THE HEALTH . 1 I CONSEQUENCES OF INVOLUNTARY SMOKING a report of the Surgeon General U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES P&k Health Smvke `.rtStCstlAs"Or*t.LI*.ND*"UI1ot.",(t~ ".s*l*GI"* DL mie, MC I 5 1986 The mnorable George Bush President of the Senetc W..hington. D.C. 20510 Desr Mr. President: It is my pleasure to transmit to the Congress the 1986 Surgeon Gener.1'. Report on the halt? consequence. of smking, . . mandated by Section g(s) of the Public Re.lth Cxgsrette S-king Act of 1969. me "e.lth Consequence* of involunt.ry Smking The current volume, entitled , exuine. the scientific evidence on the he.lth effect. re."lttng from mn.mker exposure to envirollaenr.1 tob.cc" snake. The issue of whether or mt tob.cco slake is c.rcinogeaic for humans was conclusively resolved mre thss 20 ye.=. *go when the first report on *staking *ad heslth w.. issued in 1964. Eased on the c"rrent report, the judgment c.n 11)y be tude that exposure to envim-nt.1 tob.cco s-kc csn E.".c disesse, including lung cancer, in mnstmkers. It is *la clear th.t simple .ep.r.cioa of smkers snd mns~ker. within the ..Y sirspsce uy reduce but canmt elimin.te mnsmker exposure to envirorucnt.1 tobacco slake. Ihe report .lw review. *II extensive body of evidence which e.t.bli.he. .O incressed risk of reapir.tory illness snd reduced lung function in infsnt. .nd very y~"ng children of p.rent. rbD .oke. Ihi. effect is ~)re pmmuaced if both pxent. sake than if only one p.rent sakes. A. . phy.ici.n. I believe th.t p.reot. should refr.in from -king *round s-11 children both s. . r.n. of protecting their children'. heslth and to set . pd o rqle for the child. Today, only 30 percent of the adult populstion in the United gt.te. .re *mker.-the 1are.C level of soking in the country since World Ysr II, reflecting th.t the grest msjority of the populstion h.. never mked or hr. *"cce**f"lly quit. Accompsnying this decline in over.11 prevslence of cigsrette smking h.. been sn Lcrersed cancera for protecting the he.lth .nd well being of mnsmxker., s. evidenced by the number of lr. and reyl.tion. restricting soking in public plsces. Todsy, 40 gtste. snd the District of Dlubi. hsve enacted some fotn of legislstion to restrict swking in public. Increasingly, these lr. pertsin to protecting mnswkcrs in uny different setting., including the varkplsce. B..ed on the evidence presented in this report. the choice to slake .hD"ld n"t interfere with the mn.aDker'. choice for sn environment free of tob.cco .aDke. Sincerely, . &gwhNtQ m% Otis B. gown, M.D. secretary enc1o.ure DEL 5 The ibnorable Thomas P. O'Neill, or. Speaker of the H3u.e of Representatives Washington, D.C. 20515 Oear Hr. Speaker: It is my pleasure co rransmit to the Congress the 1986 Surgeon General's Report an the health consequences of sroking, . . mandated by Section B(a) of the Public Health Cigarette Smklng Act of 1969. The current volume. entitled The Health Consequences of Involuntary Swking, examines the ocieotific evidence on the health effects resulting from nonsmoker exposure to environmental tobacco smoke. The issue of whether or mt tobscco awke is csrcimgenic for humans ~88 conclusively resolved m)re thsn 20 yesrs .go when the first report on smking and heslth YBB issued in 1964. Based on the current report. the judgment c.n now be made chat exposure to environmental tobscco sswke csn cause disease. including lung cancer, in mnsmkers. It is also c1e.r that simple separation of smkers and nonsrmkers within the s.me airap.ce msy reduce but csnnot eliminate mnsmDker exposure to environment.1 tobscco amke. The report also reviews sn extensive body of evidence which establishes .n incressed risk of respiratory illness and reduced lung function in infants .nd very young children of psrenta who smoke. This effect ia mire pmmunced if both p.rents anote th.n if only one parent amkes. As . physician, I believe that parents should refrsin from smoking emend sm.11 children both as . means of protecting their children's heslth and to set . pod ersmple for the child. Today, only 30 percent of the adult popul.tion in the United St.Ces are srtokers-the lovest level of waking in the country since YDrld Usr II, reflecting thst the great mjority of the populscion h.. never smked or has successfully quit. Accompanying this decline in overall prevalence of cigarette swking h.s been an incre.sed concern for protecting the health snd well being of nonsmokers, as evidenced by the number of lens snd regulstians restricting smking in public places. Today, 40 St.tea .nd the District of Columbia have enacted some form of legislation to restrict smoking in public. Increasingly, these 1~s pertain to protecting nonawkers in m.ny different setting., including the workplace. Based on the evidence presented in this report, the choice to srmke should mt interfere with the mnslmker's choice for an environment free of tobacco woke. Sincerely, W fl,a. Otis R. Bowen, M.D. secretary FOREWORD The data reviewed in 17 previous U.S. Public Health Service reports on the health consequences of smoking have conclusively established cigarette smoking as the largest single preventable cause of premature death and disability in the United States. The question whether tobacco smoke is harmful to smokers was answered more than 20 years ago. As a result, many scientists began to question whether the low levels of exposure to environmental tobacco smoke (ETS) received by nonsmokers could also be harmful. The current Report, The Health Consequences of Involuntary Smoking, examines the evidence that even the lower exposure to smoke received by the nonsmoker carries with it a health risk. Use of the term "involuntary smoking" denotes that for many nonsmokers, exposure to ETS is the result of an unavoidable consequence of being in proximity to smokers. It is the first Report in the health consequences of smoking series to establish a health risk due to tobacco smoke exposure for individuals other than the smoker, and represents the work of more than 60 distinguished physicians and scientists, both in this country and abroad. After careful examin ation of the available evidence, the following overall conclusions can be reached: 1. Involuntary smoking is a cause of disease, including lung cancer, in healthy nonsmokers. 2. The children of parents who smoke, compared with the children of nonsmoking parents, have an increased frequency of respiratory infections, increased respiratory symptoms, and slightly smaller rates of increase in lung function as the lung matures. 3. Simple separation of smokers and nonsmokers within the same air space may reduce, but does not eliminate, exposure of nonsmokers to environmental tobacco smoke. Exposure to environmental tobacco smoke occurs at home, at the worksite, in public, and in other places where smoking is permitted. vii The quality of the indoor environment must be a concern of all who control and occupy that environment. Protection of individuals from exposure to environmental tobacco smoke is therefore a responsibili- ty shared by all: As parents and adults we must protect the health of our children by not exposing them to environmental tobacco smoke. As employers and employees we must ensure that the act of smoking does not expose the nonsmoker to tobacco smoke. For smokers, it is their responsibility to assure that their behavior does not jeopardize the health of others. For nonsmokers, it is their responsibility to provide a supportr ive environment for smokers who are attempting to stop. Actions taken by individuals, employers, and employee organixa- tions reflect the growing concern for protecting nonsmokers. The number of laws and regulations enacted at the national, State, and local level governing smoking in public has increased substantially over the past 10 years, and surveys conducted by numerous organizations show strong public support for these actions among both smokers and nonsmokers. As a Nation, we have made substantial progress in addressing the enormous toll inflicted by active smoking. Efforts to improve and protect individual health must be not only continued but strength- ened. On the basis of the evidence presented in this Report, it is clear that actions to protect nonsmokers from ETS exposure not only are warranted but are essential to protect public health. Robert E. Windom, M.D. Assistant Secretary for Health . . . vlll PREFACE This, the 1986 Report of the Surgeon General, is the U.S. Public Health Service's 18th in the health consequences of smoking series and the 5th issued during my tenure as Surgeon General. Previous Reports have documented the tremendous health burden to society from smoking, particularly cigarette smoking. The evi- dence establishing cigarette smoking as the single largest preventa- ble cause of premature death and disability in the United States is overwhelming-totaling more than 50,000 studies from dozens of cultures. Smoking is now known to be causally related to a variety of cancers in addition to lung cancer; it is a cause of cardiovascular disease, particularly coronary heart disease, and is the major cause of chronic obstructive lung disease. It is estimated that smoking is responsible for well over 800,000 deaths annually in the United States, representing approximately 15 percent of all mortality. Thirty years ago, however, the scientific evidence linking smoking with early death and disability was more limited. By 1964, the year the Advisory Committee to the Surgeon General issued the first report on smoking and health, a substantial body of evidence had accumulated upon which a judgment could be made that smoking was a cause of disease in active smokers. Subsequent reports over the last 20 years have expanded our understanding and knowledge about smoking behavior, the toxicity and carcinogenicity of tobacco smoke, and the specific disease risks resulting from exposure to this agent. This Report is the first issued since 1964 that identifies a chronic disease risk resulting from exposure to tobacco smoke for individuals other than smokers. It is now clear that disease risk due to the inhalation of tobacco smoke is not limited to the individual who is smoking, but can extend to those who inhale tobacco smoke emitted into the air. This Report represents a detailed review of the health effects resulting from nonsmoker exposure to environmental tobacco smoke (ETS). ETS is the combination of smoke emitted from a burning tobacco product between puffs (sidestream smoke) and the smoke exhaled by the smoker. The 1986 Report, The Health Consequences of Involuntary Smoking, is a critical review of all the available scientific evidence pertaining to the health effects of ETS exposure on nonsmokers. The term "involuntary smoking" is used to ix note that such exposures often occur as an unavoidable consequence of being in close proximity to smokers. Lung Cancer and Environmental Tobacco Smoke The appropriate framework for an examination of the lung cancer risk from involuntary smoking is that of a lowdose exposure to a known human carcinogen. Over 30 years of research have conclu- sively established cigarette smoke as a carcinogen. This Report presents evidence that the chemical composition of side&earn smoke is qualitatively similar to the mainstream smoke inhaled by the active smoker, and that both mainstream and sidestream smoke act as carcinogens in bioassay systems. Data related to environmen- tal levels of tobacco smoke constituents and from measures of nicotine absorption in nonsmokers suggest that nonsmokers are exposed to levels of environmental tobacco smoke that would be expected to generate a lung cancer risk, epidemiological studies of populations exposed to ETS have documented an increased risk for lung cancer in those nonsmokers with increased exposure. It is rare to have such detailed exposure data or human epidemic logic studies on disease occurrence when attempting to evaluate the risk of low-dose exposure to an agent with established toxicity at higher levels of exposure. The relative abundance of data reviewed in this Report, their cohesiveness, and their biologic plausibility allow a judgment that involuntary smoking can cause lung cancer in nonsmokers. Although the number of lung cancers due to involun- tary smoking is smaller than that due to active smoking, it still represents a number sufficiently large to generate substantial public health concern. It is certain that a substantial proportion of the lung cancers that occur in nonsmokers are due to EXS exposure; however, more complete data on the dose and variability of smoke exposure in the nonsmoking U.S. population will be needed before a quantitative estimate of the number of such cancers can be made. Children and Infants This Report also documents a relationship between parental smoking and the respiratory health of infants and children (under 2 years of age). Infants of parents who smoke have an increased risk of hospitalization for bronchitis and pneumonia when compared with infants of nonsmoking parents. There is a relationship between parental smoking and an increased frequency of respiratory symp tams in children. A slower rate of growth in lung function has been observed in children of smoking parents. In many studies, if both X parents smoke, a stronger relationship exists than if only one parent smokes. What future respiratory burden these findings may represent for these children later in life is not known. As a former pediatric surgeon, I strongly urge parents to refrain from smoking in the presence of children as a means of protecting not only their children's current health status but also their own. Diseases Other Than Lung Cancer Several studies have provided data on the relationship between ETS and cancers other than lung cancer and on ETS exposure and cardiovascular disease. However, further research in these areas will be required to determine whether an association exists between ETS exposure and an increased risk of developing these diseases. Policies Restricting Smoking in Public Places The growth in our understanding of the disease risk associated with involuntary smoking has been accompanied by a change in the social acceptability of smoking and by a growing body of legislation, regulation, and voluntary action that addresses where smoking may occur in public. Forty States and the District of Columbia now have some form of legislation controlling or restricting smoking in various public settings. Some States limit smoking to only a few designated areas; however, States are increasingly developing and implement- ing comprehensive legislation that restricts smoking in many public settings, including the workplace. Nine States have restrictions that cover smoking not only by public employees but also by employees in the private sector. No systematic evaluation of the effects these measures may have on smoking behavior has been conducted, but there is little doubt that strong public sentiment exists for implementing such restric- tions. A number of national surveys conducted by voluntary health organizations, government agencies, and even the tobacco industry have documented that an overwhelming majority of both smokers and nonsmokers support restricting smoking in public. Public Health Policy and Involuntary Smoking The 1986 Surgeon General's Report on the Health Consequences of Involuntary Smoking clearly documents that nonsmokers are placed at increased risk for developing disease as the result of exposure to environmental tobacco smoke. Critics often express that more research is required, that certain studies are flawed, or that we should delay action until more conclusive proof is produced, As both a physician and a public health xi official, it is my judgment that the time for delay is past; measures to protect the public health are required now. The scientific case against involuntary smoking as a health risk is more than sufficient to justify appropriate remedial action, and the goal of any remedial action must be to protect the nonsmoker from environmental tobacco smoke. The data contained in this Report on the rapid diffusion of tobacco smoke throughout an enclosed environment suggest that separation of smokers and nonsmokers in the same room or in different rooms that share the same ventilation system may reduce KTS exposure but will not eliminate exposure. The responsibility to protect the safety of the indoor environment is shared by all who occupy or control that environment. Changes in smoking policies regarding the workplace and other environments necessitated by the data presented in this Report should not be designed to punish the smoker. Successful implementa- tion of protection for the nonsmoker requires the support and cooperation of smokers, nonsmokers, management, and employees and should be developed through a cooperative effort of all groups affected. In addition, changes are often more effective when support and assistance is provided for the smoker who wants to quit. Cigarette smoking is an addictive behavior, and the individual smoker must decide whether or not to continue that behavior; however, it is evident from the data presented in this volume that the choice to smoke cannot interfere with the nonsmokers' right to breathe air free of tobacco smoke. The right of smokers to smoke ends where their behavior affects the health and wellbeing of others; furthermore, it is the smokers' responsibility to ensure that they do not expose nonsmokers to the potential harmful effects of tobacco smoke. C. Everett Koop, M.D. Surgeon General xii ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Gffice on Smoking and Health, Donald R. Shopland, Acting Director. Manag- ing Editor was William R. Lynn, Acting Technical Information Officer, office on Smoking and Health. Senior scientific editor was David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Medical Center, San Diego, San Diego, California. Consulting scientific editors were Ellen R. Grits, Ph.D., Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, John H. Holbrook, M.D., Associate Professor of Internal Medicine, Department of Internal Medicine, University Hospital, Salt Lake City, Utah, and Jonathan M. Same& M.D., Professor of Medicine, Department of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico. The following individuals prepared draft chapters or portions of the Report. Neal Benowitz, M.D., San Francisco General Medical Center, San Francisco, California A. Sonia Buist, M.D., Professor of Medicine, Department of Physiolo gy, Gregon Health Sciences University, Portland, Oregon Charles Hiller, M.D., Pulmonary Division, University Hospital, Little Rock, Arkansas Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York Ilse Hoffmann, Research Coordinator, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York John R. Hoidal, M.D., Director of Pulmonary Medicine, University of Tennessee Center for Health Sciences, Memphis, Tennessee John McCarthy, M.P.H., Harvard School of Public Health, Boston, Massachusetts . . . xlll Nancy A. Rigotti, M.D., Institute for the Study of Smoking Behavior and Policy, John F. Kennedy School of Government, Harvard University, Cambridge, Massachusetts Jonathan M. &met, M.D., Professor of Medicine, Department of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico John Spengler, Ph.D., Harvard School of Public Health, Boston, Massachusetts Annetta Weber, Ph.D., Federal Institute of Technology, Zurich, Switzerland Scott T. Weiss, M.D., M.S., Associate Professor of Medicine, Chan- ning Laboratories, Harvard Medical School, Boston, Massachu- setts Anna H. Wu, Ph.D., Department of Preventive Medicine, School of Medicine, University of Southern California, Los Angeles, Califor- nia The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Elvin E. Adams, M.D., M.P.H., Director, Health and Temperance Department, General Conference of Seventh-Day Adventists, Washington, D.C. Stephen M. Ayres, M.D., Dean, School of Medicine, Medical College of Virginia, Richmond, Virginia David V. Bates, M.D., Professor of Medicine and Physiology, Department of Medicine, Acute Care Hospital, University of British Columbia, Vancouver; British Columbia William J. Blot, Ph.D., Chief, Biostatistics Branch, Epidemiology and Biostatistics Program, Division of Etiology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Benjamin Burrows, M.D., Professor of Internal Medicine, and Director, Division of Respiratory Sciences,. The University of Arizona College of Medicine, Tucson, Arizona D. M. DeMarini, Ph.D., Genetic Toxicology Division, U.S. Environ- mental Protection Agency, Research Triangle Park, North Caro- lina Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Louis Diamond, Ph.D., College of Pharmacy, University of Kentucky, Lexington, Kentucky Richard Doll, Cancer Epidemiology and Clinical Trials Unit, Imperi- al Cancer Research Fund, The Radcliffe Infirmary, University of Oxford, Oxford, England, United Kingdom XiV Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Office of the Assistant Secretary for Health, Hyattsville, Maryland Edwin B. Fisher, Jr., Ph.D., Associate Professor, Department of Psychology, Washington University, St. Louis, Missouri William H. Foege, M.D., Executive Director, Task Force for Child Survival, Carter Presidential Center, Atlanta, Georgia Joseph F. Fraumeni, Jr., M.D., Associate Director for Epidemiology and Biostatistics, Division of Cancer Etiology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Lawrence Garfinkel, M.A., Vice President for Epidemiology and Statistics, and Director of Cancer Prevention, American Cancer Society, New York, New York R.A. Griesemer, D.V.M., Ph.D., Director, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Michael R. Guerin, Ph.D., Organic Chemistry Section, Analytical Chemistry, Oak Ridge National Laboratory, Oak Ridge, Tennessee Jeffery E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Millicent Higgins, M.D., Associate Director, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Takeshi Hirayama, M.D., Director, Institute of Preventive Oncology, Shinjuku-ku, Tokyo, Japan Dwight Janerich, D.D.S., M.P.H., Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut Martin Jarvis, M.P.H., Senior Clinical Psychologist, Addiction Research Unit, Institute of Psychiatry, London, England, United Kingdom Brian P. Leaderer, Ph.D., M.P.H., Associate Fellow, John B. Pierce Foundation Laboratory, Associate Professor, Department of Epide- miology and Public Health, Yale University School of Medicine, New Haven, Connecticut Charles L. LeMaistre, M.D., President, University of Texas Systems Cancer Center, Houston, Texas Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Donald Ian Macdonald, M.D., Administrator, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, Maryland James S. Marks, M.D., M.P.H., Assistant Director for Science, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia James 0. Mason, M.D., Dr.P.H., Director, Centers for Disease Control, Atlanta, Georgia xv J. Michael McGinnis, M.D., Deputy Assistant Secretary for Health (Disease Prevention and Health Promotion), Office of the Assistant Secretary for Health, Washington, D.C. A. J. McMichael, M.D., M.B.B.S., Ph.D., Chairman and Senior Principal Research Scientist, CSIRO Division of Human Nutrition, Adelaide, South Australia D. J. Moschandreas, Ph.D., Research Director, ITT Research Insti- tute, Chicago, Illinois David Muir, M.D., Director, Occupational Health Program, Health Sciences Center, McMaster University, Hamilton, Ontario, Cana- da C. Tracy Orleans, Ph.D., Research Associate, Health Services RX+ search Center, University of North Carolina, Chapel Hill, North Carolina Richard Pete, M.A., MSc., I.C.R.F., Regius Assessor of Medicine, The Radcliffe Infirmary, University of Oxford, Oxford, England, Unit- ed Kingdom Otto Raabe, M.D., Laboratory for Energy Related Health Research, University of California, Davis, Davis, California James L. Repace, Chief of Technical Services, Indoor Air Quality Program, U.S. Environmental Protection Agency, Washington, D.C. M.A.H. Russell, F.R.C.P., Addiction Research Unit, Institute of Psychiatry, University of London, London, England, United King- dom Roy J. Shephard, M.D., Ph.D., Director, School of Physical and Health Education, University of Toronto, Toronto, Canada Frank E. Speixer, M.D., Charming Laboratories, Harvard Medical School, Boston, Massachusetts Jesse L. Steinfeld, M.D., President, Medical College of Georgia, Augusta, Georgia David N. Sundwall, M.D., Administrator, Health Resources and Services Administration, Rockville, Maryland Gregory W. Traynor, Staff Scientist, Lawrence Berkeley Laboratory, Berkeley, California Dimitrios Trichopoulos, Director, Department of Hygiene and Epide- miology, School of Medicine, University of Athens, Athens, Greece Kenneth E. Warner, Ph.D., Professor, and Chairman, Department of Public Health Policy and Administration, School of Public Health, The University of Michigan, Ann Arbor, Michigan Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland Frank E. Young, M.D., Commissioner, Food and Drug Administra- tion, Rockville, Maryland xvi The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Erica W. Adams, Chief Copy Editor and Assistant Production Manager, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Maryland Richard H. Amacher, Director, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Maryland Margaret L. Anglin, Secretary, Gffice on Smoking and Health, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Charles A. Brown, Programmer, Automation and Technical Services Department, Sterling Software, Inc., Rockville, Maryland Clarice D. Brown, Statistician, Office on Smoking and Health, Rockville, Maryland Richard C. Brubaker, Information Specialist, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Mary- land Catherine E. Burckhardt, Secretary, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Maryland Stephanie D. DeVoe, Programmer, Automation and Technical Services Department, Sterling Software, Inc., Rockville, Maryland Danny A. Goodman, Information Specialist, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Mary land Patricia E. Healy, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Terri L. Henry, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Timothy K. Hensley, Technical Publications Writer, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Mary land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Maureen Illar, Editorial Assistant, Office on Smoking and Health, Rockville, Maryland Julie Kurt, Graphic Artist, Information Center Management De- partment, Sterling Software, Inc., Rockville, Maryland Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland xvii Jerome A. Paulson, M.D., Medical Officer, Office on Smoking and Health, Rockville, Maryland Russell D. Peek, Library Acquisitions Specialist, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Mary- land Margaret E. Pickerel, Public Information and Publications Special- ist, Office on Smoking and Health, Rockville, Maryland Raymond K. Poole, Production Coordinator, Health and Natural Resources Department, Sterling Software, Inc., Rockville, Mary- land Linda R. Spiegelman, Administrative Officer, office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Automation and Techni- cal Services Department, Sterling Software, Inc., Rockville, Mary- land Debra C. Tate, Publications Systems Specialist, Publishing Systems Division, Sterling Software, Inc., Riverdale, Maryland Jerry W. Vaughn, Programmer, University of California, San Diego, San Diego, California Mary I. Walz, Computer Systems Analyst, Office on Smoking and Health, Rockville, Maryland Louise G. Wiseman, Technical Information Specialist, Gffice on Smoking and Health, Rockville, Maryland Pamela Zuniga, Secretary, University of California, San Diego, San Diego, California . . . XVlll TABLE OF CONTENTS Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Acknowledgments . . . . . . . . . . . . . . . . . . ..