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+ ENVIRONMENTAL, TOBACCO SMOKE - Measuring Exposures . and Assessung Health Effects Committee on Passive Smoking Board on Environmental Studies and'Ibuticology National Research Council NATIONAL ACADEMY PRESS - - -- --- -- - - Washington, U G. 1986

National Academy Press * 2101 Constitution Avenue, NW ' Washington, DC 20418 NOTICE: The project that is the subject of this report was approved by - the Governing Board of the National Research Council, ncil, whose members are -lrawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The membsrs of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by y a group other than the authors according to procedures approved by a Report Review Committee consisting of inembers of the National Academy of Sciences, the National Academy of Lngineering, and the Institute of Medicine. The National Research Council was established by the National Academy of Sciences In 1916 to associate the broad community of science and technol- ogy with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies - - determined by the Academy under the -authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, seif-governing membership corporation. The Council has become the principal operating - agency of both the National Academy of Sciences and the National Academy - of Engineering In the cortduct of their services to the government, the public, and the scientific and engineering communities. It In administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established In 1964 and 1970, respectively, under the charter of the National Academy of Sciences. This study was prepared under EPA Contract #68-02-4073 and De- partment of Health and Human Services, Public Health Services Grant #ASU000001-00-S1. The content of this publication does not necessarily reflect the views or policies of the U.S. Environmental Protection Agency or the Department of Health and Human Services, and an official endorsement -- should not be inferred. - INTERNATIONAL STANDARD BOOK NUMBER 0-309-03730-1 LIBRARY OF CONGRESS CATALOG CARD NUMBER 86-28622 Copyright Q 1986 by the National Academy of Sciences No part of this book may be reproduced by any mechanical, photographic, or electronic process, or In the form of a phonographic recording, nor may it be stored In a retrieval system, transmitted, or otherwise copied for public or private use, without written permission from the publisher, except for the purposes of official use by the United States Government. Printed In the United States of America 46R9e44e BOARD ON ENVIRONMENTAL STUI)Ih";.? . AND TOXICOLOGY DONALD HORNIG, Harvard University, Boston, Massachusetts, -- - Chairman ALVIN L. ALM, Thermal Analytical, Inc., Waltham, Massachusetts RICHARD N. L. ANDREWS, University of North Carolina, Chapel Hill, North Carolina WILLIAM E. COOPER, Michigan State University, East Lansing, Michigan JOHN DOULL, University of Kansas Medical Center, Kansas City, Kansas EMMANUEL FARBER, University of Toronto, Toronto, Ontario, Canada BENJAMIN a. FERRIS, Harvard School of Public Health, Boston, Maseachusetts PHILIP LANDRIGAN, Mt. Sinai Medical Center, New York,.New York RAYMOND O. LOEHR, University of Texas, Austin, Texas ROGER MINEAR, University of Illinois, Urbana, Illinois PHILIP A. PALMER, E.I. DuPont de Nemours & Co., Wilmington, - Delaware EMIL PFITZER, Hoffman-La Roche, Inc., Nutley, New Jersey PAUL PORTNEY, Resources for the Future, Washington, D.C. PAUL RISSER, Illinois Natural History Survey, Champaign, Illinois WILLIAM H. RODGERS, University of Washington, Seattle, Washington F. SHERWOOD ROWLAND, University of California, Irvine, California LIANE B. RUSSELL, Oak Ridge National Laboratory, Oak Ridge, Tennessee ELLEN SILBERaELD, Environmental Defense Fund, Washington, D.C. - PETER SPENCER, Albert Einstein College of Medicine, Bronx, - New York National Research Council Staff DEVRA LEE DAVIS, Acting Director, BEST JACQUELINE PRINCE, Staff Associate tu

