudent public health policy should consider ETS exposure as a risk factor for SIDS. 6. Passive smoking has subtle but significant effects on the respiratory health of non- smoking adults including coughing, phlegm, chest discomfort, and reduced lung function. F No conclusions are drawn regarding an association of parentalsmokina with either upper-respiratory- tract infections (colds and sore throats) or acute middle ear infections in children. 1.1 ETS AND LUNG CANCER The U.S. SG (1989) estimates that smoking is responsible for more than one of every six deaths in the United States and that it accounted for about 90% of the lung cancer deaths in males and 79°h in females in 1985. Smokers, however, are not the only ones exposed to tobacco smoke. The sidestrearn smoke (SS) emitted from a smoldering cigarette between puffs (the main component of ETS) has been documented to contain many of the same carcinogenic compounds (known and suspected human and animal carcinogens ) that have been identified in the mainstream smoke (MS) inhaled by smokers. Exposure concentrations of these carcinogens to passive smokers are variable but much lower than for active smokers. An excess cancer risk from passive smoking, however, is still 1-2

DRAFT--DO NOT QUOTE OR CITE biologically plausible, (U.S. EPA guidelines [Fed. Reg., 1986] assume that unless there is evidence to the contrary, any level of exposure to a carcinogen carries a potential risk of cancer, ) Based on the firmly established causal association of lung cancer with active smoking with a dose-response relationship down to low doses (chapter 4), passive smoking is considered likely to affect the lung similarly. The ubiquity of ETS and its absorption by nonsmokers in the general population have been well documented by air sampling and by bioassays for nicotine and cotinine (chapter 3). This raises the question of whether any direct evidence exists for the relationship between ETS exposure and lung cancer in the general population and what its implications may be for public health. This report addresses that question by reviewing and analyzing the cumulative evidence from thirty epidemiologic studies (chapter 5). These studies compare individuals with higher ETS exposures to those with lower exposures. Typically the study subjects compared are married women who have never smoked but are married to a smoker (higher exposure) and those married to a nonsmoker (lower exposure). Following the nomenclature of the literature, the more and less exposed persons are referred to as "exposed" and "unexposed.' Of course there is exposure to ETS from sources other than spousal smoking, collectively designated as "background" exposure, which applies to the so-called unexposed as well as the exposed. Background exposure is taken into account in the characterization of population risks (chapter 6),'but adjustment for other sources of ETS exposure is not required for the statistical assessment of„the evidence of excess lung cancer risks from i exposure to spousal smoking (chapter 5). The direct epidemiologic evidence of a lung cancer hazard is statistically assessed by methods of meta-analysis to obtain overall results. The data and study results included apply to female married never-smokers, but the conclusions are generalizable to all nonsmokers. Several studies include male subjects, but the percentage of male never-smokers is relatively small and the data are ~ scant by comparison. In a few instances long-term former smokers are included with never-smokers. IZ All the ETS exposures are considered to be at true environmental levels. O ~ In order to use data from the thirty epidemiology studies from eight different countries, the G: studies were first considered separately and then pooled by country. Also, the studies were evaluated C.R 1-3

DRAFT--DO NOT QUOTE OR CITE individually for their quality of design and conduct, and their likely ability to provide information about the carcinogenicity of ETS, and for some analyses placed into one of four tiers (tier one being for studies of the highest utility). Results compared both within and between countries showed significant associations for Greece, Hong Konz, Japan and the U.S., and in that order of strength of relative risk. Pooled results of the four Western European studies (3 countries) actually showed associations that were slightly stronger than those of the U.S. but were not statistically significant. Three of the four Chinese studies, which were designed mainly to determine the lung cancer effects of other indoor air pollutants, were evaluated to be in the lowest utility tier, and the Chinese studies as a whole provided very little additional data, for the weight-of-evidence evaluation of ETS carcinogenicity. Two of these Chinese studies, however, provide very strong evidence on the lung carcinogenicity of other indoor air pollutants indigenous to the areas. These pollutants contain many 1~4 GG ~. ~ ~•e, ~,~. of the same components as ETSy ~l~ N; n. n ~4-' The relative risks for Greece and Japan of 2.00 and 1.44, respectively, are probably the best estimates, since female smoking prevalence and non-tobacco related lung cancer risks, which tend to dilute the ETS effects estimates, are both low in these two countries. Also, for the time period for which ETS exposure was of interest, spousal smoking is considered to be a better surrogate for F-TS exposure in these societies than in Western countries, where other sources of ETS exposures (work, public places, and social settings) are generally higher. Based on these analyses and following the U.S. EPA guidelines for carcinogen risk assessment (Fed. Reg., 1986), EPA concludes that environmental tobacco smoke is a Group A (known human) carcinogen. This conclusion is based on a total weight-of-evidence, principally: ' Biological plausibility. ETS is taken up by the lungs and distributed throughout the body. The similarity of carcinogens identified in SS and MS, along with the established causal relationship between lung cancer and active smoking with the dose-response relationships ; down to low doses, make it reasonable to conclude that ETS is also a lung carcinogen. • Supporting evidence from animal bioassays and genotoxicity experiments. The ~ carcinogenicity of tobacco smoke has been established in lifetime inhaiation studies in the p hamster, intripulmonary implantations in the rat, and skin painting in the mouse, There are ,~ no lifetime animal inhalation studies of ETS; however, the carcinogenicity of ETS condensates O; has been demonstrated in intrapuimonary implantuions and skin painting experiments. Wa Positive results of genotoxicity tr;sting for both MS and ETS provide corrobQrative evidence C3? 1-4 ~ ~ ~