*................................ Xl11 1. Introduction, Overview, and Summary and Conclusions . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Health Effects of Environmental Tobacco Smoke Ex- posure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3. Environmental Tobacco Smoke Chemistry and Expo sures of Nonsmokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 4. Deposition and Absorption of Tobacco Smoke Constit- uents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 5. Toxicity, Acute Irritant Effects, and Carcinogenicity of Environmental Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . .225 6. Policies Restricting Smoking in Public Places and the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 xix CHAPTER 1 INTRODUCTION, OVERVIEW, AND SUMMARY AND CONCLUSIONS CONTENTS Introduction Development and Organization of the 1986 Report Overview Environmental Tobacco Smoke Constitutents Extent of Exposure Lung Cancer Respiratory Disease Cardiovascular Disease Irritation Determinants of Exposure Policies Restricting Smoking Summary and Conclusions of the 1986 Report Health Effects of Environmental Tobacco Smoke Exposure Environmental Tobacco Smoke Chemistry and Exposures of Nonsmokers Deposition and Absorption of Tobacco Smoke Constit- uents Toxicity, Acute Irritant Effects, and Carcinogenicity of Environmental Tobacco Smoke Policies Restricting Smoking in Public Places and the Workplace htroductlon Development and Organization of the 1886 Report The 1966 Report was developed by the Off&e on Smoking and Health of the U.S. Department of Health and Human Services as part of the Department's responsibility, under Public Law 91-222, to report new and current information on smoking and health to the unitedstatescongress. The scientific content of this Report reflects the contributions of more than 66 scientists representing a variety of disciplines. Individual manuscripts were written by experts known for their understanding of and work in specific content areas. These manu- scripts were refined through a series of meetings attended by the authors, Office on Smoking Health staff and consultants, and the Surgeon General. Upon receipt of the final manuscripts from the authors, the O&e and its consultants edited and consolidated the individual manu- scripts into appropriate chapters. These- draft chapters were subjeo ted to an extensive outside peer review (see Acknowledgments for individuals and their affiliations) whereby each was reviewed by up to seven experts. Their comments were integrated and the entire volume was assembled. This revised edition of the Report was resubjected to review by 17 distinguished scientists outside the Federal Government, both in this country and abroad. Parallel to this review, the entire Report was also submitted to various institutes and agencies within the U.S. Public Health Service for review and comment. The 1966 Report contains a Foreword by the Assistant Secretary for Health, a Preface by the Surgeon General of the U.S. Public Health Service, and the following chapters: Chapter 1. Introduction, Overview, and Summary and Conclu- SiOM Chapter 2. Health Effects of Environmental Tobacco Smoke Exposure Chapter 3. Environmental Tobacco Smoke Chemistry and Expo sures of Nonsmokers Chapter 4. Deposition and Absorption of Tobacco Smoke Con&it+ uenta Chapter 5. Toxicity, Acute Irritant Effects, and Carcinogenicity of Environmental Tobacco Smoke Chapter 6. Policies Restricting Smoking in Public Places and the Workplace Overview Inhalation of tobacco smoke during active cigarette smoking remains the largest single preventable cause of death and disability 5 for the US. population. The health consequences of cigarette smoking and of the use of other tobacco products have been extensively documented in the 17 previous Reports in the health consequences of smoking series issued by the U.S. Public Health Service. cSgare* smoking is a major cause of cancer; it is most strongly associated with cancers of the lung and respiratory tract, but also causes cancers at other sites, including the pancreas and urinary bladder. It is the single greatest cause of chronic obstructive lung dka~3. It c8uf4f33 cardiovascular diseases, including coronary heart disease, aortic aneurysm, and atherosclerotic peripheral vascular disease. ~atermd cigarette smoking endangers fetal and neonatal health, it contributes to perinatal mortality, low birth weight, and complications during pregnancy. More than 3CQofl premature deaths occur in the United States each year that are directly attributable to tobacco use, particularly cigarette smoking. `Ihis Eteport examines in detail the scientific evidence on involun- tary smoking as a potential cause of disease in nonsmokers. Nonsmokers' exposure to environmental tobacco smoke is termed involuntary smoking in this Fteport because the expcsure generally occurs as an unavoidable consequence of being in proximity to smokers, particularly in enclosed indoor environments. The term "passive smoking" is also used throughout the scientific literature to describe this exposure. The magnitude of the disease risks for active smokers secondary to their "high dose" exposure to tobacco smoke suggests that the "lower dose" exposure to tobacco smoke received by involuntary smokers may also have risks. Although the risks of involuntary smoking are smaller than the risks of active smoking, the number of individuals injured by involuntary smoking is large both in absolute terms and in comparison with the number injured by some other agents in the general environment that are regulated to curtail their potential to cause human illness. This Report reviews the evidence on the characteristics of main- stream tobacco smoke and of environmental tobacco smoke, on the levels of exposure to environmental tobacco smoke that occur, and on the health effects of involuntary exposure to tobacco smoke. me composition of the tobacco smoke inhaled by active smokers and by involuntary smokers is examin ed for similarities and differences, and the concentrations of tobacco smoke components that can b immured in a variety of settings are explored, as is smoke deposition and absorption in the respiratory tract. The studies that &crib the risks of environmental tobacco smoke exposure for humans are carefully reviewed for their fmdings and their validity. `I'he evidence on the health effects of involuntary smoking is reviewed for biologic plausibility, and compared with extrapolations of the risks of active 6 smoking to the lower dose of exposure to tobacco smoke found in nonsmokers. This review leads to three major conclusions: 1. Involuntary smoking is a cause of disease, including lung cancer, in healthy nonsmokers. 2. The children of parents who smoke compared with the children of nonsmoking parents have an increased frequency of respiratoryinfections, increased respira- tory symptoms, and slightly smaller rates of increase in lung function as the lung matures. 3. The simple separation of smokers and nonsmokers within the same air space may reduce, but does not eliminate, the exposure of nonsmokers to environmen- tal tobacco smoke. The subsequent chapters of this volume describe in detail the evidence that supports these conclusions; the evidence is briefly summarized here. Environmental Tobacco Smoke Constituents Important considerations in e xamining the risks of involuntary smoking are the composition of environmental tobacco smoke (ETS) and its toxicity and carcinogenicity relative to the tobacco smoke inhaled by active smokers. Mainstream cigarette smoke is the smoke drawn through the tobacco into the smoker's mouth. Sidestream smoke is the smoke emitted by the burning tobacco between puffs. Environmental tobacco smoke results from the combination of sidestream smoke and the fraction of exhaled mainstream smoke not retained by the smoker. In contrast with mainstream smoke, ETS is diluted into a larger volume of air, and it ages prior to inhalation. The comparison of the chemical composition of the smoke inhaled by active smokers with that inhaled by invohmtary smokers suggests that the toxic and carcinogenic effects are qualitatively similar, a similarity that is not too surprising because both mainstream smoke and environmental tobacco smoke result from the combustion of tobacco. Individual mainstream smoke constituents, with appropri- ate testing, have usually been found in sidestream smoke as well. However, differences between sidestream smoke and mainstream smoke have been well documented. The temperature of combustion during side&ream smoke formation is lower than during main- stream smoke formation. As a result, greater amounts of many of the organic constituents of smoke, including some carcinogens, are generated when tobacco burns and forms side&ream smoke than when mainstream smoke is produced. For example, in contrast with mainstream smoke, side&ream smoke contains greater amounts of ammonia, benzene, carbon monoxide, nicotine, and the carcinogens 7 %napthylamine, 4aminobipheny1, N-nitrosamine, ~=I+ anthracene, and benzo-pyrene per milligram of tobacco burned. Although only limited bioassay data comparing mainstream smoke and sidestream smoke are available, one study has suggested that sidestream smoke may be more carcinogenic. Extent of Exposure ~though siclestream smoke and mainstream smoke differ some- what qualitatively, the differing quantitative doses of smoke compo- nents inhaled by the active smoker and by the involuntary smoker are of greater importance in considering the risks of the two exposures. A number of different markers for tobacco smoke exposure and absorption have been identified for both active and involuntary smoking. No single marker quantifies, with precision, the exposure to each of the smoke constituents over the wide range of environmental settings in which involuntary smoking occurs. However, in environments without other significant sources of dust, respirable suspended particulate levels can be used as a marker of smoke exposure. Levels of nicotine and its metabolite cotinine in body fluids provide a sensitive and specific indication of recent whole smoke exposure under most conditions. Widely varying levels of environmental tobacco smoke can be measured in the home and other environments using markers. The time-activity patterns of nonsmokers, which indicate the time spent in environments containing EI'S, also vary widely. Thus, the extent of exposure to ETS is probably highly variable among individuals at a given point in time, and little is known about the variation in exposure of the same individual at different points in time. Llmg cancer The American Cancer Society estimates that there will be more than 135,000 deaths from lung cancer in the United States in 1986, and 85 percent of these lung cancer deaths are directly attributable to active cigarette smoking. Therefore, even if the number of lung cancer deaths caused by invohmtary smoking were much smaller than the number of lung cancer deaths caused by active smoking, the number of lung cancer deaths attributable to involuntary exposure would still represent a problem of sufficient magnitude to warrant substantial public health concern. Exposure to environmental tobacco smoke has been examined in numerous recent epidemiological studies as a risk factor for lung cancer in nonsmokers. These studies have compared the risks for subjects exposed to MS at home or at work with the risks for people not reported to be exposed in these environments. Because exposure to EIS is an almost universal experience in the more developed ~~fhs, theee studies involve comparison of more expased and less 8 exposed people rather than comparison of exposed and unexposed people. Thus, the studies are inherently conservative in assessing the consequences of exposure to ETS. Interpretation of these studies must consider the extent to which populations with different E'JJS exposures have been identified, the gradient in EXS exposure from the low-er exposure to the higher exposure groups, and the magni- tude of the increased lung cancer risk that results from the gradient in ETS exposure. To date, questionnaires have been used to classify ETS exposure. Quantification of exposure by questionnaire, particularly lifetime exposure, is difficult and has not been validated. However, spousal and parental smoking status identify individuals 6th different levels of exposure to ETS. Therefore, investigation has focused on the children and nonsmoking spouses of smokers, groups for whom greater ETS exposure would be expected and for whom increased nicotine absorption has been documented relative to the children and nonsmoking spouses of nonsmokers. Of the epidemiologic studies reviewed in this Report that have examined the question of involuntary smoking's association with lung cancer, most (11 of 13) have shown a positive association with exposure, and in 6 the association reached statistical significance. Given the difficulty in identifying groups with differing ET'S exposure, the low-dose range of exposure examined, and the small numbers of subjects in some series, it is not surprising that some studies have found no association and that in others the association did not reach a conventional level of statistical significance. The question is not whether cigarette smoke can cause lung cancer; that question has been answered unequivocally by examining the evi- dence for active smoking. The question is, rather, can tobacco smoke at a lower dose and through a different mode of exposure cause lung cancer in nonsmokers? The answer must be sought in the coherence and trends of the epidemiologic evidence available on this lowdose exposure to a known human carcinogen. In general, those studies with larger population sizes, more carefully validated diagnosis of lung cancer, and more careful assessment of M`s exposure status have shown statistically significant associations. A number of these studies have demonstrated a dose-response relationship between the level of M`S exposure and lung cancer risk. By using data on nicotine absorption by the nonsmoker, the nonsmoker's risk of developing lung cancer observed in human epidemiologic studies can be compared with the level of risk expected from an extrapolation of the d-response data for the active smoker. This extrapolation yields estimates of an expected lung cancer risk that approximate the observed lung cancer risk in epidemiologic studies of involud~ smoking. 9 Cigarette smoke is well established as a human carcinogen. The chemical composition of ETS is qualitatively similar to mainstream smoke and sidestream smoke and also acts as a carcinogen in bioassay systems. For many nonsmokers, the quantitative exposure to ETS is large enough to expect an increased risk of lung cancer to occur, and epidemiologic studies have demonstrated an increased lung cancer risk with involuntary smoking. In examining a low-dose exposure to a known carcinogen, it is rare to have such an abundance of evidence on which to make a judgment, and given this abundance of evidence, a clear judgment can now be made: exposure to ETS is a cause of lung cancer. The data presented in this Report establish that a substantial number of the lung cancer deaths that occur among nonsmokers can be attributed to involuntary smoking. However, better data on the extent and variability of E!lS exposure are needed to estimate the number of deaths with confidence. Respiratory Disease Acute and chronic respiratory diseases have ah30 been linked to hvol~ntary exposure to tobacco smoke; the evidence is strongest in infants. htig the first 2 years of life, infants of parents who smoke me more Likely than infants of nonsmoking parents to be hospital- ized for bronchitis and pneumonia. Children whose parents smoke aho develop respiratory symptoms more frequently, and they show small, but measurable, differences on tests of lung function when compared with children of nonsmoking parents. Respiratory infections in young children represent a direct health burden for the children and their parents; moreover, these infec- tions, and the reductions in pulmonary function found in the school- age children of smokers, may increase susceptibility to develop lung disease as an adult. Several studies have reported small decrements in the average level of lung function in nonsmoking adults exposed to ETS. These differences may represent a response of the lung to chronic exposure to the irritants in ETS, but it seems unlikely that ETS exposure, by itself, is responsible for a substantial number of cases of clinically significant chronic obstructive lung disease. The small magnitude of the changes associated with EX'S exposure suggesta that only Miti~uals with unusual susceptibility would be at risk of develop kg ClinicallY adent disease from E'I% exposure alone. However, ETS exposure IMY be a factor that contributes to the development of clinical disease in individuals with other causes of lug mjury. cardiovascular Disease A few studies have examined the relationship hebeen invohrn~ tarY smoking and cardiovascular disease, but no firm conclusion on 10 the relationship can be made owing to the limited number of deaths in the studies. Perhaps the most common effect of tobacco smoke exposure is tissue irrit&.ion. The eyes appear to be especially sensitive to irritation by EX'S, but the nose, throat, and airway may also be af%cted by smoke exposure. Irritation has been demonstrated to occur at levels that are similar to those found in real-life situations. The level of irritation increases with an increasing concentration of smoke and duration of exposure. In addition, participants in surveys report irritation and annoyance due to smoke in the environment under real-life conditions. Determinante of Espoi3ure &pc++ure to EX'S has been documented to be common in the United States, but additional data on the extent and determi,nanta of exposure are needed to identify individu& within the population who have the highest exposure and are at greatest risk. Studies with biological markers and measurements of EXS components in indoor air confirm that measurable exposure to l3TS is widespread. How- ever, within exposed populations, levels of cotinine excretion and presumably El% exposure vary greatly. In a room or other indoor area, the size of the space, the number of smokers, the amount of ventilation, and other factors determine the concentration of tobacco smoke in the air. The technology for the cost-effective atration of tobacco smoke from the air is not currently available, and because of their small size, the smoke particles remain suspended in the air for long periods of time; thus, the only way to remove smoke from indoor air is to increase the exchange of indoor air with clean outdoor air. The number of air changea per hour required to maintain acceptable indoor air quality is much higher when smoking is allowed than when smoking is prohibited. Environmental tobacco smoke originates at the lighted tip of the cigarette, and exposure to M`s is greatest in proximity to the smoker. However, the smoke rapidly disseminates throughout any airspace contiguous with the space in which the smoking is taking place. Dissemination of smoke is not uniform, and substantial gradienti in ETS levels have been demonstrated in different parta of the same airspace. The time course of tobacco smoke dissemination is rapid enough to ensure the spread of smoke throughout an airspace within an S-hour workday. In the home, the presence of even one smoker can GgnEcantly increase levels of respirable suspended particulates. These data lead to the conclusion that the simple separation of smokers and nonsmokers within the same airspace will reduce, but 11 not eliminate, exposure to El%, particularly in those settings where exposure is prolonged, such as the working environment. The exposure of an individual nonsmoker to ETS is also deter- m&xl by that person's time-activity pattern; that is, the amount of he spent in various locations. For adults, the duration of the spent in smoke-contaminated environments at work or at home is the principal dete rminant of E!!`8 exposure, along with the levels of smoke in those environments. For infants and very young children, the smoking habit of the primary caretaker, as well as that person's time-activity pattern, is likely to play a major role in de&mining ETS exposure. Policies Restricting Smoking Pohcies regulating cigarette smoking with the objective of reduc- ing e~l~ion or fire risk, or of safeguarding the quality of manufac- tured products, have been in force in a number of States since the late 1800s. More recently, and with steadily increasing frequency, pohcies regulating smoking on the basis of the health risk or the irritation of involuntary smoking have been promulgated. State and local governments have enacted laws and regulations restricting smoking in public places. These policies have been implemented with few problems and at little cost to the respective governments. !I'he public awareness of these policies that results from the media coverage surrounding their implementation proba- bly facilitates their selfenforcement. Public awareness may best be fostered by encouraging the establishment of these changes at the local level. Policies limiting smoking in the worksite have also become increasingly widespread and more restrictive. However, changes in worksite policies have evolved largely through voluntary rather than governmental action. In a steadily increasing number of worksites, smoking has been prohibited completely or limited to relatively few areas within the worksite. The creation of a smoke- free workplace has proceeded successfully when the policy has been jointly developed by employees, employee organizations, and man- agement; instituted in phases; and accompanied by support and assistarm for the smokers to quit smoking. This trend to protect nonsmokers from ETS exposure may have an added public health benefithelping those smokers who are at- tempting to quit to be more successful and not encouraging smoking by people entering the workforce. Summary and Conclusions of the 1988 Report The three major conclusions of this report are the following: 12 1. Involuntary smoking is a cause of disease, including lung cancer, in healthy nonsmokers. 2. The children of parents who smoke compared with the children of nonsmoking parente have an iucreased frequency of respiratory iufectiouq iucreased respira- tory symptoms, and slightly smaller rates of increase in lung function as the lung matures. 3. The simple separation of smokers and nousmokers withiu the same air space may reduce, but doea not eliminate, the exposure of nonsmokers to enviroumen- tal tobacco smoke. ,Individual chapter summaries and conclusions follow. Health Effects of Euviroumental Tobacco Smoke Exposure 1. Involuntary smoking can cause lung cancer in nonsmokers. 2. Although a substantial number of the lung cancers that occur in nonsmokers can be attributed to involuntary smoking, more data on the dose and distribution of ETS exposure in the population are needed in order to accurately estimate the magnitude of risk in the U.S. population. 3. The children of parents who smoke have an increased frequen- cy of hospitalization for bronchitis and pneumonia during the first year of life when compared with the children of nonsmok- ers. 4. The children of parents who smoke have an increased frequen cy of a variety of acute respiratory illnesses and infections, including chest illnesses before 2 years of age and physician- diagnosed bronchitis, tracheitis, and laryngitis, when com- pared with the children of nonsmokers. 5. Chronic cough and phlegm are more frequent in children whose parents smoke compared with children of nonsmokers. The implications of chronic respiratory symptoms for respira- tory health as an adult are unknown and deserve further study. 