COMMITTEE ON PASSIVE SMOKING BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina, Chairman 0LAV AXELSON, University Hospital, Linkoping, Sweden JOSEPH BRAIN, Harvard School of Public Health, Boston, Massachusetts PATRIOIA BUFFLER, University of Texas at Houston, Houston, Texas A. SONIA BUIST, Oregon Health Sciences University, Portland, Oregon DIETRICH HOFFMANN, American Health Foundation, Valhalla, New York BRIAN LEADERER, Yale University, New Haven, Connecticut aENEVIEVE MATANOSKI, Johns Hopkins University, Baltimore, Maryland JAMES ROBINS, Harvard School of Public Health, Boston, Massachusetts JOHN SPENC3LER, Harvard School of Public Health, Boston, Massachusetts NICHOLAS WALD, Medical College of St. Bartholomew's Hespital, - - London, England National Research Council Staff DEVRA LEE DAVIS, Acting Director, BEST DIANE K. WAGENER, Project Director MARVIN SOHNEIDERMAN, Senior Sta-ff- Officer RIOHARD E. MORRIS, Editor EDNA W. PAULSON, Information Specialist MARY ELLEN SOHENKENBAOH, Staff Assistant JULIETTE L. WALKER, Senior Secretary Pr-eface The Office of Air and Radiation of the Environmental Pro- ---- - - tection Agency and the Office on Smoking and Health of the - Department of Health and Human Services asked the National - Research Council to evaluate methods for assessing exposure to --- environmental tobacco smoke and to review the literature on the - health consequences from such exposures. The National Research Council responded to this request by appointing 11 scientists to serve on the Committee on Passive Smoking, in the Board on Envi- - ronmental Studies and lbxicology, under the Commission on Life - - Sciences+ The committee membership berehip represented the disciplines of toxicology, biochemistry, atmospheric science, epidemiology, - - 'bioatatistica, and pulmonary physiology. The committee's charge was to review the existing scientific - literature and to identify the current state of knowledge with respect to known facts and areas of uncertainty. Many more - --- - of the latter were found than the former. Ti the extent that ---- - they could be justified scientifically, conclusions have been stated --- and recommendations proposed. Many of the recommendations are for future research, rather than for public policy. The latter were for the most part avoided on two grounds: the data were - - frequently not sufficiently secure and the charge to the committee was primarily for scientific review. The committee conducted a public hearing on scientific stud- ies relevant to its charge on January 29, 1986. Furthermore, it reviewed the published ecientific literature and received testimony from professional societies; medical, industry, consumer, and pub- lic interest groups; academic scientists; and others involved in the generation and interpretation of scientific evidence on the health 96999449 iv

consequences of exposure to cigarette smoking. Pursuance of these activities was followed by the preparation of individual chapters by - committee members and consultants. Thereafter, chapters were discussed, revised, and integrated with each other for the full report. In producing this report, the committee confronted a complex charge under severe time constraints.. That it completed its task well and on time is a credit both to its members and the scientific staff of the National Research Council. I would like to express my personal appreciation to every one of the committee members, all of whom donated their time, intellect, and knowledge to the sub- stance stance of this report. Dr. Diane Wagener of the National Research Council assumed the difficult task of coordinating, translating, and negotiating ideas and insights among committee members, -- - consultants, and reviewers. Drs. Devra Davis and Marvin Schnei- derman worked with Dr. Wagener in ensuring the thoughtful and derman - timely completion of this report. While the committee restricted itself to analysis of the sci- entific data, it was not unmindful of the fact of modern life that smokers and nonsmokers have taken strong positions regarding the right to smoke on the one hand and a rejection of being exposed to other people's smoke on the other. Persons on each side of the issue may wish to infer information from this report that the committee did not intend. Our strategy has been to synthesize in- formation, present judgments and conclusions wherever possible, and to recognize inadequacies in existing data in order to provide - - a focus for future research. We have not taken the stance of a public policy board that necessarily has to make decisions on less- than-adequate information. Rather, we have chosen to