DRAFT--DO NOT QUOTE OR CITE for their carcinogenic potential. * Consistency of response. The four cohort studies and twenty of the 26 case-control studies observed a higher risk of lung cancer among the female never-smokers classified as exposed to ETS. Of the seventeen studies judged of higher utility, based on study design, execution and analysis (Appendices A and C), fifteen observed higher risks and six of these increases were statistically significant, despite most having low statistical power. Evaluation of the total study evidence from several perspectives leads to the conclusion that the observed association between ETS exposure and increased lung cancer occurrence is not attributable to chance. • Broad-based evidence. These 26 case-control and four prospective studies provide data from eight different countries, employ a wide variety of study designs and protocols and are conducted by many different research teams. No alternative explanatory variables for the observed association between ETS and iung cancer have been indicated that would be broadly applicable across studies. * Upward trend in dose-response. Both the largest of the cohort studies, the Japanese study of Hirayama - 200 lung cancer cases, and the largest of the case-control studies, the U.S. study by Fontham et al. - 420 lung cancer cues and two sets of controls, demonstrate a strong dose-related statistical association between passive smoking and lung cancer. This upward trend is well supported by the preponderance of evidence in the 13 case-control studies that classified data by exposure level, ' Detectable association at environmental exposure levels. Within the population of women who are lifelong nonsmokers, the excess lung cancer risk of those married to a smoker is iarge enough to be observed, Carcinogenic responses are usually detectable only in high exposure circumstances, such as occupational settings, or in experimental animals receiving very high doses. e Effects remain after adjustment for potential bias. Current and ex-smokers may be misreported as never-smokers, thus inflating the apparent cancer risk for ETS exposure. The evidence remains statistically significant and conclusive, however, after adjustments for smoker misclassification. For the U.S. the summary estimate of relative risk from nine casc- control plus two cohort studies is 1.19 (90% C.I. 1.04-1.35) after adjustment for misclassification (p < 0.05). For Greece 2.00 (1.42, 2.E3), Hong Kong 1.61 (1.25, 2.06) and Japan 1,44 (1.13, 1.a5), the estimated relative risks are higher than those of the U.S. and more highly significant after adjusting for the potential bias. The individual risk of lung cancer from exposure to ETS does not have to be very large to translate into a significant health hazard to the U.S. population because of the large number of smokers and the ubiquity of ETS. Current smokers comprise approximately 30% of the adult U.S. population and consume over one-half trillion cigarettes annually (1.5 packs per day, on average), causing nearly universal exposure to ETS. Cotinine, a metabolite of the tobacco-specific compound nicotine, is detectable in the blood, saliva, and urine of persons recently ezposetd to tobacco smoke. Cotinine has typicaily been detected in 50% to 75% of reported nonsmokers tested (50% equates to 1-5

DRAFT--DO NOT QUOTE OR CITE 63 million U.S. nonsmokers of age I E or above). The estimate of 3,0001ung cancer deaths per year in nonsmokers attributable to ETS is based on data from eleven U.S. epidemiologic studies at actual environmental exposure levels. Use of actual U.S. studies should increase the confidence in these estimates. Some mathematical modeling is required to adjust for expected bias from self-reported misclassification of smoking status and to account for ETS exposure from sources other than spousal smoking. The approach, however, does not rely on a mathematical model of dose response for low dose extrapolation of observations obtained at extraordinarily high exposure levels. The components of the 3,000 figure include approximately 1500 female never-smokers, 500 male never-smokers, and 1050 former smokers of both sexes. Additional breakdowns can be given for home exposure to spousal smoke - approximately 850 nonsmokers of both sexes - and for a:1 other sources of ETS exposure (eg. work and social settings) - 2,200 nonsmokers of both sexes. More • females are estimated to be affected because there are more female than male never- and non- smokers. Other estimates of annual U.S. nonsmoker lung cancer deaths attributable to ETS developed in this document give a range of 2,400 to 3,300. These other estimates use both mortality and cotinine exposure data from the largest U.S. study (Fontham et al., 1991). Relatively small differences in cotinine ratios, as measures of exposure from spousal smoking, can result in substantial variability in population risk estimates. The range suggested above provides estimation of the uncertainty in these estimates. Overall, however, considering the multitude, consistency, and quality of all these studies, the weiEht-of-evidence conclusion that ETS is a known human lung carcinogen, the limited amount of extrapolation necessary, and the small range of estimates provided by several quantitative procedures, the confidence in the estimate of approximately 3,000 lung cancer deaths is medium to high. 1.2 ETS AND NON-CANCER RESPIRATORY DISORDERS 1-6 -dr