6. The children of parents who smoke have small differences in tests of pulmonary function when compared with the children of nonsmokers. Although this decrement is insufficient to cause symptoms, the possibility that it may increase suscepti- bility to chronic obstructive pulmonary disease with exposure to other agents in adult life, e.g., active smoking or cccupation- al exposures, needs investigation. 7. Healthy adults exposed to environmental tobacco smoke may have small changes on pulmonary function testing, but are unlikely to experience clinically significant deficits in pulmo- 13 nary function as a result of exposure to environmental tobacco smoke alone. 8. A number of studies report that chronic middle ear effusions are more common in young children whose parents smoke than in children of nonsmoking parents. 9. Validated questionnaires are needed for the assessment of recent and remote exposure to environmental tobacco smoke in the home, workplace, and other environments. 10. The associations between cancers, other than cancer of the lung, and involuntary smoking require further investigation before a determina tion can be made about the relationship of involuntary smoking to these cancers. 11. Further studies on the relationship between involuntary smoking and cardiovascular disease are needed in order to determine whether involuntary smoking increases the risk of cardiovaaculardisease. Environmental Tobacco Smoke Chemistry and Expcwwes of Nonsmokera 1. Undiluted sidestream smoke is characterixed by significantly higher concentrations of many of the toxic and carcinogenic compounds found in mainstream smoke, including ammonia, volatile amines, volatile nitr osamines, certain nicotine decom- position products, and aromatic amines. 2. Environmental tobacco smoke can be a substantial contributor to the level of indoor air pollution concentrations of respirable particles, benzene, acrolein, N-nitrosamine, pyrene, and carbon monoxide. E!l'S is the only source of nicotine and some N- nitrosamine compounds in the general environment. 3. Measured exposures to respirable suspended particulates are higher for nonsmokers who report exposure to environmental tobacco smoke. Exposures to ETS occur widely .in the non- smoking population. 4. The small particle size of environmental tobacco smoke places it in the diffusioncontrolled regime of movement in air for deposition and removal mechanisms. Because these submicron particles will follow air streams, convective currents will dominate and the distribution of ETS will occur rapidly through the volume of a room. As a result, the simple separation of smokers and nonsmokers within the same airspace may reduce, but will not eliminate, exposure to ETS. 5. It has been demonstrated that ETS has resulted in elevated respirable suspended particulate levels in enclosed places. 14 Deposition and Absorption of Tobacco Smoke Constituenta 1. Absorption of tobacco-speciSc smoke constituents (i.e., nicotine) from environmental tobacco smoke exposures has been docu- mented in a number of samples of the general population of developed countries, suggesting that measurable exposure tc environmental tobacco smoke is common. 2. Mean levels of nicotine and cotinine in body fluids increase with self-reported EX'S exposure. 3. Because of the stability of cotinine levels measured at different times during exposure and the availability of noninvasive sampling techniques, cotinine appears to be the shortcterm marker of choice in epidemiological studies. 4. Both mathematical modeling techniques and experimental data suggest that 10 to 20 percent of the particulate fraction of side&ream smoke would be deposited in the airway. 5. The development of specific chemical assays for human expo sure to the components of cigarette tar is an important research goal. Toxicity, Acute Irritant Effects, and Carcinogenicity of Environmental Tobacco Smoke 1. The main effects of the irritants present in ETS occur in the conjunctiva of the eyes and the mucous membranes of the nose, throat, and lower respiratory tract These irritant effects are a frequent cause of complaints about poor air quality due to environmental tobacco smoke. 2. Active cigarette smoking is associated with prominent changes in the number, type, and function of respiratory epithelial and inflammatory cells; the potential for environmental tobacco smoke exposure to produce similar changes should be investi- gated. 3. Animal models have demonstrated the carcinogencity of ciga- rette smoke, and the limited data that exist suggest that more carcinogenic activity per milligram of cigarette smoke concen- trate may be contained in sidestream smoke than in main- stream cigarette smoke. Policies Restricting Smoking in Public Places and the Workplace 1. Beginning in the 19708, an increasing number of public and private sector institutions have adopted policies to protect individuals from environmental tobacco smoke exposure by restricting the circumstances in which smoking is permitted. 2. Smoking in public places has been regulated primarily by government actions, which have occurred at Federal, State, 15 and local levels. All but nine States have enacted laws regulating smoking in at least one public place. Since the mid- 19706, there has been an increase in the rate of enactment and in the comprehensiveness of State legislation. Local govern- ments have enacted smoking ordinances at an increasing rate since 1980, more than SO cities and counties have smoking laws in effect. 9. Smoking at the workplace is regulated by a combination of government action and private initiative. Legislation in 12 States regulates smoking by government employees, and 9 St&s and more than 70 communities regulate smoking in the private sector workplace. Approximately 96 percent of busi- nesses have adopted smoking policies. The increase in work- place smoking policies has been a trend of the 1980s. 4. Smoking policies may have multiple effects. In addition to reducing environmental tobacco smoke exposure, they may alter smoking behavior and public attitudes about tobacco use. Over time, this may contribute to a reduction in smoking in the United States. To the present, there has been relatively little systematic evaluation of policies restricting smoking in public places or at the workplace. 5. On the basis of case reports and a small number of systematic studies, it appears that workplace smoking policies improve air quality, are met with good compliance, and are well accepted by both smokers and nonsmokers. Policies appear to be followed by a decrease in smokers' cigarette consumption at work and an increase in enrollment in company-sponsored smoking cessation programs. 6. Laws restricting smoking in public places have been imple- mented with few problems and at little cost to State and local government. Their impact on smoking behavior and attitudes has not yet been evaluated. 7. Public opinion polls document strong and growing support for restricting or banning smoking in a wide range of public places. Changes in attitudes about smoking in public appear to have preceded legislation, but the interrelationship of smoking attitudes, behavior, and legislation are complex. 16 CHAPTER 2 HEALTH EFFECTS OF ENVIRONMENTAL TOBACCO SMOKE EXPOSURE CONTENTS Introduction Evaluation of Low-Dose Tobacco Smoke Exposures Extrapolation of Active Smoking Data to Environ- mental Tobacco Smoke Exposure Comparison of Mainstream Smoke and Side- stream Smoke Deposition of Mainstream Smoke and Side stream Smoke and Environmental Tobacco Smoke Dose Estimates Dose-Response Relationships and Threshold for Risk Pathophysiologic Considerations Cancer Lung Disease Methodological Considerations ip Epidemiologic Studies Measurement of Exposure Atmospheric Markers Personal Monitoring Questionnaires Measurements of Absorption Potentially Confounding Variables Statistical Issues Respiratory System Effeds of Involuntary Cigarette smoke Exposure Infants and Children Acute Respiratory Illness Longitudinal stud&3 Cross-Sectional Studies Case-Control Studies Cough, Phlegm, and Wheezing Pulmonary Function Bronchoconstriction Ear, Nose, and Throat Adults Acute Respiratory Illness Cough, Phlegm, and Wheezing 19 Pd.~~onary Function Bronchoconstriction Normal Subjects Asthmatics Ear, Nose, and Throat Lung Cancer Observed Risk General Methodological Issues &msal Exposure: Prospective Studies Tbe Japanese Cohort Study The American Cancer Society Cohort Study The Scottish Study Spousal Exposure: Cas&!ontrol Studies The Greek Study The Louisiana Study The Hong Kong Studies An Ongoing Study of Tobacc&elated Cancers The Ios Angeles County Study The Four Hospitals Study A United Kingdom Study The Japanese Case-Control Study The Swedish Study The German Study Other Sources of Tobacco Smoke Exposure Parental Smoking Coworker's Smoking Dose-Response Relationship Expected Lung Cancer Risk S- Other Cancers cardiovascular Diseases ~ ~- Conclusions Referencef4 20 Introduction In 1964, the fmt Report of the Surgeon General on smoking and health (TJS PHS 1964) determined that cigarette smoking was a cause of lung cancer in men and probably a cause of lung cancer in women. That Report also noted causal relationships between smok- ing and other cancers, as well as chronic lung disease. Subsequent Reports have described associations, both causal and noncausal, between tobacco smoking and a wide range of acute and chronic d&eases. Epidemiological investigations have documented the effects of tobacco smoking in humans; complementary laboratory investiga- tions have elucidated some of the mechanisms through which tobacco smoke causes disease. More recently, the effects of the inhalation of environmental tobacco smoke by nonsmokers have become a pressing public health concern. Nonsmokers, as well as active smokers, inhale environmen- tal tobacco smoke, the mixture of sidestream smoke and exhaled mainstream smoke. Various terms have been applied to the inhala- tion of environmental tobacco smoke by nonsmokers; the terms "involuntary smoking" and "passive smoking" are the most preva- lent and are often used interchangeably by researchers and the public. Many of the known toxic and carcinogenic agents found in mainstream cigarette smoke have also been demonstrated to be present in sidestream smoke. Furthermore, the combustion condi- tions under which sidestream smoke is produced result in the generation of larger amounts of many of these toxic and carcinogenic agents per gram of tobacco burned than the conditions under which mainstream smoke is generated (see Chapter 3). The characteristics of environmental tobacco smoke also differ from those of main- stream smoke because the sidestream smoke ages before it is inhaled and the mainstream smoke exhaled by the active smoker is modified during its residence in the lung. There is no evidence to suggest that environmental tobacco smoke has a qualitatively lower toxicity or carcinogenicity than mainstream smoke per milligram of smoke inhaled. In fact, the available evidence suggests that sidestream smoke contains higher concentrations of many known toxic and carcinogenic agents per milligram of smoke and is more tumorgenic than mainstream smoke in animal testing (Wynder and Hoff'mann 1967). As a result, involuntary smoking should not be viewed as a qualitatively different exposure from active smoking, but rather as a lowdose exposure to a known hazardous agent-cigarette smoke. Evaluation of Low-Dose Tobacco Smoke Exposures Assessment of the health effects of any environmental exposure poses methodological problems, particularly when exposure levels 21 are low and therefore the magnitude of the expected effect is small. me ev&ation of an effect due to a low-dose exposure such as environment& tobacco smoke requires the investigation of popula- tions with differences in exposure large enough so that an effect could be anticipated. The population studied must also be of sufficient size to quantitate the effects in the range of interest with pr&&n. Failure to fulfill these requirements may produce a false- negative result in a study of a low-dose exposure. Exposure to environmental tobacco smoke is a nearly universal experience in the more developed countries, so the identification of a truly unexposed population is very difficult. Epidemiological studies of involuntary smoking have attempted to identify populations with lower exposure and higher exposure to environmental tobacco smoke, most notably by examining nonsmokers exposed to tobacco smoke generated by the smokers of their family. The effects of environmental tobacco smoke have been investigated in a number of populations throughout the world. The diversity of these populations is likely to be accompanied by a similar diversity of their exposure to envircnmental tobacco smoke. Thus, the gradient in exposure to environmental tobacco smoke between the "exposed" and %onex- posed" groups is likely to vary widely among the reported studies. For example, the husband's smoking status may be a strong predictor of total exposure to ETS in traditional societies, such as Japan and Greece, where the wife's exposure outside the home is limited. In contrast, the husband's smoking status in the United States, where substantial exposure may occur outside the home, may not be as predictive. Sample size considerations are of particular concern for the epidemiological studies of lung cancer and involuntary smoking. Because the frequency of lung cancer in nonsmokers is low, many of these studies often included small numbers of nonsmokers and lacked the statistical power necessary to fmd the modest effect expected from this lowdose exposure. Given the constraints of sample size and the varying gradients of exposure, it would be expected that some studies would fmd no association between involuntary smoking and lung cancer, and that other studies would find associations that lacked statistical significance. Nonunifomity of the data, however, does not imply a lack of effect; rather, it is the coherence and trends of the evidence that must be judged. Thus, this Rep0l-t examines the entire body of evidence on the health effects of involuntary smoking, as the basis for its conclusions. In evaluating the hazards posed by an air pollutant such as environmental tobacco smoke, laboratory, toxicological, human exposure, and epidemiological investigations provide relevant data. Each approach has limitations, but the insights each prov&s Me Complementary. Epidemiological investigations describe the effects 22 in human populations, but their results must be interpreted in the context of the other types of investigations. Risk assessment techniques have also been used to characterize the potential adverse health effects of human exposures to environ- mental pollutants, particularly those at low levels. The four steps of risk assessment have been described by the National Academy of Sciences as hazard identification, dose-response assessment, expo- sure assessment, and risk characterization (NAS 1983). Risk assess+ ment has also been used to describe the consequences of exposure to ETS. However, unlike many environmental exposures for which risk assessment represents the only approach for estimating human risk, the health effects of ETS exposure can be examined directly using epidemiological methods. Although this Report reviews several risk assessmenta done by individual researchers on ETS, its conclusions are based on the laboratory, toxicological, and epidemiological evidence. Extrapolation of Active Smoking Data to Environmental Tobacco Smoke Exposure Comparison of Mainstream Smoke and Sidestream Smoke A detailed comparison of mainstream and side&ream smoke can be found in Chapter 3. Mainstream smoke (MS) is the term applied to the complex mixture that is inhaled by the smoker from the mouthpiece of a cigarette, cigar, or pipe with each puff. Side&ream smoke (SS) is the aerosol that comes from the burning end of the cigarette, pipe, or cigar between puffs. Environmental tobacco smoke (ETS) is the term applied to the combination of SS and exhaled MS, which is diluted and aged in an area where smoking has taken place. Most of the existing data on mainstream and sidestream smoke characteristics relate to cigarette smoking and relatively little information is available pertaining to cigar and pipe smoking. &cause both MS and SS are generated from the tip of the burning tobacco product, it is not surprising that their compositions are similar. Of the thousands of compounds identified in tobacco smoke, many have been identified as present in both MS and SS. Among these are carcinogens, gases such as carbon monoxide and the oxides of nitrogen, and nicotine. Since there is a wealth of information relating to the toxicity and carcinogenicity of MS, it should be emphasized again that ETS cannot be treated as a new environmen- tal agent for the purpose of assessing health risks. The presence of the same agents in MS and SS leads to the conclusion that ETS has a toxic and carcinogenic potential that would not be expected to be qualitatively different from that of MS. Quantitative differences between the active smoker's exposure to MS and the involuntary smoker's exposure to ETS are likely to be. the more important 23 determjnant of the differing magnitudes of risks associated with them3 two exposures. werences in the composition of MS and SS primarily reflect their generation at different temperatures in different oxygen environments. also, SS is diluted very rapidly, under most circum- ww, and has the opportunity to age before inhalation. The h~luntary smoker usually inhales E'IS, not SS, the aerosol that comes from the tip of a burning cigarette. In considering the &u&e&tics of SS, it must be emphasii that much of the existing data about the composition of MS and SS is derived from studies carried out in special chambers rather than by sampling MS and SS generated by smokers. In these chamber studies, SS has been sampled by a probe located close to the burning tip. This experimen- tal situation clearly differs from that of a room with one or more smokers freely smoking. In that situation, SS is mixed with exhaled MS, diluted and aged. Nevertheless, these &amber studies provide very useful information about the compounds present in the SS. These studies have established that SS in comparison with MS has a higher PHI, smaller particle size, and more carbon monoxide, benzene, toluene, acrolein, acetone, pyridine, ammonia, methyl- amine, nicotine, aniline, cadmium, radon daughters, beru@ajpyrene and benzIa]anthracene. Comparison of the relative concentrations of the various compo- nents of SS and MS smoke prcvides limited insights concerning the toxicological potential of ETS in comparison with active smoking. As described above, SS characteristics, as measured in a &amber, do not represent those of E!I'S, as inhaled by the nonsmoker under nonexperimental conditions. Further, the dose-response relation- sbips between specific tobacco smoke components and specific diseases are not sufficiently established for the necesssq extrapola- tions from active smoking to environmental tobacco smoke exposure for individual agents. For that reason the extrapolations in this section are confined to the doseresponse relationships of whole smoke for those diseases with established dose-response relation- ships. With regard to the potential of EX'S to cause lung cancer, UdilUted SS has 20 to 100 times greater concentrations of. highly carcinogenic volatile. N-nitrosamin es than MS (Brunnemam et al. 1978) as well as higher concentrations of benxopyrenes and benzCa]anthracenes. For mum&want effecta on airways and the lung parenchyma, the agents responsible for the development of acute and chronic respiratory disease have not been identified, although many tobacco smoke components have been shown tc cause lung injury (US DHHS 19&Q). Presumably, both vapor phase (gaseous) and particulate phase kW components of MS are involved. Both airways disease and 24 parenchymal disease are probably a response to the total burden of respiratory insults, some of which, like active smoking, may be sufficient by themselves to cause physiologic impairment and ultimately, clinical disease. Others, such as ETS, may contribute to the total burden but be insufficient, individually, to cause clinical disease. Deposition of Mainstream Smoke and Side&ream Smoke and Environmental Tobacco Smoke Dose Estimutes The dose of tobacco smoke delivered to the airways and alveoli depends, among other factors, on the volume of MS, SS, or E'I'S inhaled, on the rate and depth of inhalation, and on the sixe, shape, and density of the individual particles or droplets. Patterns of deposition of MS in the lungs have been described, but similar information about deposition patterns for ETS is not yet available. Without such data, it is necessary to extrapolate from the informa- tion on MS. The major factors that affect the pattern of deposition and retention for particles are particle size distriiution and breathing pattern. The particle sire range and mean aerodynamic diameter for particulates in sidestream smoke are similar to those of mainstream smoke (particle sire range of 0.01 to 0.8 pm for sidestream smoke and 0.1 to 1.0 v for mainstream smoke, and mean aerodynamic diameter 0.32 p for sidestream smoke and 0.4 pm for mainstream smoke) (see Cbapters 3 and 4). `l'he deposition site is determined largely by the size of the particles, with large particles being deposited preferentially in the nasopbarynx and large conducting airways. Smaller particles are deposited more peripherally, and very small particles tend to be exhaled and to have a very low deposition fraction. The particulates of ETS, because of their size range, are likely to be deposited peripherally. The breathing patterns for the inhalation of MS and EYI'S are also different; MS is inbaled intermittently by the smoker with an intense inhalation, often followed by a breathhold that resulta in a more equal distribution. Environmental tobacco smoke, on the other hand, is inhaled continuously with tidal breaths when the passive smoker is at rest and with deeper inhalations when the passive smoker is physically active. Breatbholding does not normally occur with tidal breathing. Estimates of the equivalent exposure, in terms of cigarettes per day, resulting from ETS, as compared with MS, vary quite widely and depend on the way in which the estimates were made. Bepace and Lowrey (1985) estimated that nonsmokers in the United States are exposed to from 0 to 14 mg of tobacco tar (average 1.4 rag) per day. Vutuc (1984) estimated that the exposure to environmental cigarette smoke is equivalent to 0.1 to 1 cigarette per day actively 25 smoked. Estimates of ETS exposure, based on cotinine measure- ments, suggest that involuntary smokers absorb about 0.5 to 1 percent of the nicotine that active smokers absorb (Jarvis et al. 1984, Haley and Hoffmann 1965; Wald et al. 1984; Russell et al. 1966). Dose-Response Ret!ationships and Threshold for Risk -response relationships for active smoking can provide in- sights into the expected magnitude of disease resulting from the exposure of nonsmokers to ETS. These data are reviewed to de&mine whether disease can be expected in association with E'I'S. Data from cohort and cas+control studies demonstrate dose- response relationships for lung cancer, which extend to the lowest levels of reported active smoking. The dose-response relationship of active smoking with lung cancer risk has been described by several investigators in several different date sets (Whittemore and Altshu- ler 1976; Doll and Pet0 1978; Pathak et al. 1986). Although the mathematical forms of these models vary, none have included a threshold level of active smoking that must be passed for lung cancer tc develop. The dose-response relationship for active smoking and lung cancer has been used to project the lung cancer risk for nonsmokers (Vutuc 1964). Such projections yield risk estimates of 1.03 to 1.36 for exposures, considered to be reasonable estimates of involuntary smoking exposures, i.e., 0.1 t.c 1.0 cigarettes per day. The reference population for these risk estimates is the risk for nonsmokers as a group, including those with higher and those with lower exposures to environmental tobacco smoke. In contrast, the reference population for the risk estimates in studies of involuntary smoking is the lung cancer risk in only that group of nonsmokers who have lower exposure to EITS. Comparisons of lung cancer risk estimates from active smoking studies with those from involuntary smoking studies require reference to the same exposure group for proper mterpreta- tion. In general, the lung cancer experience .of all nonsmokers (i.e., those with higher and lower involuntary smoking exposure com- bined) has been used to establish the reference rate of lung cancer occurrence (i.e., set as a risk of 1) in studies of active smoking. The use of all nonsmokers as the reference group averages the lower risks of nonsmokers with less ETS exposure with the higher risks of those with more ETS exposure. Thus, with the relative risk for the entire group of nonsmokers set to unity, the relative risk for nonsmokers with lower exposure is below 1 and that for the group with higher exposure is above 1. As a consequence, relative risk estimates from studies of involuntary exposure cannot be directly compared with risk estimates extrapolated from active smoking, unh c(qm%on to a single level of exposure is possible. Failure to 26 consider the differences between the reference populations explains the apparent discrepancy noted by Vutuc. Consider, for example, the mortality study reported by Hirayama (1981a). In this study, the relative risk of lung cancer for nonsmoking wives of