prepare a scientifically responsible report that will be intelligible to a lay audience and useful to a scientific one. ' BARBARA S. IiULKA, Chairman - Committee on Passive Smoking I Acknowledgments The preparation of this report by the Committee on Passive Smoking vaould not have been possible without assistance from a large number of people. Thq committee consulted with a number of experts about var- ious topics. We would like to thank the Office on Smoking and ' Health, particularly Clarisse Brown, who provided us with the many statistics and data that were requested by various mem- bers of the committee. We would also like to thank William Cain and Edward LaVoie for their contributions. Other individuals who gave special assistance in the preparation of the report in- clude-Lesl'te Waters Barger, Kiran Nanchahal, Simon Thompson, Christopher Frost, and Don Blevins. The committee thanks all the peer reviewers of the report: Their constructive remarks contributed to the improvement of presentations of technical information and its readability. We would like to express our thanks to the NRC staff for their work in supporting the committee. We would especially like to thank Edna W. Paulson and the staff of the Toxicology Information Center, who were of great assistance. 66~9~~g ~~ vii

Contents flf}69QlZR I EXECUTIVE $UMMARY ........................................ 1 Introduction, I Environmental Tobacco Smoke, 2 Measures of Exposure, 3 In Vive and In Vitro Studies, 7 Health Effeets, 7 1 INTRODUCTION ........................................... .13_ DeHnitions, 14 Trends in Cigarette Usage, 15 Organization, 20 References, 21 Part I I'NYSICOCHEMICAL AND TOXICOLOGICAL STUDIES OF ENVIRONMENTAL TOBACCO SMOKE 2 THE PHYSICOCHEMICAL NATURE OF SIDESTREAM SMOKE AND ENVIRONMENTAL TOBACCO SMO_ KE ........................................ . . 25_ - Introduction, 25 Sidestream Smoke, 28 - - Principal Chemical Constituents of Environmental Tobacco Smoke, 36 Radioactivity of Environmental Tobacco Smoke, 37 - - Toxic and Carcinogenic Agents in Tobacco Smoke, 44 Summary and Recommendations, 45 References, 48

3 IN VIVO AND IN VITRO ASSAYS TO ASSESS THE HEALTH EFFECTS OF ENVIRONMENTAL TOBACCO ACCO SMOKE .................64 Introduction, 54 In Vivo Assays on Environmental Tobacco Smoke, 55 In Vitro Assays on Environmental Tobacco Smoke, 58 Summary and Recommendations, 59 References, 61 Part II ASSESSING EXPOSURES TO - ENVIRONMENTAL TOBACCO SMOKE 4 INTRODUCTION ........................................... 6b ASSESSING EXPOSURES TO ENVIRONMENTAL TOBACCO SMOKE IN THE EXTERNAL ENVIRONMENT ........................................... .69 Tracers for Environmental Tobacco Smoke, 70 Personal Monitoring, 76 Concentrations of Environmental Tobacco Smoke in Indoor Environments, 79 Modeling, 81 Summary and Recommendations, 94 References, 97 6 ASSESSING EXPOSURES TO ENVIRONMENTAL TOBACCO SMOKE USING QUESTIONNAIRES .......101 Exposure Histories Derived from Questionnaires, 102 Environmental Tobacco Smoke Exposure Data for Studies of Acute and Chronic Health Effects, 107 Data Quality, 108 Other Variables, 115 Summary and Recommendations,116 References, 118 EXPOSURE-DOSE RELATIONSHIPS FOR ENVIRONMENTAL TOBACCO SMOIfE ................ 120 Estimating Dose, 120 Particle Size, 121 - Breathing Pattern, 122 Deposition of Cigarette Smoke Particles, 123 Particle Retention in the Lungs, 126 Gases in Environmental Tobacco Smoke, 127 Summary and Recommendations, 129 References, 131 8 ASSESSING EXPOSURES TO ENVIRONMENTAL TOBACCO SMOKE USING BIOLOGICAL MARKERS ..... . .. .. .... ... . . . ............ 1gg Biological Markers in Physiological Fluids, 134 Genotoxicity of the Urine, 148 Future Needs, 152 Summary and Recommendations, 152 References, 154 Part III HEALTH EFFECTS POSSIBLY ASSOCIATED WITH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE BY NONSMOKERS INTRODUCTION ......................................... 163 10 SENSORY REACTIONS TO AND IRRITATION EFFECTS OF ENVIRONMENTAL TOBACCO SMOKE .......................................166 Odor, --- 166 Irritation, 172 Hypersensitive Individuals, 176 Summary and Recommendations, 177 References, 179 xi