DRAFT--DO NOT QUOTE OR CITE Exposure to ETS from parental smoking has been previously linked with increased respiratory disorders in children, particularly in infants, Several studies have confirmed the exposure and uptake of ETS in children by assaying saliva, serum, or urine for cotinine. Cotinine concentrations were highly correlated with smoking (especially by the mother) in the child's presence. Nine to twelve million American children under five years of age may be exposed to cigarette smoke in the home (American Academy of Pediatrics, 1986). With regard to the non-cancer respiratory effects of passive smoking, this report focuses on epidemiologic evidence appearing since the two major reports of 1986 (NRC and U.S. SO) that bears on the potential association of parental smoking with detrimental health effects in their children. These include symptoms of respiratory irritation (cough, sputum, or wheeze); acute diseases of the lower respiratory tract (pneumonia, bronchitis and bronchiolitis); indications of chronic middle ear infections (predominantly middle ear effusion); reduced lung function (from forced expirator. volume and flow-rate measurements); incidence and prevalence of asthma, and exacerbation cf symptoms in asthmatics; and acute upper-respiratory-tract infections (colds and sore throats) Tr.r fifty or so recently published studies reviewed here essentially corroborate the previous conclus;or.s of the NRC and U.S. SG regarding respiratory symptoms, respiratory iilnesses, and pulmonar) function; and strengthen support for those conclusions by the additional weight-of-evidence. For example, new data on middle ear effusion strengthen previous evidence to warrant the stronger conclusion in this report of a causal association with parental smoking. Furthermore, recent studies establish associations between parental smoking and increased incidence of both childhood asthma and SIDS. Additional research also supports the hypotheses that in utero exposure to mother's smoke and postnatal exposure to ETS alter lung function and structure, increase bronchial responsiveness, and enhance the process of allergic sensitization, changes that are known to predispose children to early 7 respiratory illness. Early respiratory illness can often lead to long-term pulmonary effects (reduced lung function and increased risk of chronic obstructive lung disease). The NRC and U.S. SO reports conclude that both the prevalence of respiratory symptoms of irritation and the incidence of respiratory tract infections are higher in the children of smoking 1-7

EPA ECAO CIN FAX NO. E;?5ez_-_ „ DRAFT--DO NOT QUOTE OR CITE the eighteen studies of respiratory symptoms subsequent to the two reports, increased ,cough, phlegm and wheezing) were observed in a range of ages from birth to mid-teens, ty in infants and preschool children, In addition to the studies on symptoms of respiratory , nine new studies have addressed the topic of parental smoking and acute lower respiratory a children, and eight have reported statistically significant associations. The cumulative ;e indicates strongly that parental, tspecially the mother's, smoking causes an increased nce of respiratory illnesses in the first eighteen months to three years of life, particularly for :hitis, bronchiolitis and pneumonia. Overall, the cumulative evidence confirms the previous Iusions of the NRC and U.S. SG. Recent studies also solidify the evidence of a link between ental smoking and increased middle ear effusion in young children, At the time of the U.S. SO report on passive smoking, there were only sufficient data to onclude that maternal smoking may influence the severity of asthma in children. The recent studies Iviewed here confirm these results. In addition, the new evidence clearly indicates that ETS exposure causes asthma in many children, although the results are statistically significant mostly with children whose mothers smoke 10 cigarettes per day or more. si:17 This document also summarizes the evidence for an association between ETS exposure and SIDS, which was not addressed in the NRC or SG reports. SIDS is the most common cause of death in infants aged one month to one year. The cause(s) of SIDS is unknown; however, it is widely 7 believed that some form of respiratory failure is generally involved. The eurr nt evidence =N of~~ demonstrates unequivocally that infants whose mothers smoke are at an increased risk of dying .= ~.~. ~ SIDS, independent of other known risk factors for SIDS. Regarding the effects of passive smoking and lung function in children, the U.S. SG and NRC reports both conclude that children of parents who smoke have small decreases in tests of pulmonary output function of both the larger and smaller air passages when compared with the children of nonsmokers. As noted in the NRC report, if ETS exposure is the cause of the observed decrease in lung function, the effect could be due to the direct action of agents in ETS or an indirect consequence -=Trence of acute respiratory illness related to ETS. ~ ~ C~ 1-9