smoking husbands (current and former) compared with nonsmoking wives of nonsmoking husbands (as calculated from Figure 1 in Hirayama 1981a) was 1.78. If the relative risk for nonsmoking wives of nonsmoking husbands were expressed in relation to the combined group of nonsmoking women, then a value of 0.63 is obtained, while with a similar calculation, that for nonsmoking wives of smoking husbands (both current and former), yields a value of 1.12. Thus, when the appropriate comparison is made, the risk estimates developed by extrapolation of the active smoking data (1.03 to 1.36) closely approximate those actually found in a study of lung cancer risk due to involuntary smoking. Dose-response relationships between active smoking and the level of lung function, the rate of decline of lung function in adult life, and the development of chronic airflow obstruction are well established (US DHHS 1984). Different measures of dose have provided the strongest correlation with functional decline in different studies. Pack-years, a cumulative dose measure, was the strongest predictor of the level of forced expiratory volume in 1 second (FEVI) in the Tucson epidemiologic study (Burrows, Knudson, Cline et al. 1977). Duration of smoking and the amount smoked were found to be the best predictors in male subjects in a study of three U.S. communities (Reck et al. 1981), and pack-years was the best predictor in female subjects. In both of these studies, however, the estimated dose accounted for only about 15 percent of the variation of age- and height-adjusted FEW1 levels. The relatively low predictive capability of cigarette smoking variables in these studies most likely reflects a lack of information on the dete rminants of individual susceptibility to tobacco smoke. Further, exposure variables obtained by question- naire, such as the number of cigarettes smoked daily, may only roughly approximate the dose delivered to target sites in the respiratory tract. Many factors, such as puff volume, lung volume at which inhalation starts, and airways geometry will influence the smoke dose and its distribution within the lungs. Extrapolation from the results of these studies to the pulmonary effects of exposure to ETS is, therefore, likely to be inaccurate. Another approach for assessing lowdose exposures is to consider the information available from studies involving children and teenagers who have recently taken up smoking. Even with brief smoking experience, cross-set tional studies of active cigarette smok- ing by children and adolescents have demonstrated an increased frequency of respiratory symptoms (Rawbone et al. 1978; Rush 1974; Bewley et al. 1973; Seely et al. 1971) and small but statistically 27 significant reductions in lung function (Seely et al. 1971; Peters and Ferris 1967; Lim 1973; Walter et al. 1974; &&house 1975; Woolcock et aL 1984). Longitudinal studies involving children and adolescents have demonstrated that a physiologic impairment attributable to smoking may be found in some children by age 14 and may be present after only 1 year of smoking 10 or more cigarettes per week in children with previously normal airways (woolcock et al. 1934), and that relatively small amounts of cigarette use may lead to significant effects on FEVl and on the growth of lung function in adolescents (Figure 1) (`l'ager et al. 1935). When considering the risk of lowdose exposures for the develop ment of chronic respiratory disease, the existence of a spectrum of risk and a distribution of dose within the population should be taken into consideration. The characteristics of the part of the population most susceptible to involuntary smoke exposure is still being clarified. Evidence is accumulating that airways hyperrespon- siveness, atopy, childhood respiratory illness, and occupational exposures may all influence response to ETS. Current understanding of lung injury suggests that individuals with one or more of these characteristics that place them at the most sensitive end of the susceptibility curve may be the most likely to develop symptoms or functional changes es a result of ETS exposure. Dose of ETS also varies in the population, and the coincidence of high dose and increased susceptibility may convey a particularly high risk. Fur- thermore, ET3 exposure may damage lungs that are also affected by other insults. Pathophysiologic Cbsiderations Cancer Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell with uncontrolled replication. Carcinogenesis has been conceptualixed as a multistage process involving a sequence of alterations in cellular DNA that terminate with the development of a malignant cell. Agents acting early in this sequence are referred tc as initiators; those actii later are referred to as promoters. Compounds with both initiating activity and promoting activity have been identified in tobacco smoke. Carcinogenesis reflects DNA damage; although some repair may take place, biological models have not suggested that there is a threshold of damage that must be exceeded. Rather, carcinogenesis has been considered to involve a series of changes, each occurring at a rate dependent on the dose of a damaging agent. Higher doses increase the probability that the entire sequence will be completed, but lower doses may also lead to mahgnancy. o 0 10,ooo 20300 30,ooo 4o.wo 50,ooo 60,ooo 70,Doo 30,ooo Number of cigamtes consumed 150 d o ? ? o o ? ? ? o o ? o o o o o o o o s + 25 0 lO,ooa 2a.ooo 30,ooo 40,ow 5o.ooo ewoo 70,ooo 3o.ooo Number of cigarettes consumed FIGURE l.-Relationship between levels of predicted for FEW, (A) and FEFSWIJ (B) at examination 8 and cumulative number of cigareti smoked during examinations 4 through 8 NOTEzMenandwome.nmmbined@J-44). SOURCE: Tagor et al. (1936). 29 with the PiZZ or other phenotypes, are modest particulate exposures likely to increase the risk for disease to an appreciable extent. The development of acute and chronic airzoay disease or symptoms of cough, phlegm production, and wheeze may require a considerably smaller exposure than changes in the lung parenchyma, and it is not unreasonable to hypothesize that these symptoms may be related to repeated and continuous exposure to EYES in the susceptible individu- al. Strong evidence that lowdose active smoking causes increased rates of respiratory symptoms and functional impairment comes from the studies of children and adolescents discussed earlier (Woolcock et al. 1984; Tager et al. 1985). Because of the length of exposure, it is likely that these reflect airway rather than parenchy- mal effects. Another pathophysiological mechanism by which exposure to EX'S may increase an individual's risk for the development of chronic airflow obstruction is through respiratory viral infections. Mounting evidence indicates that the very young child (under 2 years of age) exposed to ETS is at increased risk for lower respiratory tract viral infections (Harlap and Davies 1974; Colley 1974; Colley et al. 1974; Leeder et al. 1976a; Fergusson et al. 1981; Dutau et al. 1979; Pedreira et al. 1985). There is also increasing, though still inconclusive, epidemiologic evidence that respiratory viral infections in early life may be associated with an accelerated decline in F'EVl and, therefore, an increased risk for the development of chronic airflow obstruction in adult life in smokers (Burrows, Knudson, Lebowitz 1977; Samet et al. 1983). By increasing the occurrence of viral infections of the lower respiratory tract in early life, exposure to ETS in childhood may have an appreciable, but indirect, effect on the risk for the development of chronic airflow obstruction in adult life. The structural basis for this increased susceptibility has not yet been elucidated, however. Furthermore, the child whose parents smoke is also more likely to take up smoking than is the child of nonsmoking parents. Thus, the child made susceptible to the effecta of active smoking by prior PITS exposure is also more likely to become an active smoker. The possibility that exposure to constituents of tobacco smoke in utero may exert a prenatal effect must also be considered. This exposure is clearly not the same as ETS exposure, since the lungs of the fetus are not being exposed to ETS; rather, the developing fetal lung is exposed to compounds absorbed by the mother and delivered to the fetus transplacentally. Evidence of an in utero effect in pregnant rats has been reported by Collins and coworkers (1985). These investigators reported that pregnant rats exposed to smoke from day 5 to day 20 of gestation, in comparison with control rats, showed reduced lung volume at term and saccules that were reduced in number and increased in size as a result of the reduced formation 31 Lung Disease The noncarcinogenic pathophysiologic effects of active smoking on the respiratory tract can be separated into (1) effects on the airways and (2) effects on the lung parenchyma. In the airways, the structural changes include inflammation in the small airways and mucous gland hypertrophy and hyperplasia. In the parenchyma, the main structural change is alveolar wall destruction. Both the airways and the parenchymal changes are caused by active smoking, but the interrelationships of these changes are not clear. They may be independent pathophysiologic pi, linked only by their joint association with tobacco smoking. As discussed earlier, there is evidence showing an approximately linear d-response relationship between F'EWl level and amount smoked; however, the d-response relationships have not been as well described for the underlying pathophysiologic changes in the airways or in the lung parenchyma. Host factors and other environ- mental factors presumably interact with active smoking to affect an individual's risk for the development of disease. In this regard, present evidence would suggest that only 10 to 15 percent of smokers develop clinically significant airflow obstruction, although parenchy- mal and airways changes can be demonstrated in a substantially higher percentage at autopsy (US DHHS 1984). Extrapolation from the evidence on active smoking to the likely effect of exposure to environmental tobacco smoke on the airways and parenchyma suggests that pathophysiologic effeds on both the airways and the lung parenchyma might be expected. Because the dose of smoke components from ETS exposure is small in comparison with the dose from active smoking, the extent of lung injury would most likely also be much smaller than that found in active smokers. Small changes in the lung may be below the threshold for detection on pulmonary function testing. If clinically significant chronic airflow obstruction occurs in nonsmokers exposed to EYES, the risk is likely to be concentrated among those individuals highly susceptible to the airway or parenchymal effects of cigarette smoke. This susceptible group may include individuals with bronchial hyperre sponsiveness and with other, as yet unidentified, genetic and familial risk factors. Identifying the risk factors for susceptibility to the airway and parenchymal effects of both mainstream smoke and EL'S is an important priority. The dose of environmental tobacco smoke received by the nonsmoker is unlikely, by itself, to he sufficient to cause a clinically significant degree of purmchymul disease (em- physema) unless an individual is at the extreme end of the susceptibility distribution. Any particulate load is likely to increase the elaatase burden in the lungs by causing an influx of neutrophils. However, only in the individual with very inadequate lung defenses, specificaIly severe deficiency of protease inhibitor (pi) associated 30 of saccule partitions. These hypoplastic lungs showed an internal surface area that was decreased. Whether this study in rats has any relevance to humans is not yet clear, but this issue deserves further investigation. Whether continued exposure to EX'S during childhood, while the lung is remodeling and growing, affects the process of growth and remodeling is not yet clear. In general, rapidly dividing cells and immature organs are more susceptible to the effects of enviromnen- tal toxins than are cells undergoing a normal rate of division and mature organs. Apart from the evidence, cited above, linking lower respiratory tract viral infections in very early life to an accelerated decline of F'EVl in adult life, there is no information yet to link the rate of growth of lung function during childhood to the rate of decline of hmg function in adult life hecause the nw longitudi- nal studies have not heen done. More information is needed to describe the relationship of exposure to ETS at various times during childhood to the maximal level of lung function achieved at full lung growth. Mefiod~logical Considerations in Epidemiologic Studies Measumnent of Expure h mamsing the health effects of EX'S exposure, as with other enknmental pollutant8, accurate assessment of exposure is critical for obtaining estimates of this agent's effects. Both random and systematic misclassification of the exposures of subjects in an investigation are of concern. Random misclassification refers to errors that occur at random; the consequence of such random misclassification is to bias toward fmding no effect. Systematic misclassification refers to nonrandom errors in exposure assessment; the consequence maybe to bias toward a greater or lesser effect than is actually present. Biased answers in response to a questionnaire may introduce systematic misclsssification. Some misclassification occurs in most observational (nonexperi- mental) epidemiological studies, and is inherent in all epidemiologi- cal studies of ETS. Tobacco smoking is ubiquitous in nearly all environments; few people escape being exposed to EX'S. Thus, the exposure variables for ETS in epidemiological studies do not separate nonexposed subjects from exposed subjects, rather, they identify groups with more or less exposure, or with a qualitative or semiquantitative gradient of exposure. In assessing exposure to ETS, the information should cover the biologically appropriate time period for the health effkct of interest and be collected in a form that permita the construction of biologically appropriate exposure measures. However, the collection of a full lifetime history of IZTS exposure, as in a study of malignancy, may not he feasible, and the accuracy of the informa- 32 tion may he limited. In evaluating the effects of ETS exposure, cumulative exposure, duration of exposure, and intensity of exposure may each influence the magnitude of effects, as may the timing of exposure in relation to age and level of development. Because of the difficulties inherent in assessing exposures through questio maims, increased emphasis has been placed on meamuing exposure through the use of molecular or biochemical markers. With available markers, this approach is limited to providing an indica- tion of recent (within 48 hours) exposure, which may not necessarily correlate with past exposure. A marker has not yet been devised for total integrated dose. Nevertheless, biological markers provide another method for classification of current exposure, and a stan- dard for validating questionnaires. The strengths and weaknesses of the existing methods of measur- ing exposure are further discussed below. Atmospheric Markers A number of different markers of atmospheric contamination by tobacco combustion products can be feasibly measured. Ideally, the atmospheric levels of the air contaminant or class of contaminants that are implicated in producing the adverse health effects would be measured. A variety of contaminants have been measured as indicators of ETS, but no single measure can adequately index all of its myriad components. Further, some contaminanta are produced by sources of environmental contamination other than tobacco smoke. Nicotine is ahsorbed only from tobacco and tobacco combustion products. Some of the pollutants that have heen measured include (1) carbon monoxide, (2) respirahle suspended particulates CRSP), (3) nicotine, (4) a number of aromatic hydrocarbons, such as benzene, toluene, benxopyrene, and phenols, and (5) acrolein. Some of these are in the vapor phase and some in the particulate phase. Some, such as nicotine, may exist in one phase (particulate) in MS and in the other (gas) phase in SS. Until more is learned about the contaminants and their physical state in ETS, the results of monitoring for a particular ETS component will be difficult to relate to ita diseasecausing potential. At a practical level, the technology for measuring nicotine levels and RSP levels is available and accurate. Personal Monitoring Both active and passive personal monitors can be used to measure an individual's total exposure to an air contaminant at the breathing xone. Active personal monitoring systems .employ pumps to concen- trate the air contaminants on a collection medium for laboratory analysis or to deliver the air to a continuous monitor. Passive 33 personal monitoring systems use diffusion and permeation to concentrate gases on a collection medium for laboratory analysis. Personal monitoring should provide a more accurate estimate of the dose of a contaminant than area mOnitoring, because the actual air in the breathing zone is sampled and the subject's time-activity pattern is inherently considered. As with area monitoring, the results for a particular component of ETS may not adequately characterize exposure to other components responsible for a particular disease or effect. Respirable suspended particulates can be measured with accuracy and give a reasonably accurate measurement of current exposure. Questionnaires me que&ionnaire has heen the most frequently used means of estimating exposures for epidemiological investigations. Question- naires typic&y have obtained information about the smoking habits of parents, spouses, or other family members and often about exposure outside the home. From this information, the subject is classified as exposed or not exposed to Errs, and the extent of exposure may be estimated. The questionnaire approach for exposure estimation has several potential limitations. First, the information obtained cannot exhaus- tively cover lifetime exposure to ETS; therefore, a completely accurate reconstruction of integrated dose over the years cannot be achieved. Second, in evaluating El% exposure in the home, the usual daily smoking of the smokers has often been used as a measure of exposure intensity at home. This assumption may not be correct, since smoking does not occur only in the home. For example, a one- pack-a-day smoker may smoke only five cigarettes a day in the home environment and smoke the rest at work or elsewhere outside the home. Third, quantitation of exposure in the workplace is inherently Sfficult because of changes in jobs and the varying exposure in any particular workplace. Despite these shortcomings, the information obtained by question- taires does discriminate between more exposed and less exposed ubjects. The evidence validating the questionnaire method is trongest for domestic exposure. In several studies, levels of cotinine m body fluids have varied with reported exposure to tobacco smoke at home (Greenberg et al. 1984; Wald and Ritchie 1984; Matsukura et al. 1984; Jarvis et al. 1984). In fact, residence with a smoker may identify a population that is more tolerant of ETS, and therefore more likely to be exposed outside the home. Evidence in support of this speculation is provided by a study of urinary cotinine levels in nonsmoking men in the United Kingdom (`Wald and Ritchie 1984). In this study, the men married to women who smoked reported a 34 greater duration of exposure outside the home than men married to women who did not smoke. Until accurate and inexpensive exposure markers are available for cumulative ETS exposure, the questionnaire approach will remain the simplest means of obtaining exposure information. It is, there fore, important to consider the misclassification that can be intro duced by using this indirect measure of exposure, In studies of the effect of ETS exposure, two types of misclassification are of concern: misclassification of current or former smokers as never smokers and misclassification of the extent of ETS exposure. Because active smoking has a greater effect on the lungs than exposure to ETS? the inclusion of active smokers within a larger group of nonsmokers may lead to the fmding of a significant effect on lung function, which is actually attributable to active smoking rather than to involuntary smoking. Misclassification of undeclared active smoking is a particularly important source of error in studies involving teenagers. Misclassification of smoking status is also of concern in casecontrol studies of the association between exposure to M`S and lung cancer. Information about smoking habits for these studies often comes from interviews with a surviving spouse or surrogate, who may have been a close family member, neighbor, or friend, or from a review of medical records. The smoking habits of the subject may he incorrectly reported. Classification of individuals who are current or former smokers as never smokers would lead to a spurious increase in the relative risk for lung cancer in nonsmokers exposed to ETS, because the smoking habits of spouses tend to be correlated. The extent of this bias in the case-control studies is uncertain. The proportion of people reported as never smokers, but who in fact did smoke in the past, is unknown. The proportion of current smokers who report themselves as nonsmokers can be estimated from studies using markers to validate questionnaires. Using biochemical markers of tobacco smoke ahsorption, the propor- tion would appear to he about 0.5 to 3 percent, depending on the population studied and the questionnaire used (Wald et al. 1981; Saloojee et al. 1982). Misclassification of the extent of ETS exposure can also occur, and may reduce the observed risk if a nonsmoking spouse of a smoker is not exposed to smoke at home. Friedman and colleagues (19831, reporting on a survey of 38,000 subjects, noted that 47 percent of nonsmoking women married to smokers reported that they were not exposed to tobacco smoke at home. Measurements of Absorption The difficulties inherent in estimating exposure and dose have provided the impetus for the development of biological markers for exposure to both MS and ETS. The marker that at present holds the 36 highest promise is cdhine, the mqjor metabolite of nicotine. Cotinine may he measured in saliva, blood, or urine. Numerous studies have demonstrated that there is good correlation between these measures of cotinine and the estimated exposure to tobacco smoke under laboratory conditions (Russell and Feyerabend 1975; HofEnann et al. 1984) and under conditions of daily life (Russell and Feyerabend 1975; Feyerabend et al. 1982; Foliart et al. 1983; Wald et al. 1984; Wald and Ritchie 1984; Jarvis et al. 1984; Matsukura et al. 1984; Greenberg et al. 1984). Cotinine is probably the best marker for tobacco smoke intake because it is highly sensitive and specitlc for t&acc~ smoke and because it can be detected both in active smokers and in individuals exposed to EX'S. Further details about cotinine and other markem are to be found in Chapter 4. Pohntiully Gmfounding Variables In any epidemiological study, the confounding factors must be considered and their effects controlled. Confounding refers to the bii effect of a factor that independently influences the risk for the disease of concern and is also associated with the exposure under evaluation. Confounding is of particular concern when the effects of the exposure of interest are expe&d to be small. The potential confounding variables depend on the health outcome of interest. For lung cancer, occupational exposures, diet, and exposure to other combustion products are of concern. For acute and chronic pulmonary effects, potential confounders include airways hyperresponsiveness, other indoor air pollutants, outdoor air pollu- tion, respiratory tract infections, occupational exposure, and socio economic status, which may potentially influence disease risk through its environmental correlau23. While this list is extensive, it may not be inclusive; in any single investigation it may not be possible to meesure and control all potentially confounding vti- able& In general, the evidence on active smoking in combination with the dosimetrp of involuntary smoking leads to the conclusion that the effecta of ETS on a population will be substantially less than the effecta of active smoking. The effects of E!R3 on infants and young children are an important exception. The association of E'IS with an adverse effect in an individual study may reflect bias, chance, or a causal relationship. Statistical signiticance testing is used to quantitate the role of chance; by convention, a p (probability) value less than 0.05 is deemed statisti- cally significant. A p value less than 0.05 means that the observed results would occur by chance less than 5 times out of 100, if there is 36 truly no association between ETS and the effect. The choice of 0.05 is arbitrary, and as the significance level declines, the probability that the observation could have occurred by chance lessens. For effects of small magnitude, as may he anticipated for some consequences of exposure to ETS, a large study population may be necessary to demonstrate statistical significance. The absence of statistical significance for an association may refled an inadequate sample sixe and is not always indicative of the absence of an association. In this regard, reports describing the absence of effects of ETS should provide the calculations needed to demonstrate the study's statistical power (ability to detect effects of the magnitude expected) or a confidence interval for the estimate of effect. An additional statistical issue is the directionality of statistical significance testing. Either one-sided or two-sided tests may he used, in the fmt, only effects in one direction are considered a possibility, whereas twosided tests consider the possibility of effects in opposing directions, i.e., increase or decrease of risk Given the strength of the evidence on active smoking and disease risk, one-sided testing in the direction of an adverse effect seems appropriate for most potential consequences of ETS. However, one-sided tests have not been performed in all investigations of ETS; the use of two-sided tests makes these studies conservative, as statistical significance will less often be attained. Respiratory System Effects of Involuntary Cigarette Smoke Exposure This section reviews the evidence on involuntary smoking and the adverse physiologic effects, respiratory symptoms, and respiratory diseases in nonsmoking adults and children. Health effects related to fetal exposure in utero from active smoking by the mother are not discussed. Lung growth and development may he influenced by in utero exposure, and the effects of such exposures have not been separated from those of exposure after birth. More complete treatments of this issue have heen published (US DHEW 1979; US DHHS 1980, Abel 1980; Weinberger and Weiss 1981). This section begins with a review of the data on infants and children who are exposed primarily through parental smoking. The health effects examin ed are increased respiratory illnesses, of both the upper and the lower respiratory tracts, increased chronic respiratory symptoms and illnesses, and alterations in lung growth and development. Studies of adults, whose exposures to environmen- tal tobacco smoke occur in a variety of settings, are examined with regard to symptoms and changes in measures of lung function. The potential for J3TS to produce bronchoconstriction in asthmatic and nonasthmatic subjects is also examined. 