11 EFFECTS OF EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE ON LUNG FUNCTION AND RESPIRATORY SYMPTOMS ............................ _ 182 Lung Function and Symptoms in Active Smokers, 182 Plausibility for an Effect Due to Passive Smoking, 194 Methodologic Considerations for Epidemiologic Studies, 185 Cross-sectional Studies, 188 Longitudinal Studies of Lung Function in Children and Adults, 200 The Effect of Passive Smoking on Respiratory Infections, 202 When Do Pulmonary Effects of Passive Smoking Occur?, 209 Studies of Acute Pulmonary Effects, 212 Summary and Recommendations, 216 References, 218 12_ EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER ........................... 223 Using Biological Markers to Estimate Risk, 224 Assessing the Risk From Epidemiologic Studies of Lung Cancer and Exposure to ETS, 227 Corrections to Estimates for Systematic Errors, 231 Other Considerations, 242 Summary and Recommendations, 245 References, 246 13 CANCERS OTHER THAN LUNG CANCER ............ 250 Smoking-Related Cancers, 250 Cancers Not Related to Smoking, 252 Interpretation, 254 Summary and Recornmendations, 255 References, 255 14 CARDIOVASCULAR SYSZ'-EM ........................... _ 25q Acute Cardiovascular Effects of Environmental Tobacco Smoke Exposure, 257 Cardiovascular Disease Morbidity and Mortality, 262 Summary and Recommendations, 265 References, 266 ZO~'i99449 Xli 15 OTHER HEALTH CONSIDERATIONS IN CHILDREN ................................................ 2_ 269 Environmental Tobacco Smoke Exposure by Nonsmoking - Pregnant Women, 269_ Growth in Children, 271 Chronic Ear Infections, 272 - Summary and Recommendations, 273 • References, 274 + APPENDIXES A. Guidelines for Public and Occupational Chemical Exposures to Materials That Are Also Found in Environmental Tobacco Smoke ............................ . 279 B. Method of Combining Data From Studies of Environmental Tobacco Smoke Exposure and Lung Cancer ................................................284 Case-Control Studies, 284 Prospective (or Cohort) Studies, 286 Summing Over Studies, 287 - References, 288 C. Adjustments to Epidemiologic Estimates of Excess Lung Cancer in Persons Exposed to Environmental Tobacco Smoke , ............................ 289 Using Cotinine Measurements to Correct Misreporting, 290 References, 293 D. Risk Assessment-Exposure to Environmental Tobacco Smoke and Lung Cancer ..........................294 James Ro6ins Introduction, 294 D-1 Estimation of the Ttue Relative Risk, 297 D-2 The Carcinogen-Equivalent Number of Actively Smoked Cigarettes Inhaled Daily by Passive Smokers: Comparisons of Epidemiologic with Dosimetric Estimates, 301 D-3 Estimating the Number of Lung Cancer Deaths in Nonsmokers in 1985 Attributable to ETS, 304 D-4 Lifetime Risk of Death From Lung Cancer Attributable to ETS, 306 Discussion, 311 Technical Discussions, 313 References, 336

, Executive Summary , INTRODUCTION A Committee of the National Research Council's (NRC's) Board on Environmental Studies and Toxicology prepared this re- port in response to requests from two federal government agencies, the Office of Air and Radiation of the Environmental Protection Agency (EPA) and the Office of Smoking and Health of the De- partment -- - partment of Health and Human Services. The report evaluates methodologies in epidemiologic and related studies for obtaining measurements of exposure to environmental tobacco smoke (ETS) by nonsmokers and also outlines the possible health effects of such exposures as reported in the published literature. This committee was asked to review original research data and identify research needs but was not charg,ed with preparing policy statements or rec- ommendations for public health actions. In particular, the NRC . was asked to: e review the chemical and physical characterizations of the - -- - constituents of ETS; - --- * include a toxicological profile of sidestream and environ- mental tobacco smoke; - -- --- * review the epidemiologic and related literature on the health effects of exposure to ETS; 'and * recommend future exposure monitoring, modeling, and -- epidemiologic research. To address these and related issues, the NRC fnrmed the - Committee on Passive Smoking in the Board on Environmental Studies and Toxicology of the Commission on Life Sciences. The ~0698~~8 ! . i