37 InfantsandChildren Acute Respimtory Illness Longitudinal Studies A number of studies, based on a variety of different designs, have examined the effects of involuntary smoking on the acute respira- tory illness experience of children (Table 1). Several different end points have been ev&&ed in these investigations: hospitalization for bronchitis or pneumonia as 888e88ed by hospital records (Harlap and Davies 1974; Rantakallio 1978); questionnaire assessment of hospitalization for bronchitis or pneumonia or of doctor's visits (Colley 1971; Leeder et al. 1976a) or both G'ergusson et al. 1981; Fergusson and Horwood 1985); questionnaire assessment of reapira- tory illness within the last year (Cameron et al. 1969; Schenker et al. 1983; Ware et al. 1984); chest illness before age 2 (Schenker et al. 1983); hospitalization for respiratory syncytial virus 0 infection (Sims et al. 1978; pullan and Hey 1982); physiciandiagnosed bronchitis, tracheitis, or laryngitis (Pedreira et al. 1985); and tonsillectomy as an indication of recurrent respiratory infection (Said et al. 1978). These diverse end points range from illnesses associated with a specific etiologic agent, e.g., RSV bronchiolitis, to clinician&agnosed syndromes, e.g., bronchitis of undetermined etiology. The possibility of reporting bias must be considered for the studies that have used questionnaires to measure iUness experience. In most of these studies, parents, usually the mother, have responded for the child and reported on the child's illness experience. Some investiga- tors have suggested that mothers with respiratory symptoms are more likely to report symptoms for their children and that stratifica- tion of subjects by the symptom status of their parents removes this element of recall bias (Lebowitz and Burrows 1976). Removal of symptomatic parents, however, may result in overcorrection for recall bias because cigarette smoking is associated with symptoms in the adult. This analytical strategy would not be expected to adjust for biased parental recall of early life events. Additionally, in all studies in which potential reporting bias was examined, control for parents' status reduced, but did not eliminate, associations of involuntary smoking with health -outcomes (Colley et al. 1974; Leeder et al. 1976a,,b; Schenker et al. 1983; Ware et al. 198.4). Further, the consistency of these studies, in spite of differing study populations and methods, weighs against bias as the sole explanation for the effect of involuntary smoke exposure. Harlap and Davies (1974) studied 10,672 births in Israel between 1965 ad 1968 and observed that infants, whose mothers, at a prenatal visit, reported that they smoked, had a 27.5 percent greater hospital admission rate for pneumonia and bronchitis than children 38 TABLE 1.-E&y childhood reepiratory illnew and involuntary c@arette smoking 0 l-10 11-m m+ C-Y' 2$4x birth& 1963-1966, fJt&hdm bItmdLiti/ 7.6 10.4 11.1 153 (1971) prhemo&tIrrtyeuoflifo 10.3 16.1 14.6 292 Fa=1.78 for a?m pumt maker RR=280 fbr two puwlt mllokam numberaEm&rwx l&d-rhdr TABLE ~-continued Study Saidetal. w78) 8ohenkeretalal. mfw Eht&b fihP Dlneu~ rata per 100 ckllnumb 3,920 children, ajpd lo-!20, -w ondhr 28.2 41.4 60.9 ~&~notobu France edem, geaiemlly before pmultmmkiDghmldt~rspac age6,Milldi&orof~ueult timediredb-~ mepimtoly tact infedion r wP== lo+ Y=- 4,071 children, eged 6-14, che6tiuaembeforeage2 6.7 7.9 11.6 Trend#forbothsirmrhMt united stata ChdUblW>SdQ%3iDptlCt 8.8 11.8 13.6 Ye= Parent- NOMIlWkGI chrmlt- camerolJ et al. w60) Leederetal US?Bp, b) am8 et al. (1978) 168 children, agmi M; Reepimtory iuners, rertricted 1.33 1.4 lllneumportednot~ parenta t&phone activity sad/or medical notclearhoymportbgbdult quationnaire, united stata conmllhllwhlutyeu ml&dtoohud -ludy 2J4!3 infant& born l96s- RR - 2.0 for Wants with two Not provided Puew mlponu bin unlikely, 1986, EngLand amokhg per&a el&cte-Torinfmltod -P-P-e- Rp&wIul~~not invutigatod Lcmgiw Btlldy 36 children, hcapitakad, Bonierline eipifhlt in- in Not pmided R8vblvndlioli~36 Noh6niCant&ctfor matelnalmlloking,6lwtye8rof colltro~ E&end ?? ???o?*?? o ? life emountemokedorabrfw RR=266 IYLm~ofMthncul~ c---M* TABLE l.-Continued lZd&dliO (1Qw Pullan and Hey ww l&t21 children of amoking sienifieant incream in Not `& FlUBpdiV8fOllOUUpddda motbera hapMid for rupiratory vidt4hoapi~dmtba l&322 children of ilhemduringfimt6yeamoflih uPbrsas&- n-king mothem RRz1.74 alldingwal~ FWmd Iaaei-w 190 children hooPitaliced, 8ignis~teffe!ctofmatemal Not prwidd c---M-b B8vinfectioQfh%tywIrof (Rk1.96) and ~&msJ (RR-1.62) life; 111 nonhonPi~ smoking at time of rtudo; -hb FwNd Eignaant maternal lrmobhg effectduringiintyenroflife (RR=l.M) F&&a et al. ww Nommokex hoker -- 1,144 infanta in prdintric 8ignibntincreer,inrupiratory Brolrchitis 71 109 l%dia~nothlimkdb pi-act& united 8tatu ibUDESunonp~O~ 21 40 eqmuwmaffactmfa childrcm 4 7 LV" tia of nonsmoking mothers. In addition, they demonstrated a dose- response relationship between the amount of maternal smoking and the number of hospital admissions for these conditions. The infants were classified by the mothers' prenatal smoking behavior and not by the mothers' smoking behavior during the first year of the child's life. Maternal smoking habits would probably have remained relatively stable across the short observation period. British. investigators (Colley et al. 1974) followed children born between 1963 and 1985 in London and also observed an increased frequency of bronchitis and pneumonia during the first year of life in the children of parents who smoked. This difference did not persist at 2 to 5 years of age. Tbis effect was independent of the parents' personal reports of winter morning phlegm and increased with the amount of smoking by parents. The annual incidence of bronchitis and pneumonia during the first year of life also increased with a greater number of siblings. This variable was not controlled in the original analysis, however, Leeder and colleagues (1976b) subse quently reported that, in this same cohort, a dose-response relation- ship with parental smoking persisted for bronchitis and pneumonia in the first year of life, after control for parental respiratory symptoms, the sex of the child, the number of siblings, and a history of respiratory illness in the siblings. Fergusson and colleagues (1981) studied 1,265 New Zealand children from birth to age 3. They demonstrated an increase in bronchitis and pneumonia and in lower respiratory illness during the first 2 years of life in children whose mothers smoked compared with child.ren whose mothers did not smoke. Correction for maternal age, family size, and socioeconomic status did not affect the relationship between the amount of maternal smoking and the rate of respiratory illness. The effect of maternal smoking declined with increasing age of the child. In a second report (Fergusson and Horwood 1985) the followup was extended to include the first 6 years of life. The results conf%rmed the initial fmdings. Maternal, but not paternal, smoking was associated with a statistically significant increase in lower respiratory illnesses during the first 2 years of life. However, after age 2 there was no signif?cant effect of maternal smoking on respiratory illness occur- rence. Rmbkdlio (1978) followed more than 3,696 children during the first 5 years of life; half of the children had mothers who smoked cigarettes during pregnancy and half did not. The children of mothers who smoked had a 70 percent greater chance of hmpi&- tion for a respiratory illness than the children of nonsmoking mothers. Pedreira and associates (1985) prospsctively studied 1,144 infants and their families in the greater Washington, DC., area. Mate& 42 smoking was associated with an excess frequency of acute bronchitis, tracheitis, and lary&tis, as diagnosed by the pediatricians caring for these families. Episodes of croup, pneumonia, and bronchiolitis were not increased by maternal smoking. A family history of chronic respiratory symptoms ~88 also associated with excess respiratory illness. Ware and coworkers (1984) studied more than 10,009 children in six American cities. Maternal cigarette smoking was associated with increased parental reporting of a doctordiagnosed respiratory illness before the age of 2 years and of an acute respiratory illness within the past year. The prevalence of positive questionnaire responses increased consistently with the current daily cigarette consumption of the mother; the d-response relationships were unchanged by adjustment for maternal symptoms and educational status. Cross-Sectional Studies Schenker and coworkers (1983) studied 4,071 children between the ages of 5 and 14 years in a cross-sectional study in Pennsylvania. Both chest illness in the past year and severe chest illness before age 2 were more frequently reported in nonsmoking children of parents who smoked. These investigators found that symptom and illness rates were higher in children of parents with respiratory symptoms. However, a significant effect of maternal smoking on these illness variables remained after adjustment for the parents' own respira- tory symptom history. In a study of 1,355 children between 6 and 12 years of age in the Iowa public schools, Ekwo and coworkers (1983) found that the presence in the home of at least one parent who smoked was significantly associated with reported hospitalization of the child for a respiratory illness during the first 2 years of life. As in other studies, the effect was stronger for maternal smoking than for paternal smoking. Case-Control Studies In England, Sims and colleagues (1978) examined 35 children at 8 years of age who had been hospitalized during infancy for RSV bronchiolitis and compared them with 35 control children of similar age. Maternal smoking was associated with a relative risk of 2.65 for hospitalization due to bronchiolitis. The sample size was small, and this effect of maternal smoking was not statistically significant. Pullan and Hey (1982) studied children who had been hospitalized with documented RSV infection in infancy. They found significantly greater smoking by their mothers at the time of the infection, compared with children hospitalized for other illnesses, including respiratory disease for which RSV infection was not documented. At 43 age 10, the children previously ill with RSV infection had an excess reported occurrence of wheeze and asthma and had lower levels of pulmonary function in comparison with the controls. The research- ers could not determine whether the RSV infection had caused persistent damage that affected the maturation of the lung or whether these children were already more susceptible to severe RSV infection because of pulmonary problems that antedated the RN infection. In summary, the results of these studies show excess acute respiratory illness in the children of parents who smoke, particularly in children under 2 years of age. This pattern is evident in studies conducted with different methodologies and in different locales. The increased risk of hospitalization for severe bronchitis or pneumonia associated with parental smoking ranges from 20 to 40 percent during the first year of life. Young children appear to represent a more susceptible population for the adverse effects of involuntary smoking than older children or adults. The timeactivity patterns of infants, which generally place them in proximity to their mothers, may lead to particularly high exposures to environmental tobacco smoke if the mother smokes. Acute respiratory illnesses during childhood may have long-term effects on lung growth and development, and might increase the susceptibility of the lung to the effects of active smoking and to the development of chronic obstructive lung disease (Samet et al. 1983; US DHHS 1984). Cough, Phlegm, and Wheezing A number of crossse&onal studies from different countries (Table 2) have shown a positive association between parental cigarette smoking and the prevalence of chronic cough and chronic phlegm ,in children; some studies have shown a relationship for persistent wheeze. However, not all studies have shown a positive relationship for all symptoms. The results of some of these studies may have been confounded by the child's own smoking habits (Colley et al. 1974, Bland et al. 1978; Kasuga et al. 1979). The association with parental smoking was not statistically &i&ant for all symptoms in all studies (Lebowits and Burrows 1976; Schilling et al. 1977; Schenker et al. 1983). However, the majority of studies showed an increase in symptom prevalence with an increase in the number of smoking parents in the home. A recent report (Charlton 1984) provides crosssectional data on parent-reported cough for 15,000 children, 8 to 19 years of age, in northern England. Chronic cough in the children was related to their age and to their own cigarette smoking status. However, with control of these factors by stratification, the number of parental smokers in the home was positively associated with the occurrence of chronic 44 TABLE Z.-Chronic respiratory symptoma in children in relation to involuntary smoke exposure Bates per 100 by numb8r of amoking parents Study SUhjfXbJ Beapiitory eymptonu or illness 0 1 2 c!ammellte Wley et al. (1974) 2,426 children, agfd 614, Chronic cough; quentionnaire blend completed by parent 16.6 17.1 22.2 Trend eignifican~ reportiog bina -pcmible result of parent symptoma or ecth smoking in children, ldikdYtOC!IpL3blflIU&CtOf trend Bland et al. W378) 3.106 children, awl 12-13, did not admit-te-ever emoking cigarettes., England Couah durina day or at nkht - . Morning oough 16.4 19.0 29.6 1.6 2.8 2.9 Croewectional study children's self-reported symphme end emoking hietory a&&d aimul~ual~ morning end daytime-&e&- different dimeen, could be difference in expoeure (expomre more likely awnke than deep) Crowaxtionel study, adju&d for cbild'e own smoking habita Wek et al. 8E4 children, aged 6-9, wm United States Chronic wugh end phlegm 1.7 2.1 3.4 Per&tent wheeze 1.8 6.8 11.8 Tread not rign&ant Tend significant Cmm-wtional study, edjueted for parental symptoms and child% ~WII SmOkiIlg Charkon aw 16,ooO children, eged S-19 yeara, E&and 40.0 46.0 66.0 TABLE 2.4htinued Study Subject.3 Wee per 100 by number of smoking parent-g Respiratory 6ymptoms or illness 0 1 2 Comment8 Dodge (1982) 628 children, grades 3-4, twwparent households; parent questionnaire response, United States Any wheeze 27.6 27.9 40.0 Phlegm 6.4 10.9 12.0 Cwxh 14.6 23.0 27.8 Au trends tdgnlfiwn~ some aFect might relate to po.renM Wm@moa but no trend influence !ik.ely &os-e&onal study Schenker et al. u9w Lehowitz and Burrowx (1976) SchiIllng et al. (1977) Kaeuga et al. (1979) 4,071 children, aged 6-14, United States 1,625 children, <16 yenm old, United States 816 children, age 7+, United States 1,937 children, aged 6-11, Jaw Chronic cough chronic phlegm Persistent wheeze Pereietent cough Pen&tent phlegm whesre couph, phMm, wheeze wheeze. asthma Trend not significant not austed for parental eymptome, although parental symptom effect dyr-ed Croeee&ional study Hiiher rates in symptomatic parent .houeebol&, trends persisted for asymptomatic households; no adjustment for child`e own smoking Cros+e&ional etudy Specific data not provided -ional study Adjust.4 for distance of home from main tratl-ic, highway cmee-sectional study Ekwo et al. (1983) 1,366 children, eged 6-12, United States Coughs with adds Wheeeing apart from c&3 6.2 1.0 8.3 4.1 4.8 4.0 1.2 7.7 6.4 Never Parent smoker . smoker 3.7 7.2 10.0 12.8 23.4 94.1 No swcant effect Increased prevalence in heavy smoker (>21 &/day) family less clear effect in light smoker (~21 c&z/day) family Odds ratios: 1.4 for smoker father, I.6 for smoker mother 2 if only Bnlpker mother Gasstmeuse measnrd not contded for; no con&tent doe+ ZEZtional study cough. The mother's smoking had a greater effect than the father's smoking. Burchfiel and colleagues (1986) have conducted a longitudinal study of 3,482 subjects from Tecumseh, Michigan. Subjects were initially between the ages of birth and 10 years and were followed up by questionnaire and examination 15 years after entry into the study. Age-specific incidence rates were calculated for a number of chronic respiratory symptoms, including cough, phlegm, wheeze, and bronchitis. Incidence rates for all symptoms were higher for children with two parental smokers when compared with children of non- smokers. Adjustment for potential confounding variables, including age, parental education, family size, and personal smoking, did not explain these results. British researchers &eeder et al. 1976b) studying a birth cohort over a 5-year period demonstrated an increased incidence of Nheez- ing among nonasthmatic children with two parents who smoked in comparison with children whose parents did not smoke, one parent who smoked, or parents whose smoking changed during the study (Leeder et al. 1976a). However, when this association was examined by logistic regression with control for. other factors, parental smoking was not a significant predictor of wheeze or of asthma. McConnochie and Roghmann (1984) performed a retrospective cohort study to examin e the influence of mild bronchitis in early childhood on wheezing symptoms 8 years later when the subjects had reached a mean age of 8.3 years. Involuntary smoking was a significant predictor of current wheezing (odds ratio 1.9). In a related study (McConnochie and Roghmann 1985) with these same children, involuntary smoking did not affect lower respiratory tract illness experience. In a study of 650 children aged 5 to 10 years (Weiss et al. 19801, a significant trend in the reported prevalence of chronic wheezing with current parental smoking was found; the rates were 1.9 percent, 6.9 percent, and 11.8 percent for children with zero, one, and two parents who smoked, respectively. Although the data given are for all households, when the analysis was restricted to those households where neither parent reported symptoms, the results were identical. The stability of the fmdings with this restriction suggests that reporting bias introduced by parental symptoms W&B not responsible for the observed results. Schenker and coworkers (1983) e xamined the influence of parental smoking and symptoms on the reporting of chronic respiratory symptoms of cough, phlegm, and persistent wheezing in children. These investigators found that the mothers were more likely than the fathers and symptomatic mothers were more likely than asymptomatic mothers to report these symptoms in their children. 47 Parental smoking had no significant effects on chronic respiratory symptoms. L&,,~z m,j BU~OWB (1976) assessed the effects of household mea=' smoking on respiratory 8ymptoms in 6% `hwm Chihhn younger b 15 y- of age. children from homes with current smoke= m higher symptom rates than those from homes with ex- smokers ad ee never smokers. However, the effect of household Bmow w w88 atistically significant only for persistent cough. h a general population s~u&, &hilling and ~lleagues (1977) reported no mhtion between wheeze and involuntary smoking. ware md ~i&,es (1984) enrolled 10,106 children between 6 and g Y- of we from six U.S. cities in a prospective study. The pmdene of persistent cough and persistent wheeze, measured at the second mtion, was higher in children whose parents smoked. `JJg effect was greater for maternal smoking than for paternal smoking. Symptom prevalence rates increased linearily tith the number of cigarettes smoked daily by the mother. In a multiple logistic model, the effect of maternal smoking persisted after adjustment for reported ilhess in the parents. Dodge (1982), studying third and fourth grade children in Arizona, found that symptoms, including wheeze, were related to both the presence of symptoms in the parents and the number of smokers in the household. In summary, children whose parents smoke had a 30 to 80 percent excess prevalence of chronic cough or phlegm compared with children of nonsmoking parents. For wheezing, the increase in risk varied from none to over sixfold among the studies reviewed. Many studies showed an exposurerelated increase in the percentage of children with reported chronic symptoms as the number of parental smokers in the home increased. Misclassification as nonsmokers of children who are actively smoking could bias the results of these studies. Adolescent 8mokers may be reluctant to accurately report their smoking habits, and more objective measures of exposure may not help to distinguish active experimentation with cigarettes from mvohmtary exposure to smoke Cl'ager 1986). Although miscla&fica- tion of children who are actively smoking as nonsmokers must be considered, many studies showing a positive association between P-nM smoldng amI symptoms in children, including children at 4P bdke f%#.ficant experimentation with cigarettes is prevalent. h addition, many 8tudies (Bland et al. 1978; Weiss et al. 1980; Chm-hn 19% Schenker et al. 1983, Dodge 1982; Burchfiel et al. 19%) found significant effects of parental smoking after ~~ide~g active smoking by the children. chronic resPbtorY symptoms represent an immediate health h&n for the child. However, the long-term simlcance of chrodc r@PhtorY sYmPbmS for the health of the child is unclear. &et 48 available data are cross-sectional, and followup studies of chroticdy symptomatic children are necessaq to determine the long-term health consequences of chronic respiratory symptoms. In recent YW, the effect of parental cigare&e smokjng on pulmonary function in children has been examined in crossgedional studies (Table 3) and a few longitudinal studies. The crmonal studies have demonstrated lower values on tests of pulmonary function (FEV75z, LEVI, FEFLJMS, and flows at low lung volumes) in children of mothers who smoked compared with cmdren of non- smoking mothers. The longitudinal studies (Table 4) have confirmed the cross-sectional results and provide some insight into the imp&+ tions of the cross-sectional data. Dose-response relationships have been found in both cross-se&on- al and longitudinal studies Stager et al. 1979; Weiss et al. 1980; Ware et al. 1964; Berkey et al. 1986); the level of function decreases with an increasing number of smokers in the home. As would be anticipated from the mother's greater contact time with the child, maternal smoking tends to have a greater impact than pa&Id smoking. Younger children seem to experience greater effects than older children (Tager et al. 1979; Weiss et al. 1960), and in older children the effects of personal smoking may be additive with those of involuntary smoking (Tager et al. 1979,1985). As noted by Tager (1986), the effect of maternal smoking on lung function may vary with the child's sex. Some studies have reported greater effects on flows at lower lung volumes in girls than in boys (Burchfiel et al. 1986; Tashkin et al. 19% Yamell and St. Leger 1979; Veda.l et al. 1964). Flows at higher lung volumes seem more affected in boys (Burchfiel et al. 1986, Yarnell and St. Leger 1979; F&-key et al. 1986; Tad&in et al. 1964). Whether these sex effects represent differences in exposure, differences in susceptibility to environmental cigarette smoke, or differences in growth and devel- opment is unclear. Tager and colleagues (1983) followed 1,156 children for 7 years to determine the effect of maternal smoking on the growth of PRO- nary function in children (Figure 2). After correcting for previous level of FEVI, age, height, personal cigarette smoking, and correla- tion between mother's and child's pulmonary function level, mater- nal smoking was associated with a reduced annual increase in F'EVI and FEFs75, using two separate methods of analysis. If the effect of ma&d smoking is maintained to 20 years of age, then a 3 to 5 percent reduction of FEV, and FEFz+75 due to maternal Smoking would be projected. The validity of this PrOjeCtion remains to be &&h&ed. Because few mothers changed their smoking habits, the 49 TABLE 3.-~uhonary ~UC&~UI in CII.WEW exposed to involuntary smoking Study Subjecta SchiIling et al. (1977) 816 children, aged 7-17, Comwcticut and South ceroh united statm FEV, 88 percent pITdictA No e!Tect of parental amokin No control for db&ip ab Or comlntion of eihliug pllmoaur function; for dludren who nevw enlow vwu60 elgdamtly lean in cbikhn with!Jmokhglnotbm T-r et al. om w&u et al. a9w Vddetd. (lgw Lebowlte end BIllTowS (ls7s) 444 children, e&fed 619, 3ht Bcmfml, Massaehusetb, united state &5ochudren,aged~,Eeet Boston, Memlechueetb, united state6 r,oca children, aged MS, united stake 371 houoehol&, complete hietnriee of parent Emokiug and pulmonery flmctlon of children, age >6, Tucson, Ak-hna. united ststa MMEF in etadad deviation units MMEF in etandard deviation unite m,, Fvc, vmuKJl vcdm VUdO FBV,, Fvc, o,, vmu7s derivedfromM?dEPVcune8, ea etaderd deviation units signll~t effect of parental Ml2Oki43 slgnifimt effect of parental ~Okhg FVC poaitivcly emocietedl flown negatively omocieti Noeffectofpnmbdemoking c!mtmued for oitahip aim and cadetion of sibling pulmowy fll&iOll controlled for nibobip aim and -htiOlOf&UBgpllmoovy function FlowBdaab-raporuewlth emountarnokedbymother chggahioa: may bs d dlfferenm in hdonr leveb of rlspa_mcomprsdwithmors no*rly climebe L8bmitz et al. (1982) 339 childreb Tuaon, Arimm, united stat83 FEV,, I acorn No effect of pan&al wnokhg Higher lweb of puhoaaq flulctlon for 4Thikhn of tmokiqparenbtbanforna- emokeexpwalchudren TABLE t.-Continud subjocte Pulmonery function meanued Outcome 668 chilhll, aged 8-10, Arir.om united St.&n No effect of parental smoking PotenW pnrticipation rate bias;cram+e&onaldatanot corkroIled for child hei& allmud FEx,/lP at e 8, 9, and 11 oonsietently gxater in nonomoking houoehobio tblm hreperent smoker hou&o@ 0tatica.I tast not lligdbnt lil&khetal. ww Chen and Li wm Haaeelblad et al. (1981). 1,080 noMmoking, nonasthmatic children, Lctl Al&e& united stateu 671 children, aged 6-16, chine 16,689 children, aged 5-17, eeven geqinphic regione, u0it.d state3 L, Vmu7~ Vd FE&e-7s FEV, snd MMEF FEV, 88 percent pwdkted Delmamd0~,0~forboys, Noeffe&ofp&malemoking and FJZFrm, k,m,a for &la with mnoking mother at led Slltly decremd FEV, Adjuoted for child's own fC4dMMEFiIlChUdWSl@XpOOd smotiae~gas~~ to peteal cigarette Emoke w-d v-mm Significant effect of mE4ternal Largenmnherofchihiren but not paternal smoking exchdedforinvdidpuImonq tiuxtion data or mieoing porental omoking data Speizer et al. ww Lehowitz ww Ekwo et al. (1983) 8,120 children, eged 6-10, oix U.S. cltlm 117 femiliea, Tucaon, Arlmw united stat&i 1,266 chuhn, eged 6-12, Iowe City, low4 unitad SW40 FVC end FEV, en percent predicted FVC end FFW, FEV,, Fvc No effect for FEV, or PVC No effect of parental smoking No e.ffect of parental emoking Recent anelyeie demon&eted en effezt for FVC end FEV, Almemeaxd,lWendcaone rat&3hedIittIeeffect Data for thin outcome not epeciflallly enal- innasal blmchid reepfmlllvene4o emong imokm children Spineci et al. 2,386 echoolchildren, Turin, usw Italr statistialuy aigniiamt effect of metemel omoking No pemlve emoking effect diffemna betmen boyo and l&b c TABLE 4.-Pulmonary function in cm&n exposed to involuntary smoking; longitudina\ ddies Study Subjecta Pulmonary funOti0n mOamld Outcame c!ommenta `l&r et al. u9w 1,166 children, aged 6-10 at lnltial mvey, Enat Boston, Mamachuaetta, United St&M FEW,, FEFow Sicantly decreasai FEW, and FJ!Tws growth rate for chUdren of emoking mothem `I-year followup; no eff$=-t of paternal amok&; magnitude roughIy 4 to 6 Pemnt ware et al. 10,000 children, aged 8-11, ww six U.S. cities WC, ml WC poeitively aooociaw with smoking; FEV, ne&ively amociated with omoke expooure FEV, dose-response with amount omoked hy mother; magnitude of e&ct estimate 6 prant Berkey et al. mw 7,834 children, agad 610, six U.S. cities WC, FEV, Slightly higher FVC level, slightly lower FXV, level in omcbexposed; gmwth of both decreased by smoke expomue coneistent with 3 penxlt de&it in FEV, growth Burchfiel et al. (l=w 3,432 children, aged MO, Tecumeeh, Michigan, United Statee WC, FEV,, vrrdn FEV, level and growth decread by maternal smoking Dwe-reuponoe in maIe chlhimn with nuder of parental omokem LOwmt20% Mile go% Highest20% Dialibution Of syear mean FN, FIGURE 2.-Percenwe of children with mothers who were current cigarette smokers at initial examination (black columns) and sixth examination (white columns), according to distribution of mean age, height, and sex- corrected FEV, over the firat six examinations N(rPE:~20W,middle60%,andhiehat20%nefertoEhildraaarithvllluainthe~ollati(th,middla tliltxrfiftho, and upper onbflfth, rssp&vely. of the - FEY, diotributio~ nlmlbBnl in parentheua todioate number of children in each gmup; the three circlen rap&went the BVeraga pbresnt pImdh?d value4 of FEW, for the the group; remlta for male and famals children were combined, because difference t&mm - vu not signifmt. SOURCE: !hget et al. w33). study could not establish the ages at which children were most vulnerable to exposure to tobacco smoke. Ware and colleagues (1964) followed 10,106 white children for two successive annual examin ations as part of the Harvard Air Pollution Health Study in six U.S. cities. The forced vital capacity was significantly higher for children of mothers who were either current smokers or ex-smokers. However, children whose mothers were current smokers had a 0.6 percent lower mean FEVl at the first examination and 0.9 percent lower mean F'EVl at the second examination. Maternal smoking had a greater effect than paternal smoking, although the effects of both were sign&ant. The changes in level of FEYI observed were small. For exposure to a mother who smoked one pack of cigarettes per day, the FEVl was estimated to be decreased by less than 1 percent, or 10 to 20 mL for a child with an F'EVl between 1.5 and 2.5 liters. Projecting the effect cumulatively to age 20 yields an approximately 3 percent deficit. This effect is comparable to that observed by Tager and colleagues (1963). These small average effects may underestimate the effects on populations of susceptible children. 53 A mom e&hve analysis of longitudinal data from the Harvard cohort wm performed using a mathematical model to describe lung growth (Be&y et al. 1966). This ~IM&B~S included 7,834 Children beben 6 & 10 year6 of age who were evaluated from two to five hm over a ~-year period. The model estimated that a smoke expOeed child at age 8 would have an FE571 0.81 percent lower than a non-emokeexpoa3ed child, and growth of FEVI would be 0.17 percent lower per year. ~0th effects were statistidy significant. For ~I.I 8 yw& child tith an F'EVl of 1.62 liters, these result-8 translate into a deficit of 13 J.UL in FEVI and of 3 mL in annual increase in MI. `&e magnitude of the maternal smoking effect is consistent with a de&it in J?EVl of 2.8 percent in naturally attained growth, if the effect, ia sustained throughout ~hildhd. Burchfiel and colleagues (1966) have conducted a longitudinal study of 3,462 children observed over a E-year period in Tecumseh, &.&h&an. The mean increase in FXVI for nonsmoking boys between the ages of 10 and 19 years was 82.3, 76.2, and 74.5 mL per year for subjects with zero, one, and two smoking parents, respectively. Boys with one parent who smoked experienced 92.6 percent and boys with two parents who smoked experienced 90.5 percent of the growth in FEVl seen in male children with nonsmoking parents. EXfecta of parental smoking were not found in girls. The available data demonstrate that maternal smoking reduces lung function in young children. However, the absolute magnitude of the difference in lung function is tnnall on average. A Emall reduction of function, on the order of 1 to 5 percent of predicted value, would not be expected to have functional consequences. However, some children may be affected to a greater extent, and even small differences might be important for children who become active cigarette smokers as adults. A minority of adult cigarette smokers develop chronic obstructive lung disease, and factors influencing lung growth and development during childhood might predispose to disease in adulthood (Samet et al. 1983; Speizer and Tager 1979). In Figure 3 is depicted a model of growth and decline in pulmonary function from childhood through adulthood, as measured by the F'EXl. Pulmonary function peaks in early adult life and declines steadily thereafter in both smokers (curve B) and nonsmokers (curve A). In people who develop chronic lung disease (curve CL a more rapid decline has occurred. Childhood factors could predispose to the development of disease by reducing the functional level at which decline begins tjr by increasing SusCePtibfitV to cigarette smoke and increasing the rate of d-be. Thus, in this model, small decrements in the ' Ily atwed led Of PuhnOnary function may be important in identifying &e susceptible smoker. However, the prerequisite longitudinal stu&es needed to test this hypothesis have not yet been conducted, FEV, as percent of value at age 2h25 I I I L 5 10 15 20 30 40 50 90 70 50 Age (uem) FIGURE 3.-Theoretical curves representing varying rates of change in FJSV, by age SOURCE: SpeLer and Tager (1979). Bronchoconstriction Nonspecific bronchial responsiveness has been considered a poten- tial risk factor for the development of chronic obstructive lung disease in both adults and children (US DHHS 1984). This physiolog- ic trait may be influenced by environmental exposures such as involuntary smoking by children and active smoking by adults, and by respiratory infections at all ages. Asthma is a chronic disease characterized by bronchial hyperre sponsiveness. Epidemiologic studies of children have shown no consistent relationship between the report of a doctor's diagnosis of asthma and exposure to involuntary smoking. Although one study showed an association between involuntary smoking and asthma (Gortmaker et al. 1982), others have not (Schenker et al. 1983; Horwood et al. 1985). This variability may reflect differing ages of the children studied, differing exposures, or uncontrolled bias. In several recent studies (Murray and Morrison 1986; O'Connor et al. 55 1986, web et al. 1985; Martinez et al. 198% Ekwo et al. 19831, noMpecific broncm responsiveness Was examined in relationship b ~voluntary smoking. The results of these ytusm .sugge"t that exposure b matid cigarette smoking b assocmted mth increased noMpecific wap req&ven~. Some ,repo* suggest that the hm respoevena is present only m chi&+% kWWn to be w-tic (Murray and Morrison 1986; o'~nnOr et al. 1986), whereas othm sw~ that the increased respo~iveness is seen in 4 cmw (~kw~ et al. 1983; Martinez et al. 1985). The pathophysi- ological magi underlying the increased responsiveness and the lowm~m consequences of the increased responsiveness remain horn. m s&ion reviews the studies on asthma and on bronchial hyperresponsiven~. &rtln&er amj coworkers (1982) studied the relationship between paren~ ~&ing and the prevalence of asthma in children up to 17 ;years of age. Random community-based populations in Michigan (3,072 &U.ren) and Massachusetts (894 children) were surveyed. parents reported on their own smoking habits a&l on the asthma histories of t&r children. Biased reporting by parents who smoked ~88 d by e=mimng the relationship between parena smoking and other conditions, and considered not to be present. A&IM prevakmce declines with age, and asthmatic children are unlikely to tolerate active smoking; therefore, misclassification of activelp smoking asthmatic children ss nonsmokers seems unlikely. In comparison with children of nonsmokers, children whose parents smoked were more likely to have asthma (relative risks of 1.5 and 1.8 for Michigan and Massachusetts children, respectively) and sevely! asthma (relative risks of 2.0 and 2.4, respectively). The investigators estimated that between 18 and 23 percent of all childhood asthma and 28 and 34 percent of severe childhood asthma is attributable to exposure to maternal cigarette smoke. Schenker and coworkers (1983) studied 4,071 children between 5 and 15 years of age in western Pennsylvania. These investigators found no relationship of parental smoking to the occurrence of asthma, after adjustment for potential confounding factors. Horwood and coworkers (1985) conducted a cohort study of 1,058 children in New Zealand who were followed from birth to age 6 ye- A fdy history of allergy and male sex were the ody significant predictors of incident cases of asthma. Neither parental smoking nor respiratory illnesses were predictive of the occurrence Of asthma in this investigation. A recently reported cross-sectional study by Murray and Morrison (1986) suggests a mechanism by which maternal cigarette smoking might influence the severity of childhood asthma. These mvestiga- h-s StUdkd 94 children, aged 7 to 17 years, with a history of asthma. The children of mothers who smoked had 47 percent more symp- 56 41 2- 1 - 0.5 - 0.25 - 0.125 - 0.06 - 0.03 - 049 Nonsmoker smoker 00 0 0 0 %I? 0 p=o.o02 FIGURE 4.-P% in two groupa of children with a history toms, a 13 percent lower FEYI, and a 23 percent lower FEFws than the children of nonsmoking mothers. Forty-one children, who had been able to discontinue medication and had no recent respiratory illness, underwent a histamine challenge test. There was a fourfold greater responsiveness to hi&amine among the asthmatic children of mothers who smoked (Figure 4) compared with asthmatic children of nonsmoking mothers. Dose-response relationships were present for all outcome variables in this study: symptoms, pulmonary function, and airways responsiveness. The differences between children of smoking mothers and children of nonsmoking mothers were greatest in the older children. The father's smoking behavior did not influence the child's asthma severity. The sample of asthmatic children with mothers who smoked was small (N = lo), and only 41 of 96 children had histamine challenge tests. Given the heterogeneity of asthma, the variable nature of bronchial hyperreactivity in asthma, and the potential for biased selection, these results must be interpreted with caution. O'Connor and coworkers (1986) studied 286 children and young adults, 6 to 21 years of age, drawn from a community-based sample, 57 and confirmed the findings of Murray and Morrison (1986). Bronchi- al responsiveness was measured with eucapneic hyperpnea to subfreezing air. Among the 265 subjects without asthma there was no significant relationship between maternal cigarette smoking and nonspecific bronchial responsiveness. However, in the 21 subjects 6th adive asthma, maternal smoking was significantly associated with increased levels of bronchial responsiveness. In a study of 1,355 children 6 to 12 years of age, significant increases in FEW and FF,F25-7s were observed following isoproterenol administration in children whose parents smoked (E~wo et al. 1983). Increases after isoproterenol were not observed in children of nonsmoking parents. Weiss and coworkers (1985) evaluated 194 subjects between the ages of 12 and 16 drawn from the same population as those reported by O'Connor and coworkers (1986), with eucapneic hyperpnea to subfreezing air as a test for bronchial responsiveness and allergy skin tests as a test for atopy. Subjects defmed as atopic (any skin test wheal greater than or equal to 5 mm) had twice the frequency of lower respiratory illnesses in early childhood and were twice as likely to have a mother who smoked. However, there was no relationship between maternal smoking and increased bronchial responsiveness. Martinez and associates (1985) studied 170 9-yearold children in Italy. Nonspecific bronchial responsiveness to methacholine and allergy prick test positivity in these subjects was significantly associated with maternal cigarette smoking. These data suggest that maternal cigarette smoking may influence the severity of asthma; a mechanism for this effect may be through alteration of nonspecific bronchial responsiveness. Further investi- gation is needed to determine whether exposure to environmental cigarette smoke can induce asthma in children and whether ETS exposure increases the frequency or severity of attacks of broncho- constriction in asthmatics. The effect of involuntary smoking on increased bronchial responsiveness in asthmatics and in norm&h- matics has only recently been addressed. These initial data are provocative, but the magnitude of the effect, the target population at risk, the underlying mechanisms, and the long-term consequences have not been described. Furthermore, the complex interrelation- sops ==`u3 respiratory illness, atopy, parental smoking, and tin-w responsiveness have not been clarified and require further study. Ear, Nose, and Thmat Five studies (Said et al. 1978; Iverson et al. 1985; Kraemer et al. 1983; Black 1985; Pukander et al. 1985) show an excess of chronic 58 middle ear effusions and d&eases in children exposed to parental smoke. Said and colleagues (1978) questioned 3,920 children between IO and 20 years of age about prior tonsillectomy or adenoidectomy, considered an index of frequent upper respiratory or ear infections. The investigators reported that, in general, this surgery was performed before the children were 5 years old. The prevalence of prior surgery ~INXMS~ with the number of currently smoking parents in the home. Iverson and coworkers (1985) prospectively studied 337 children enrolled in all day-care institutions in a municipality over a 3month petid to evaluate the importance of involuntary smoking for middle ear effusion in children. Middle ear effusion was assessed with tympanometry, and the overall prevalence was found to be approxi- matsly 23 percent. Although various indoor environmental factors were assessed in this investigation, only parental smoking was significantly associated with middle ear effusion. The effect of parental smoking persisted with control for the number of siblings. The overall age-adjusted odds ratio was 1.6' (95 percent confidence interval 1.0-2.6). In 5- to 7-year-old children, 10 to 36 percent of all chronic middle ear effusions could thus be attributed to smoking on the basis of these results. Kraemer and coworkers (1983) performed a cas+control study of 76 children to examin e the relationship of environmental tobacco smoke exposure to the occurrence of persistent middle ear effusions. Frequent ear infections, nasal congestion, environmental tobacco smoke exposure, and atopy were all more frequent in children with ear effusions. The effect of involuntary smoking was observed only if nasal congestion was present, and was greatest in children who were atopic. Black (1985) performed a case-control study of glue ear with 150 cases and 300 controls. Parental smoking was associated with a relative risk of 1.64 (95 percent C.I. 1.03-2.61) for glue ear. In Finland, Pukander and coworkers (1985) conducted a mntrol study of 264 2 to 3-year-old children with acute otitis media and 207 control children and found an association between parental smoking and this acute illness. These studies are consistent in their demonstration of excess chronic middle ear effusions, a sign of chronic ear disease, in children exposed to parental cigarette smoke. Potential confounding factors for middle ear effusions should be examined carefully in future studies. The long-term implications of the excess middle ear problems deserve further study. 59 Acute Reqimtory Illness There are no studies of acute respiratory illness experience in adulta exposed to environmental cigarette smoke. cbugh, Phlegm, and wheezing Few studies have addressed the relationship of chronic respiratory symptoms in nonsmoking adults with environmental tobacco smoke exposure. Schilling and colleagues (1977) found that symptoms in adult men and women were related to personal smoking habits and that the occurrence of cough, phlegm, or wheeze in nonsmokers was not related to the smoking habits of their spouses. Schenker and colleagues (1982) confirmed these results in a telephone survey of 5,000 adult women in western Pennsylvania. White and Froeb (1980) reported on 2,100 asymptomatic adults drawn from a population enrolled in a physical fitness program (Table 5). They reported statistically significant decreases in FEVl and maximum midexpiratory flow rate 0 as a percent of predicted in nonsmokers exposed to tobacco smoke in the work environment for at least 20 years compared with nonsmoking workers not exposed. The magnitude of effect was comparable to that of actively smoking 1 to 10 cigarettes per day. However, the absolute magnitude of the difference in mean levels of function between the smokeexpoeed group and the unexposed group was smalh 160 mL (5.5 percent) for FEW1 and 465 I& per second (13.5 percent) for MMEF. Carbon monoxide levels were measured in selected work- places and ranged from 3.1 to 25.8 ppm. The study population was se&selected, and the exposure classification was crude and did not account for people who changed jobs. It is unclear how the ex- smokers in the population were handled in the analysis. Kentner and coworkers (1984) performed a cross+ectionai investigation on 1,351 workers and found no influence of involuntary smoking on pulmonary function. In this study, involuntary smoking at home and at work was considered. Comstock and colleagues (1981) examined 1,724 subjects drawn from two separate studies in Washington County, Maryland. Male and female nonsmokers married to smokers did not have a sign& CaMJy increased risk of having an FEWI less than 80 percent of Predicted or an F'EJVAWC ratio less than 70 percent. Schilling and colleagues (1977) also did not find an effect of involuntary smoking in adults. Effects were not examined within strata defined by age in either of these studies. 60 TABLE S.-Pulmonary function in adults exposed to involuntary smoking Study Subjecta Pulmonary function measured Outcome Comments White end Froeb 2,100 adults, Sen Diego, (1980) California, United States Fvc, FBV,, end MhfF m percent predictcd significant effect of office exposure to involuntary smoke Potential e&&ion biaq only current c@rette emoke expceure & treatment of exsmokere unclear Comtwk et al. a9811 1,724 adulte, Washington County, Maryland United St&S FEV, 88 percent predicted No effect of wives' smoking on hueband's pulmonary function Includea edulte eged 20+ cmeweetional etudy Kauffmann et al. mw 7,818 adulta, mlectd subgroups, seven cities, Frence FFW,, FVC, end MMEF All meeauw signiEcant effect in wives of smoking husbands; only MMEF signGent in husbands of smoking wives Not height edjw dear- reeponmtoamolmtof husbands' smoking for MMEF in wivce; no effect below age 40 Brunekreef et al. w-w Kentner et al. (1984) 173 adult.% subaroupe of larger study, the - Netherlands 1,851 adult of&e workers, Germany Peak flow. in8Diratorv vital Significant effect in wives of smoking huebenda for peak flow FEW, cmmsctionally; no effect longitudinelly NO effect of work exposure on pulmonery function Chmectionel study Smell sample .3&e thmectional .&udy Kauffmann and colleagues (1983) suggested that the effects of exposure from a spouse who smoked may be manifest only after many years of exposure. These investigators asses& the effects of marriage to a smoker in 7,818 adults drawn from several cities in France. Among 1,985 nonsmoking women aged 25 to 59,58 percent of whom had husbands who smoked, the level of MMEF was significantly reduced in women married to smokers compared with women married to nonsmokers; this effect did not become apparent until age 40. The reduction was small, on average. Recently, studying another population, KaufXnann and colleagues (1986) suggd,ed that the FEWI/FVC ratio may be a more sensitive test for detecting differences between exposed and nonexpoeed subjects, particularly in those with symptoms of wheexing; however, this suggestion has not been evaluated in other populations. Rrunekreef and coworkers (1985), from the Netherlands, reported on 173 nonsmoking women who were participants in a larger longitudinal study of pulmonary function. The women were classi- fied by whether they were or were not exposed to tobacco smoke at study onset or at followup. Cross-sectionally, significant differences in pulmonary function were observed between smoke-expoeed and nonexposed women. However, the rate of decline of lung function king the followup period was not affected by tobacco smoke exposure in the home. This study had a small number of subjects and inadequate statistical power to detect effects of exposure on rate of decline that were not extremely large. Jones and colleagues (1983) selected women with either high or low FEVs from a population-based longitudinal study in Tecumseh, Michigan. Exposure to cigarette smoke at home from husbands who smoked was not significantly different in the two groups of women. Nonsmoking men who participated in the Multiple Risk Factor Intervention Trial had significantly lower levels of pulmonary function if their wives smoked in comparison with similar men whose wives did not smoke (Svendsen et al. 1985). The physiologic and clinical significance of the small changes in pulmonary function found in some studies of adults remains to be determined. The small magnitude of effect implies that a previously healthy individual would not develop chronic lung disease solely on the basis of involuntary tobacco smoke exposure in adult life. Whether particular characteristics increase susceptibility, such as Childhood exposures or illnesses, atopy, reduced pulmonary function from whatever cause, and increased airways responsiveness, rema,fns unknown. These sndl changes may also be markers of an irritant response, possibly transient, to the irritants known to be present in environmental tobacco smoke. 