i committee consists of professionals in a variety of fields, includ- ing epidemiology, toxicology, biochemistry, atmospheric science, biostatistics, and pulmonary physiology. The subject of the committee's report is the use of epidemiol- ogy and related disciplines for the study of possible health effects of exposure to ETS by nonsmokers. Smokers are also exposed to ETS, but the health effects of this exposure, which are likely to be less intense than those of active smoking, are not the subject of - this report. The primary goal of the studies reviewed in this report is to determine whether there is a relationship between health out- comes in hum- an populations and ETS-exposure of nonsmokers. It is a formidable task to assess exposure to the complex mixture of ETS with enough precision to permit use in analytic studies, including quantitative risk estimation. For some health outcomes the relevant durAtion of exposure may be minutes, for others it may be decades. Numerous factors, in addition to exposure to smoke, can influence the risk of illness. These other factors must be taken into account if the magnitude of the effects of exposure - - to ETS is to be evaluated. ENVIRONMENTAL TOBACCO SMOKE More than 3,800 compounds have been identified in cigarette smoke. The major source, by far, for ETS is sidestream smoke - (SS) which is emitted from the burning end of a cigarette in be- tween - _ -- tween puffs. The remainder of ETS consists of exhaled mainstream smoke (MS), smoke which escapes from the burning end during puff-drawing, and gases which diffuse during smoking through the cigarette paper. Each of the mixtures, MS, SS, and ETS, is an aerosol consisting of a particulate phase and a vapor phase. How- ever, the smokes of MS, SS, and ETS differ, as the result of changes in the concentrations of individual constituents, the phase (partic- ulate or vapor) in which the constituents are present, and various secondary reactions that chemically and physically alter ("age") the composition of the smoke. Undiluted SS contains higher con- centrations of some toxic compounds than undiluted MS, including ammonia, volatile aminea, volatile nitrosamines, nicotine decom- position products, and aromatic amines. However, concentrations of these SS emissions are considerably diluted in the indoor space where ETS exposures take place. 'The hydrophobic vapor phase V0G991,49 constituents of ETS are likely to enter the lung of the exposed indi- vidual, while the hydrophilic vapor phase constituents are likely to be absorbed in the upper respiratory tract. Particles <2.5 Nm (in this report referred to as respirable suspended particulates [RSP)) dominate the particulate phaee of ETS and can be inhaled deeply into the lung. Standard laboratory procedures have been established to as- sess the physicochemical properties of SS and MS. Research is needed to standardize both the collection and evaluation of ETS so that the effects of ETS can be studied in laboratories and in human populations. The changes in distribution of particular constituents of ETS as the smoke ages in the indoor environment are largely unknown. For example, it is known that almost all of the nicotine shifts from the particulate phase in MS and fresh SS to the vapor phase in ETS. Consequently, indoor air-cleaning systems designed to remove particles will not greatly alter the nicotine exposure, but may alter the concentrations of other noxious or toxic components. Research is needed to determine the distribution of constituents in the particulate and vapor phases of aged ETS. Also, the efficiency of air-cleaning systefns in removing the constituents needs to be studied. Indoor radon comes from sources in the environment and decays to short-lived radon daughters, which may become bound to the RSP in ETS. However, some long-lived radon daughters come from tobacco itself. Research should be conducted on possible interactions between ETS and radon daughters, especially as radon n daughters can adhere to RSP and increase the potential hazard of ETS. MEASURES OF EXPOSURE There are currently no direct measures of the dose absorbed of ETS in a population under study. Exposures to ETS, however, can be assessed by questionnaires, air monitoring, modeling of concen- trations, or biological markers. Future epidernioloyic studies should incorporate into their design several of these exposure assessment metAods in order to assess exposures to ETS more accurately and to estimate dose.