62 Bronchoconstriction Normal Subjects Only limited data have been published on the acute effects of inhalation of environmental tobacco smoke on pulmonary function in normal subjects (Table 6) and none on bronchial responsiveness. The available data have been obtained in exposure chambers under carefully monitored and controlled circumstances (Pimm et al. 1978; Shephard et al. 1979; Dahms et al. 1981). Pimm and colleagues (1978) exposed nonsmoking adults to smoke in an exposure chamber. Relatively constant levels of carbon monoxide (approximately 24 ppm) were achieved in the chamber during involuntary smoking. Peak blood carboxyhemoglobin levels were always less than 1 percent in these subjects before smoke exposure, but were significantly greater after the study exposure, Lung volumes, flow volume curves, and heart rates were measured for all subjects. Measurements were made at rest and following exercise under control and smoke-exposure conditions. Flow at 25 percent of the vital capacity was reduced at rest in men and with exercise in women. Although statistically significant, the magnitude of the change was small: a 7 percent decrease in flow in men and 14 percent in women. Shephard and coworkers (1979) utilized a similar cross-over design in a chamber of exactly the same size as that used by Pimm and associates. Their results were similar, with a small (3 to 4 percent) decrease in FVC, FEVI, Vti, and Vma~26. They concluded that these changes were of the magnitude anticipated from exposure to the smoke of less than one-half of a cigarette in 2 hours (the exposure anticipated for an involuntary smoker). Dahms and colleagues (1981) used a slightly larger chamber and an exposure with an estimated peak carbon monoxide level of approximately 20 parts per million. They found no change in FVC, FEVl, or FEFs76 in normal subjects after 1 hour of exposure. The active smoker manifests acute responses to the inhalation of cigarette smoke; thus, highdose involuntary exposure to tobacco smoke may plausibly induce similar responses in nonsmokers. The magnitude of these changes is quite small, even at moderate to high exposure levels, and it is unlikely that this change in airflow, per se, results in symptoms. Asthmatics Dahms and colleagues (1981) exposed 10 patients with bronchial asthma and 10 normal subjects to cigarette smoke in an environmen- tal chamber. Pulmonary function was measured at 15-minute intervals for 1 hour after smoke exposure. Blood carboxyhemoglobin levels were measured before and after the l-hour exposure. The 63 2 TABLE 6.-Acute effects on pulmonary function of passive exposure to cigarette smoke; normal subjects Study Type of expceure Magnitude of expmure Effecta Comments Pimm et al. (1978) Chamber 14.6 In, furniture sparse, smoking machine in mm Peak [Co] - 24 ppm; particulatea >4 mgfni' Men: 6% increaee PVC, 11% increnee RV, 4% decrease 0 m.zm during exercise Women: 7% decreaee V- after exercise; no effects on vc, TLC, PVC, FEW,., v,, No-km; timage age, men 22.7, *omen 21.9; eham expomm ax control Shepherd et al. ww Dahma et al. ww A0 above Chamber SO m, climate controlled Low exposure: peak [CD] - 20 ppm, particulate8 - mg/m'; high expowe: [Co] - 31 ppm Room levels not meanured; e&mated at peak [CO] - 20 wm Low exposure: 3% decmaee FEW,, 4% decrease vm 6% decrease V- with exerch no increaeed effect with high =poeu~ 0.9% increaee in Fvc, 6.2% increaw in m,, 2.2% llmenee in F+EF at 1 hour Nonmokem: average age, men 23, women 25; sham expoeure en control; iubjwt eatiited inhalation - l/2 cigar&e!2 how 10 nonsmokera; a2e range 24- 63 yenm; not blinded; no aham expmure carboxyhemoglobin levels in subjects with asthma increased from 0.82 to 1.20 percent. In normal subjects the increase was from 0.62 to 1.05 percent. The increases in carboxyhemoglobin in the two study groups were not significantly different. Asthmatic subjects had a decrease in forced vital capacity @`VC), FEVI, and MMEF to a level significantly different from their preexposure values. The decreases in asthmatic subjects were present at 15 minutes, but worsened over the course of the hour to approximately 75 percent of the preexpo sure values. Normal subjects had no change in pulmonary fundion with this level of exposure. In this study, subjects were not blinded as to the exposure and were selected because of complaints about smoke sensitivity. Shephard and colleagues (1979), in a very similar experiment, subjected 14 asthmatics to a Zhour cigarette smoke exposure in a closed room (14.6 ms). The carbon monoxide levels (24 ppm) were similar to those predicted in the study of Dahms and coworkers (1981). Blood carboxyhemoglobin levels were not measured. Subjects were randomized and blinded to sham (no smoke) and smoke exposure and tested on two separate occasions. Data were expressed as the percentage change from the sham exposure. Signi&ant changes in FVC and FEYI were not observed between the sham and the smoke exposure periods, although 5 of 12 subjects did report wheezing or tightness in the chest on the day of smoke exposure. Wiedemann and associates (1986) examined nonspecific bronchial responsiveness to methacholine in 9 asthmatic subjects and 14 controls and the effect of acute involuntary smoking on nonspecific bronchial responsiveness. At the time of the study, all asthmatics were stable with normal or near normal pulmonary function. The subjects underwent baseline pulmonary function and methacholine challenge testing. On a separate day they were exposed to cigarette smoke for 1 hour at 40 to 50 ppm of carbon monoxide and underwent pulmonary function and methacholine challenge testing. J?uhnonary function was not influenced by exposure. Nonspecific bronchial responsiveness decreased significantly, rather than increasing, as would be anticipated following an irritant exposure. Acute exposure in a chamber may not adequately represent exposure in the general environment. Biases in observation and the in selection of subjects and the subjects' own expectations may account for the widely divergent results. Studies of large numbers of individuals with measurement of the relevant physiologic and exposure parameters will be necessary to adequately address the effects of environmental tobacco smoke exposure on asthmatics. Ear, Nose, and Throat There are no studies of chronic ear, nose, and throat symptoms in adults with involuntary smoking exposure. 65 Lung Cancer This se&ion reviews the epidemiological evidence on invohmtary smoking and lung cancer in nonsmokers, which has been derived from retrospective and prospective epidemiological studies. First, common methodological issues that apply to all these Studies are considered. Second, for each type of study design, individual studies are reviewed for their methodological approach (Tables 7 and 81, findings associated with tobacco smoke exposure (Table 9, Figure 5), and strengths and limitations. Third, the lung cancer risk associated with involuntary smoking is e xamined as a low-dose exposure to cigarette smoke by combining the d-response relationships for active smoking with the exposure data for involuntary smoking to predict the expected lung cancer risk due to involuntary smoking. This expxted risk is then compared with the actual risks observed in studies of involuntary smoking. Finally, the existing epidemiologicsl evidence is summarized and the plausibility of the association between lung cancer and involuntary smoking is evaluated on the basis of our current knowledge. ObfBNd Risk Geneml iUethodological Issues For both retrospective and prospective studies, the common methodoltic concerns are disease misclassi&ation and miscla&fi- cation of the subject's personal smoking status or exposure to ET& Disease misclassification, for example, refers to the incorrect classifi- cation of the lung as the primary site of a cancer that originated elsewhere. Disesss misclassification is of greatest concern in studies in which the diagn~is of lung cancer was not histologically confirmed. Such misclsssification tends to be random and to bias relative risk estimates toward unity (Copeland et al. 1977). Patients with lung cancer, or any disease associated with cigarette smoke exposure, may report exposure to ETS more frequently than controls becauseofbiasinrecall. Misclassification of the subject's personal smoking status may occur in both retrospective and prospective studies; this misclassifi- cation refers to incorrectly classifying a subject as a nonsmoker when the subject is actually an ex-smoker or a current smoker, or to incorrectly chdfying the subject as a smoker when the subject is a nonsmoker. Biochemical markers such as cotinine and nicotine, which can be used to detect unadmitted active smokers, are sensitive only to a recent exposure to tobacco smoke; thus, they are not Ptiicuh+Q useful for identifying ex-smokers who deny their past SIIlOking hisb?k~. Mis&ss&ation of smokers or ex-smokers as nonsmokers may produce the appearance of an involuntary smoking effect when, in fact, the true relationship is with aeve smoking. &urcz of subjects Age- Yeara of earollment l&St year of followup Method of followup VerScation of diagncei.9 Metbodandtypeof information obtained hdex of pamive smokiug Number of lung cancer deaths in nonsmokers ceusus population, 29 he&h districts, Japan 1966 1961,1962 Recordlinkagebstweaa ri&factarrecvrdaand death certitica~ lnterview 0): smoking auddrinkinghabita, dietary history, oocupation, other health-related variables Husband's smoking at entry ooasmoker, ex- smoker, curteat smoker (oiglday) mom 176769 (F) 85-84 196%1960 1972 llIonitored by ACS volunteers, death eartificatee from locallstate hsmlth departmenta Verified method of dlagnosi9aud tilo6y for 6rat 6 yeam' followup self -red qw3tiomlaisz education, real- ocoupational exposure, smokiw and medical history H&and's smoking atentrj? -km current smoker, and OigldaJy exsmokers exoluded 163 0 mea 1,917 (F) 45-64 19724976 1962 Recordlioh@witb Lomlcauoerre&try Spouse's smoklug at eatrJTcurrentm uever smoker, ex- smokers edlded (quit 26 year8 before atrg) 6 0,8 0 ~uRcE:Hirayama(19818,1@33,1964a b), -(1961),~e.tal.(198(1 Misclassification of involuntary smoking exposure refers to the incorrect categorization of exposed subjects as nonexposed and of nonexposed subjects as exposed. Most studies of lung cancer to date have used the number of cigarettes smoked by spouses as a measure of exposure to involuntary smoking, and thus have disregarded duration of exposure, exposure from other sources, and factors that influence exposure, such as proximity to the smokers or size and ventilation of the room where the exposure occurred. Moreover, all 6'7 TABLE &-Description of case-control studies Study cmntry case Source end type control Source end type confirmed histology Iudexofpemd~ Respondent and Pathologicel/ mole: habita of type of interview cytological Adermarchoma spouam end others Trichopouka Greece et al. (1981, 1983) C&set and can& hospitals, 77 NS (FJ Orthopedic hcepital; 225 Ns; not matched Selfi not blinded 65% Correa et al. (1989) New Orleans, United States Hoepit+ 30 NS (8 M, Same hospitals, non-~ Self, and proxy 97% 54% among current spoues 22 F) related diaeaaes; 313 NS bm, 23% women RYPe, amount Fk (180 M, 133 Q matched for control, 11%); parents age, sex, raw hmitd blinded Chsn and Hong Kong Four hoepit& Orthopedic, same hoepit& Self; not blinded 82% 45% Ndapouee Fun8 ww 64 NS 0 189 NS; not matched w=if-bi- quiwtiom at home andatwork Koo et al. Hong Kong Eight lmpitale; Population; 137 N& Self; not blinded 97% 69% Currentandr- wa 1981) 88 NS 0 matched for egm, race, sex, m b--k emioewllomlc status, YmwiP@-B lwldence dlstrlct other cohablti& am&em (amount PIW K&at and united statea Most from one NY Same hospital 0; non- Self; not blinded 10096 M%td cul7ent spouss Wynder (19S4) hoepi~ 134 NS; tabaamrelated dieeasq 78 14% F of @nrentww passive smoking data NS (25 M, 63 p); matched 134 NS fmoking habite on only 78 NS (26 M, for age, sex, raa+ hoepital, l?urrentwat Mm date of interview, hnmeandwork nonsmoking status TABLE 8.-Continued St&- country caes Sourceandtype Contml Soweandtype confll histology hiexofpamive Respondent and Patholo6icaV srook habit8 of type of inte.rvlew ~hw Adenocarcinonm qouam and othara wu et al. w=) Population; 62 N9; matched self; not blinded 100% 100% current and former for age, ram sex, spa- (amount, nelghborImcd IT& puent* cohabitant4 (=mt, Yd, coworkers &r/day, P-4 Garfinkel et al. (1985) New Jersey, Ohio, united St&S Four hoopit& 134 NS 0 Same haepitale, o~lorectal cancer patients; 402 NS; matched for age, hospital, IlonsmoLiDg status self (cab& 12%; control, ?) and prory; blinded 100% 66% Current spouse or cohabitant (total and at home: amu& ~3); other ew-re, a-w hrdday (at home, worl, other) 5 and 2syrsbefore diagm!&chiMhad em-- d TABLE &-Continued Study Country case Source and type Control Source end type confirmed hb3bi~ Index of paudve Respondent and Patholcgical/ smoke:, habite of type of interview cytological Adenocarcinoma spousee and others Lee et al. wm United Ha&al-beeed; 47 NS KlllgdOlll (15 M, 32 l9 Same hmpitals, 96 NS (30 Self, hospital 1 1 current spoum M, 66 F); matched for age, inpetient (smoking habit sex, marital status, hoepital interview; duriag admission spouse, followup yr ad maximum intarvie-w; not during marrio& fqecified other expceure at home, at work, dur@ travel end leisure Akiba et al. ww Japan Hllhlma and Nagasekl bomb survivors; 103 NS (19 M, 84 F) Same cohort, noncancer or self (c-am, 10%; 67% 7 curlent spoum chronic respiratory disease; control, 12%) end bow llee de 380 NS (110 M, 270 IQ prow, not blinded aBgestop,yra matched for age, eeq city cohabitiS; perenta of residence, vital statue, yr of death Perehagen et al. (in press) Sweden National census of Sweden end Swedish TwlnFhgi&y; 67 NS 0 Two controls from each soume; 347 Ns; matched for year of bii, vital status at followup end for twin regktry control Self, and proxy (case, almost all; mntrol, 265%); not applicable, mailed questionnaire 99% 57% spouse lived with longeat kImour& Yd; parenb TABLE 9.-Results from selected prospective and cast+ control studies; lung cancer risk associated with spowes' smoking Study Spousee smoking Nonsmoker Ex-amoker Hirayama (19W Garfinkel (1981) 1.0 Nonsmoker 1.0 (l.ot:.O) (l.cy2.4) 41 pack-p 1.6 3.1 (0.6. 3.8) (1.1. 8.6) No 1.0 Nonsmoker YeS 0.8 (0.5, 3.1) &5,ooo hrs' >wm hln 1.3 1.0 (0.8, 2.4) (0.2, 2.7) No YeS Kabat and Wynder 1.0 ww ,.&, Nonsmoker l-20 ym 21+ yrs wu et al. 1.0 i1985) (0.4t.4q.9) (O.`i% Nonsmoker Cigar/pipe 15 cigarettes/day or 1 pack of pipe tobacco/week during 2 30 years ofmarriaga. 71 IO. 8. a, 7. x 6. g5 = 4 3 ,' of the published studies have baaed involuntary smoking exposure measures on questionnaires without validation of these data with biochemical markers or environmentally measured concentrations of tobacco smoke constituents. Misclassification of involuntary emoking exposure is likely to be random and to bias the effect measures toward the null (Copeland et al. 1977). Misclassification of exposure to environmental tobacco smoke is inherent in epidemiological studies of involuntary smoking. Tobacco smoking has not been re&icted in most indoor environments until recently, and exposure has been almost inevitable in the home, the workplace, or other locations. Studies with the biological markem nicotine and cotinine confirm that tobacco smoke exposure is widespread; detectable levels of these markers are found even in people without reported recent exposure. Thus, the exposure vari- ables employed in epidemiological studies do not separate nonex- posed subjects from exposed subjeds; instead, they discriminate more exposed groups from less exposed groups. As a result, the 72 epidemiological approach is conservative in estimating the effects of involuntary smoking. A truly nonexposed but otherwise equivalent comparison population has not been identified. The extent of the resulting bias cannot be readily estimated and probably varies with the exposure under consideration, which may be one reason for the variability in risk estimates obtained by different studies. Information bias is an added concern in cas+control studies, since neither interviewer nor respondent bias can be ruled out. It is not feasible to blind interviewers to the case or control status of respondents because of the usually obvious manifestations of lung cancer and because of the setting in which some of the interviews are conducted. Moreover, blinding of interviewers and respondents to the study hypothesis is difficult because the majority of questions are concerned with exposure to tobacco smoke. The direction of the information bias may be dependent on the type of respondent. Self- respondents may be more apt to interpret their d&ease as related to exposure to tobacco smoke and thus overreport the exposure. However, the direction of the information bias is less clear when interviews are conducted with surrogate respondents. The ability of a surrogate to provide accurate information may depend on the relationship of the surrogate respondent to the subject, whether the surrogate lived with the subject during the time frame of the questions asked, the degree of detail requested, and the amount of time elapsed since the event in question @or&s 1982; Pickle et al. 1983; Lerchen and Samet 1986). Surrogate respondents may mini- mize the reporting of their own smoking because of guilt, or may overreport about involuntary smoking exposure in an attempt to explain their relative's illness. Thus, depending on the direction of the information bias, it may dilute or strengthen the effect being. measured (Sackett 1979). In general, however, the information on smoking status and on amount smoked provided by surrogatea has been found to be fairly comparable to that provided by the individuals themselves (Blot and McLaughlin 1985). F'inally, participants and nonparticipants in case-control studies may be inherently different with respect to their exposure to involuntary smoking because their awareness of the hypothesis under study may motivate the decision to participate. However, participants in cas+control studies are generally not informed of the hypothesis under study. Spousal Exposure: Prospective Studies The Japanese Cohort Study Hirayama (1981a, 1983, 1984a) has presented data from a large cohort study that included 91,540 nonsmoking married women who were residents of 29 health districts in Japan. Subjects were 49 years 73 of age or older at enrollment in 1965; infOrm&iO~ W88 collected on smoking and drinking habits, diet (e.g., green-yellow vegetables, meat), occupation, and other health-related variables. me initial report on invohmtary smoking ~88 baaed on 14 gears of f&owup (lg6&1979). The husbands' smoking histories were avail- able for 174 of 240 lung cancer cases identified among the non- smoking &ed women (Hirayama 1981a); this number increased to 2~ with 2 additional years of followup -yama 1983, 1984a). &db p&thing to the association of spouses' lung cancer risk with the husbands' smoking were essentially identical in the first and second reports. On the basis of the smoking habits of the husbands at entry, the 206 nonsmoking women were classified as married to a nonsmoker, an ex-smoker, or a current smoker. The lung cancer mortality ratios &d&jzed by husband's age were 1.90,1.36,1.42,1.58, and 1.91 for women whose husbands were nonsmokers, ex-smokers, and daily smokers of 1 to 14,15 to 19, and 20 or more cigarettes, respectively (one-sided p for trend, 0.002). Similarly sign&ant dose-response trends were observed when the mortality ratios were standardized by age of the wives, by occupation of the husbands (agricultural, industrial, other), by age and occupation of the husbands, and by the time period of observation (19661977 versus 1978-1981). The risk of lung cancer &ong nonsmoking wives of smokers was reduced to 0.7 (two-sided p=O.O5) if they ate green-yellow vegetables daily com- pared with 1.0 if they ate such vegetables less often than daily (Hirayama 1984b). No other characteristic of the wives (e.g., drinking habits, parity, occupation, nonvegetahle dietary items) or of the husbands (e.g., drinking habits) was significantly predictive of lung cancer risk. Nonsmoking men whose wives were smokers also showed an elevated lung cancer risk. On the basis of 67 lung cancers in nonsmoking married men, the lung cancer mortality ratios were 1.00,2.14, and 2.31 if their wives had never smoked or had smoked 1 to 19 cigarettes or 20 or more cigarettes per day, respectively (one- sided p for trend, 0.023) (Hirayama 198413). This study has been critically discussed in correspondence since its initial publication. Because a detailed breakdown of the at-risk population was not presented in the initial report, the lung cancer mortality rate was thought by some to be higher in the unmarried nonsmoking women than in the nonsmoking women marriedto smokers CRutsch 1981; Grundmann et al. 1981). This impression was clarified by the researcher (Hirayama 1981b,c,d) and shown to be the result of incorrect interpretation of data in the original paper. Other potential problems cited were sampling bias in the study cohort, misclassification in the diagnosis of lung cancer, misclassification of the nonsmoking status of wives, misclassification of involuntary 74 smoking exposure, failure to control for potential confounders, and inadequate statistical treatment of data. Each of these points of criticism is discussed below. MacDonald (1981a,b) questioned the representativeness of the 29 health districts selected in the study cohort and suggested that, industrial pollution, such as asbestos exposure from shipbuilding industries specific to the selected health districts, may have biased the results. However, the levels of exposure to this factor would have to coincide with the husbands' smoking level to explain the effect observed. Such an association seems unlikely. If the cohort were not representative, the generalizibility but not the validity of the findings would be challenged (Criqui 1979). The accuracy of the diagnosis of primary lung cancer on the basis of death certificates and the adequacy of the data without informa- tion on the histology of the tumor were questioned (Grundmann et al. 1981; MacDonald 1981a). From a sample of 23 cases, Hirayama (1981b) reported that the distribution by histology of lung cancer in nonsmoking women whose husbands smoked was similar to that in women who smoked. Failure to discriminate in some cases between primary and metatastic lesions to the lung may be a potential problem with disease diagnosis. Although Hirayama was unable to assess the accuracy of the diagnosis listed on the death certificate, there is no reason to believe that error in recording the causes of death of wives was influenced by the smoking habits of their husbands, and any misclassification is likely to be random. Inclusion of nonlung cancer cases would tend to bias the risk ratio toward unity or no effect (Barron 1977; Greenland 1980). The relatively high risks observed for nonsmokers whose husbands smoked led to speculation that Japanese women may report them- selves as nonsmokers when they actually smoke (Lehnert 1934). However, some assurance of the reliability of the smoking data provided by the Japanese women comes from an investigation in Hiroshima and Nagasaki (Akiba et al. 1986) that found strong concordance between smoking status reported by the women them- selves and that reported by their next of km. Classifying nonsmoking women solely on the basis of the smoking habits of their current husbands probably does not quantify their exposure with precision because it accounts for only one of the many possible sources of tobacco smoke exposure. Moreover, using the number of cigarettes smoked per day by the husbands as a measure of exposure dose assumes that the husbands' increasing daily cigarette consumption is directly related to an increasing ETS exposure of the wives (Kornegay and Kastenbaum 1981; Lee 1982b). The analyses were further criticized for not accounting for potential confounding factors such as socioeconomic status (SES) and exposure to indoor air pollutants (e.g., from heating and cooking 75 smrces) (Sterling 1981). However, Hirayama showed a fairly consis- tent relationship between involuntary smoking exposure and lung mcer across SES categories. The role of indoor air pollutants could not be addressed directly in the study, but data from one health distrkt in the study indicated no association between heating or cooking practices and the smoking habits of the husbands (Hirayama 1981b). The researcher's failure to specifically describe the methods for age standardixation in the initial report led to speculation that the statistical methods used were incorrect (Kornegay and Kastenbaum 1981; Mantel 1981; Tsokos 1981; Lee 1981); however, the calculations were later confirmed (Harris and DuMouchel 1981; Hammond and EM&off 1981). The choice of stratification variables used for age standardixation was also criticixed because the husbands' ages instead of the wives' ages and U&year age groups instead of narrower ones were used (Tsokos 1981; MacDonald 1981b). Later publications confhmed that similar results were obtained regardless of, the method of standardixation (Hirayama 1984a). The American Cancer Society Cohort Study A second prospective study (Garfinkel 1981) that examined the effects of involuntary smoking was the American Cancer Society (ACS) study of about 1 million people living in 25 States. A self- admimstered questionnaire on education, residence, occupational exposure, and smoking and medical history was completed by the study subjects upon enrollment. This report on involuntary smoking was based on 12 years of followup (1966-1972) and included 176,739 nonsmoking married women whose husbands' smoking habits were available and whose husbands