Questionnaires The simplest measure of E"fS exposure is contained in the reply to the questions: "Are you a cigarette smoker?" and "lf you are a nonsmoker, do you live with, or work with, or have regular contact with persons who are smokers?" There are great , difficulties in developing uniform questions that elicit unambigu2 ous replies and, more particularly, in using these replies to make`` firm quantitative estimates of exposure. They can be used, how- ever, as a-b- asis for classifying individusls into broad categories of exposure, recognizing the problems such as incorrectly estimating exposure through errors in reporting of current smoking habits, neglecting exposure to ETS in other environments like workplaces or public places, and reporting an exsmoker as a nonsmoker. Re- po#ts of whether or not the subject has smoked can be obtained with reasonable reliability from surrogate respondents. However, quantification of integrated exposure over many years is not likely to be fully reliable or precise. At best, such quantification pro- vides an approximation of exposure, whether the information is obtained from the individual himself or from a surrogate. To esti- mate integrated exposure to ETS, future studies need to estimate a long-term ETS exposure history, including what fraction of the day is spent in the presence of ETS and at what ages these exposures occurred. The data from such a history should be entered into a specific time-place model, from which cumulative exposure can be estimated. Monitoring The use of air monitoring (personal or indoor space) is hand- icapped by the lack of a clear definition of the physicochemical nature of ETS and the identification of the individual, or target, constituents of ETS associated with the health or comfort effects under study. Proxy, or surrogate, constituents have been mea- sured in a number of studies as indicators of ETS exposure in both personal and indoor space monitoring. RSP, carbon monox- ide, nicotine, nitrogen oxides, acrolein, nitroso-compounds, and benzo(alpyrene are some of the compounds or classes of air con- taminants that have been measured under field conditions as in- dicators of ETS exposure. While some of the ETS constituents, particularly nicotine and RSP, have proved to be useful surrogates S©G98US 5 for ETS, no single measure has completely met all the criteria for an ideal ETS surrogate. To facilitate the study of the health effects of ETS exposure, an ideal marker or tracer of exposure to ETS should be unique (or nearly unique) to tobacco smoke, should be a constituent of tobacco smoke, that is present in su -fficient quantity so it can be measured even at low ETS levels, and should stand in a fairly constant ratio across brands of cigarettes to other tobacco smoke constituents (or contaminants) of interest. Reliable infor- mation needs to be obtained on the quantity, transport, and fate of such chemicals in ordinary indoor environments. A majority of field studies have used RSP as an indicator of exposure to ETS because of the substantial emission of RSP in indoor spaces from tobacco combustion. ETS is the dominant con- tributor to the indoor levels of RSP. The total RSP, as measured by personal monitors, has been found to be substantially elevated for individuals who reported being exposed to M as compared with those who reported no such exposure. Both air monitoring and modeling clearly indicate that RSP concentrations will be elevated over background levels in indoor spaces when even low smoking rates occur. The importance of variation in_ the_ input parameters- such as room size, temperature, humidity, air exchange rate, and numbers of cigarettes smohed--ahould be noted when interpreting the data on the constituents of ETS obtained from personal moni- tors and indoor space monitora. Biological Markers In theory, dose of ETS to the tissues or organs could be mea- sured directly through the use of biological markers that accurately indicate uptake in the tissues or organs. Optimal assessment of ex- posure to ETS should derive from measures made on physiological fluids of exposed persons. Several chemicals found in such fluids may be able to serve as biological markers of recent exposures. The criteria for acceptable biological markers are similar to those for measuring ETS in the external environment. The biological markers that have been most ost useful for as-g sessing recent exposures to ETS are nicotine and its metabolite, - -- - -- -- - cotinine. Nicotine and cotinine derive virtually exclusively from - -- - tobacco products, of which tobacco smoke ke is the most important ---- -- - direct source. They can be identified and quantified in saliva, -- -- - --- - - blood, or urine. Generally, the mean concentrations of nicotine