were never smokers or current smokers. In the total cohort of nonsmoking women, 564 lung cancer deaths occurred, and data on the husbands' smoking habits were available for 153 (27.1 percent). Wives of ex-smokers and of cigar or pipe smokers were excluded from the analysis. A small, statistically nonsignificant increased risk for lung cancer was found for nonsmokers married to smokers. The mortality ratios for lung cancer in nonsmoking women were 1.0,1.27, and 1.10 when the husbands were nonsmokers, daily smokers of fewer than 20 cigarettes, and daily smokers of 20 `or more cigarettes, respectively. The results were essentially unchanged after accounting for the potential confounding effects of age, race, education, residence, and husband's occupational exposure. The ACS study, like the Japanese study, was not designed to study the long-term effects of involuntary smoking. However, the ACS study does provide an estimate of the extent of misclassification of lung cancer. On the basis of medical record verification, the death 76 certificate diagnosis of lung cancer in nonsmoking women was incorrect for 12 percent of the cases. Although confirmation of diagnosis was sought only for the first 6 years of followup, the available data suggest that some misclassification of lung cancer occurred. To the extent that passive smoking is related to lung cancer in nonsmokers, inclusion of nonlung cancers would tend to dilute a true effect. A limitation of the ACS study is the nonavailability of smoking information on the husbands of a large proportion of the nonsmoking women who died of lung cancer. Because smoking habits are correlated with various social characteristics, this large loas of information may have created a bias in this study. The researcher stated that an index of tobacco smoke exposure based only on smoking habits of current husbands may be particularly inadequate for the United States, with its high rate of divorce and substantial proportion of women working outside the home. This speculation is supported by data from a group of 37,881 nonsmokers and ex- smokers who were members of a health plan in California. Friedman and colleagues (1963) stated that 47 percent of the nonsmoking women and 39 percent of the nonsmoking men married to smokers reported no exposure at home. Moreover, being married to a nonsmoker did not assure the absence of exposure to tobacco smoke, since 40 percent of the nonsmoking women and 49 percent of the nonsmoking men married to nonsmokers reported some exposure to tobacco smoke during the week. Thus, random misclassification could have biased the results toward unity and led to an underesti- mate of the effect of passive smoking. The Scottish Study Gillis and colleagues (1984) conducted a prospective cohort study of 16,171 Scottish men and women, aged 45 to 64 years, from two urban areas, who attended a multiphasic health screening clinic between 1972 and 1976. A questionnaire on smoking habits and symptoms of respiratory and cardiovascular diseases was completed at entry into the study. The preliminary analysis of involuntary smoking, representing 6 to 10 years of followup, was based on the 2,744 nonsmokers among the 8,128 subjects who lived as couples and could be paired according to smoking habits. Subjects who lived alone or whose partner did not participate and ex-smokers who had stopped smoking for 5 years or more were excluded. The nonsmokers were classified as nonsmokers not exposed to environmental tobacco smoke or as nonsmokers exposed to environmental tobacco smoke, according to the smoking habits of their spouses. A higher age-standardized lung cancer mortality rate was reported for nonsmoking men exposed to tobacco smoke (13 per 10,006) than 77 for nonsmoking men not exposed (4 per 10,000); however, no statistical tests were conducted because of the small number of cancers. Lung cancer rates were similar for nonsmoking women regardless of the status of their exposure to tobacco smoke (4 per 10,000). The extremely small number of observed lung cancer deaths (6 men, 8 women) limit the interpretation of the study's findings. Spu8al Expomre: Case-Control Studies Table 8 summa&es the car+control studies that have examined the relationship between involuntary smoking exposure and lung cancer. The Greek Study Trichopoulos and colleagues (1981, 1983; Trichopoulos 1964) examined the effect of involuntary smoking on lung cancer risk in a case-control study of 51 Caucasian female lung cancer patients (excluding adenocarcinoma and terminal bronchiolar carcinomas) from three chest hospitals and 163 female controls from an orthopedic hospital in Athens, Greece. All subjects were interviewed in person by one physician who questioned them regarding their personal smoking habits and those of their current and former husbands. Thirty-five percent of the cases were diagnosed only on the basis of clinical or radiologic information; the remainder were cytologically (37 percent) or histologically (28 percent) confirmed. Nonsmoking women were classified by the smoking habits of their current or former husbands. Husbands were nonsmokers if they had never smoked or had stopped smoking more than 20 years previous- ly, ex-smokers if they stopped 5 to 20 years previously, and current smokers if they were smoking or had stopped less than 5 years before the interview. Being never married, widowed, or divorced was equated as being married to a nonsmoker or an ex-smoker, depend- ing on the length of time in the category. The initisl report was based on 40 nonsmoking cases and 149 nonsmoking controls. The odds ratios (0R.s) for women married to nonsmokers, ex-smokers, current smokers of 1 to 20 cigarettes per by, and current smokers of 21 or more cigarettes per day were 1.0, 1.9,2.4, and 3.4, respectively (two-sided p for trend, < 0.02). In a later report on 77 nonsmoking cases and 225 nonsmoking controls, the ORa were somewhat lower: 1.0, 1.9, 1.9, and 2.5, respectively t'lltchopoulos et al. 1983; Trichopoulos 1984). The findings of this study were questioned because the diagnosis of cancer was not pathologically confirmed for 35 percent of the cases (Hammond and Selikoff 1981; Lee 1982b). The inclusion of cases that were not lung cancers would tend to dilute the results toward the null because they may not be related to involuntary smoking. 78 Terminal bronchial (alveolar) carcinoma and adenocarcinoma of the lung were excluded from the pathologically confirmed group; this exclusion may have been premature (Hammond and Selikoff 1981; Kabat and Wynder 19&Q), as the causal association between personal smoking and adenocarcinoma of the lung is well established (IARC 1986). Because the controls were selected from a different hospital than were the cases, selection bias cannot be ruled out. Interviewer bias is also possible, since all subjects were interviewed by a single physician who knew the case or control status of each subject, and also knew the hypothesis under investigation. The index of exposure to tobacco smoke used in this study included the smoking habits of former and current husbands. Since the definition of ex-smokers excluded those who had stopped smoking recently (within the last 5 years), it was unanticipated that the risks observed for women whose husbands were ex-smokers (i.e., quit 5 to 20 years previously) were as high as for those whose husbands were current smokers. Additional information on the smoking habits of these ex-smokers would be valuable. The Louisiana Study The cas+control study by Correa and colleagues (1983) was based on 1,338 primary lung cancer cases, of which 97 percent were pathologically confirmed. Controls (N= 1,393) were matched to cases by race, sex, and age (+5 years) and were patients at the same hospitals as cases but without a diagnosis related to tobacco smoking. Standard&d interviews were conducted with the subjects (76 percent of cases, 89 percent of controls) or their next of kin. Questions on occupation, residency, personal smoking and drinking habits, and smoking habits (including type of tobacco smoked and amount and duration of smoking) of the current spouse and parents were asked. Thirty nonsmoking ever-married lung cancer (excluding bron- chioalveolar cell) patients (8 men, 22 women) and 313 ever-married nonsmoking controls (189 men, 133 women) were classified according to their spouse's total lifetime pack-years and current daily amount smoked at the time of interview. After adjusting for sex, ORs of 1.60, 1.48, and 3.11 were observed when spouses had smoked none, 1 to 40 pack-years, and 41 or more pack-years, respectively (two-sided p< 0.05). The results based on current daily number of cigarettes smoked by spouses were similar. The study is limited by the small number of nonsmoking cases, but the consistency of the results for men and women strengthens the findings. Misclassification of involuntary smoking is possible because only smoking habits of the current husband were assessed, ignoring the effect of divorce, remarriage, and exposure from coworkers. Exposure from parents during childhood was determined, but case 79 numbers were too small for a mea&gful analysis of this factor among nonsmokers. The Hong Kong Studies me high rates of lung cancer, particularly adenocarcinoma of the lung, among women of Chinese descent in Hong Kong are unexpect- d in the face of their low rates of tobacco smoking. The role of involuntary sm&.ng was investigated in two studies conducted in Hong Kong (Chan et al. 1979; Ghan and Fung 1982; KOO et al. 1983, 1984). Chm and colleagues (1979) examined the role of involuntary smoking among 84 female lung cancer patients and 139 orthopedic control patients, none of whom had ever smoked. Of the 34 nonsmoking cases, 69 (82 percent) were pathologically confirmed, and 38 of these 69 cases were adenocarcinoma of the lung. The controls were from the same hospitals as the cases, but were not individually matched to the cases on any characteristics. Cases and controls were questioned regarding their residence, education, occupation, cooking practices, and personal smoking habit. One question on exposure to others' tobacco smoke was included: "Are you exposed to the tobacco smoke of others at home or at work?" The researchers reported that the controls lived with smoking husbands more frequently (47.5 percent) than the cases (46.5 percent) (OR 0.771, but did not explain how this question was used to classifs the habits of the spouse alone. The method used to classify currently unmarried respondents (i.e., never married, wid- owed, divorced) with regard to exposure to their spouses' smoking was not described, and it is not known if the nonsmoking cases and controls were comparable in terms of current marital and employ-, ment status. Thus, insufficient information on the measure used to assess El% exposure, and on the comparability of the nonsmoking cases and controls, limits interpretation of this study's results. The study by Koo and colleegues (1983,1934) involved 200 Chinese female lung cancer patients who were identified from eight hospitals in Hong Kong; almost all cases were pathologically confirmed (97 percent). Among these women, 68 had never smoked, of whom 52 (59 percent) had adenocarcinomas of the lung. An equal number of "healthy" population controls, individually matched to cases by age (f5 years), socioeconomic status, and district of residence, were interviewed. Among the controls, 137 had never smoked. Using a sernistructured questionnaire, taped interviews were obtained and information on residence, occupation, family and medical history, personal smoking habits, and smoking habits of all cohabitants and coworkers was elicited. ETS exposure was quanti- fied in hours and years according to who (i.e., husband, parents, in- laws, children, others) smoked in the subject's presence and where (i.e., at home, at work) the exposure occurred. The analysis was based on a cumulative smoke exposure index (in total hours and total years) specific to place of exposure. The investigators concluded that there was no association between involuntary smoking and lung cancer in nonsmoking Chinese women, regard&s of the index of smoke exposure used. A small, but statistically nonsignificant, increased risk (RR 1.24) was associated with any exposure to tobacco smoke. There were no significant differences between the cases and the controls in total hours or total years of exposure. The results remained unchanged when exposure hours were categorized into three levels of exposure. Odds ratios of 1.09, 1.28, and 1.02 were associated with no, low ( 5 35,900 hours), and high (> 35,000 hours) exposure levels, respectively. There was no apparent trend of lung cancer risk with the age when exposure to tobacco smoke began. The ORs for never exposed and first exposed at ages 0 to 19,20 to 39, and 40 or older were 1.09,0.96,1.53, and 0.91, respectively (Koo et al. 1984). AnaIysis by cell type suggested that the effects of involuntary smoking may be more pronounced for Kreyberg I tumors (squamous, smallcell, and largeceIl carcinomas) (OR 1.47, 95 percent C.I. 0.34, 3.33) than for adenocarcinoma (OR 1.11, 95 percent C.I. O-49,2.59) (ILoo et al. 1985), but these numbers were amaR. The design of this study addressed the criticisms of other studies that an index of involuntary smoking exposure based only on spouses' smoking habits is inadequate, and broadened the exposure assessment to include alI locations of tobacco smoke exposure. However, the cumulative exposure index created in this study may have Iimited validity. Unlike personal smoking, where there is essentiaIIy one source (personal smoking), one dose (usual or maximum amount smoked), and one duration of exposure (age at start and age at stop), EYES exposure derives from diverse sources at different doses and durations of exposure. The accuracy of the information on exposure to EIS will depend on the amount of detail requested, the age of the respondent, the temporal course of the exposure, and the source of the exposure. Weighing each type of exposure equally in a cumulative index (in total hours) may be incorrect because it assumes that all sources of exposure should be quantified in the same way and that each source of tobacco smoke contributes equally, disregardiug intimacy of contact and proximity to smokers and conditions of exposure (e.g., room size, ventilatory factors). Thus, random misclassification of the expoeure variable by inclusion of data from less relevant exposures than spousai smoking may obscure an association of involuntary smoking exposure with lung cancer risk. In this study, interviewer and respondent bias should also be considered because a structured questionnaire was not 81 An Ongoing Study of Tobacco-Related Cancers All of the cases of primary lung cancer in nonsmokers were selected (Rabat and Wynder 1984) from an ongoing case-control study of tobacco-related cancer conducted in five U.S. cities between 1971 and 1980 (Wynder and Bellman 1977). For each case, one control was individually matched by age (r+5 years), sex, race, hospit,& date of interview (+_2 years), and nonsmoking status. controls were selected from a large pool of hospitalized patients who were interviewed over the same time period as the cases and who had diseases not related to tobacco smoking. Information on demo- graphic factors, residence, height and weight, drinking habits, previous diseases, and occupational exposure were obtained. Ques- tions on tobacco smoke exposure at work, at home, and from current spouse were added in 1978, and revised in 1979. Information on EYl!S exposure was available for 25 of 37 nonsmoking male cases, 53 of 97 nonsmoking female cases, and their respective matched controls. A higher percentage of female controls than of female cases reported exposure to E'I'S at home (32 percent), at work (59 percent), and from spouses (66 percent). `Ihe percentages of female cases who reported exposure at home, at work, and from spouses were 39,49, and 54 percent, respectively. None of the case-control differences in women were statistically significant. Male cases reported more frequent exposure at work (OR 3.27, p= 0.045) and at home (OR 1.26), but no difference in the smoking status of their spouses (OR 1.60). The process for selecting the nonsmoking controls from the larger pool of controls in the ongoing study and for selecting the non- smoking csses and controls who were questioned with regard to ETS exposure was not described adequately. It is not clear whether the 25 of 37 male and 53 of 97 female nonsmoking cases and controls who provided information on involuntary smoking were all interviewed during or after 1978 when the questions on involuntary smoking were introduced. `I'he proportion seemed high, since it represented 68 percent of male and 55 percent of female nonsmoking cases interviewed during the 10 years of data collection. The study was not designed to specifically address the effect of involuntary smoking, and a variable subset of questions on involuntary smoking was asked, depending on when the subjects were interviewed. Misclassifi- cation of the exposure is possible because it is not clear whether the cases and controls answered the same set of questions and whether a comparable amount of information was obtained. The researchers acknowledged the limitations of this study and presented its results as prebinary findings. 82 The Los Angeles County Study In the case-control study by Wu and colleagues (1985), 220 white female lung cancer patients (149 with adenocarcinoma and 71 with squamous cell carcinoma) and 220 population controls were individu- ally matched on sex, race, age (f5 years), and neighborhood of residence. Cases were identified from the population-based tumor registry of Los Angeles County. All cases were histologically confirm& the histological type was based on the pathology report from the hospital of diagnosis. Using a structured questionnaire, cases and controls were directly interviewed by telephone and were asked about their own personal smoking habits and the smoking habits (amount and years of smoking) of current and former husbands, parents, and other household members during childhood and adult life. Exposure to tobacco smoke at work (in hours per day) was obtained for each job of at least 6 months' duration. Information on medical and reproduo tive history, heating and cooking sources, and dietary intake of vitamin A were obtained. Of 149 patients with adenocarcinoma of the lung, 29 had never smoked, nor had 2 of 71 patients with squamous cell carcinoma. The analysis of involuntary smoking was based on the 29 nonsmokers among the adenocarcinoma cases and 62 nonsmokers among the controls. A subject was classified as married to a smoker if any of her husbands had ever smoked. Similarly, a subject was considered exposed at work if she was exposed to tobacco smoke for at least 1 hour per day at any of her jobs. There were small, but nonsign& cantly increased risks associated with ETS exposure from spouse or spouses (OR 1.2; 95 percent C.I. 0.2,1.7), and from coworkers (OR 1.3; 95 percent C.I. 0.5,3.3). Increased risk was not associated with smoke exposure from either parent (OR 0.6; 95 percent C.I. 0.2, 1.7). Exposure to tobacco smoke from spouses and from coworkers was combined in an index representing smoke exposure during adult life. There was an increasing trend in risk with increasing years of exposure. The ORs were 1.0,1.2, and 2.0 for 0,l to 30, and 31 or more years of involuntary smoking exposure during adult life, respective ly, but the results were not statistically significant. Because the exposures may have occurred concurrently, the years of exposure represented units of exposure rather than calendar years of expo sure. This study is limited by the small number of nonsmoking cases and controls. Unlike the two case-control studies that excluded adenocarcinoma or bronchioalveolar cell carcinoma (Trichopoulos et al. 1981; Correa et al. 1983), cases in this analysis were of these cell types (17 adenocarcinoma, 12 bronchioalveolar); this case mix may explain the weak association observed. The Four Hospitals Study A Mntrol study by Garfinkel and colleagues (1985) included 134 nOnsmOking female lung cancer cases selected from three hospitals in New Jersey and one in Ohio over an 11-year period, 1971-1981. Medical records served as the initial source of informa- tion on smoking status of the subject, and the nonsmoking status of each case and control was verified at interview. Three controls, color&al cancer patients matched to cases by age (f5 years) and hospital, were interviewed for each case, giving a total of 402 controls. All diagnoses of cases and controls were pathologically confirmed. Interviewers, blinded to the diagnosis of the subjects and to the study hypothesis, administered a standard questionnaire to subjects or their next of kin. Information on the smoking habits of current spouse (total and amount smoked at home), tobacco smoke from other sources (in hours per day at home, at work, and in other settings), and exposure to tobacco smoke during childhood were obtained. Subjects were classified according to the smoking habits of current husbands. Smoking habits of a cohabitant in the same household was used for single women or those who no longer lived with their spouses. Of the cases, 57 percent were classified according to the smoking habits of husbands; the corresponding percentage in controls was not provided. Nonsmoking women living with a smoker showed an elevated risk for lung cancer (OR 1.31). The ORs for lung cancer in nonsmoking women were 1.09, 1.15, 1.03, and 2.11 when the husbands were nonsmokers, daily smokers of less than 10,lO to 19, and 20 or more cigarettes at home, respectively (one-sided p for trend, <0.025). Similarly, a significant positive linear trend (one- sided p < 0.025) was shown when the husbands' total amount smoked was categorized into four levels. However, there was no apparent dose-related trend by years of exposure to the husbands' smoking (0, <20,20-29,30-39,40+ years). There was no apparent association between lung cancer and tobacco smoke exposure from other sources. Cases and controls did not differ in their reported exposure to tobacco smoke during childhood or in their average hours of exposure per day to other's t&m0 smoke during the last 5 years and 25 yeam before diagnosis. The results remained unchanged when exposures at home, at work, and in other settings were e xamined separately. The odds ratios were highest for exposure in other settings, but they were based on a small number of positive responses. There was no consistent pattern by ~tologic type. Squamous cell carcinoma showed the strongest relationship with involuntary smoking, based on the husbands' smoking habits at home (RR 5.0,95 percent C.I. 1.4,20.1), but failed to show any relationship when involuntary smoking exposure was classifkd by hours of daily exposure. This caswzontrol study has the largest number of nonsmoking lung cancer cases to date and provides estimates of the mis&s&ica- tion of disease and of the smoking status of the subjects. Among the published studies on involuntary smoking, this is the only one involving independent verification of the diagnoses of all cases. This verification showed that 13 percent of the cases classified as lung cancer were not primary cancers of the lung. This study showed that 40 percent of the women with lung cancer who had been classified as nonsmokers (or smoking not stated) on hospital records had actually smoked, compared with 9 percent of the controls. The inclusion of lung cancer patients who had actually smoked would have substan- tially increased the odds ratios with involuntary smoking, because 81 percent of the potentially misclassified cases had husbands who smoked compared with 68 percent of the %ue" nonsmoking patients with lung cancer. It should be noted that none of the other studies on involuntary smoking and lung cancer based classification of smoking status solely on data from medical records. The measure of involun- tary smoking based on smoking habits of husbands attempted to differentiate between current total smoking habits and current smoking habits at home. The interview also included RTS exposure not only at home but at work and in other settings. The exposure information presented in this study is potentially limited by its extensive reliance on surrogate interviews. Owing to the need to assemble sufficient nonsmoking cases, diagnoses as early as 1971 were included, so proxies were interviewed for a high percentage of the deceased cases. Among the cases, 12 percent of the interviews were conducted with the subject, 25 percent with the husband, 36 percent with offspring, and 27 percent with an informant who had known the subject for at least 25 years. The corresponding distribution of informants in the control series was not presented. Although the ORs did not. vary consistently by respondent group, the OR for smoke exposure based on the hus- bands' smoking tended to be lower when husbands were the respondents. Presumably, the husbands reported their own smoking habits, and it cannot be determined whether bias resulted. The information provided by surrogates may be particularly inaccurate for exposures outside the home. Systematic bias between personal and surrogate interviews and systematic bias by informant status must also be considered. Given that the topic of involuntary smoking is potentially sensitive for the family of a lung cancer patient, it is possible that some surrogates may not have provided accurate histories, particularly with regard to their own smoking habits. Surrogate respondents for cases might have been more likely to underreport exposure than those for controls, such differential reporting would have led to an underestimation of the true effect. The multiple regression analysis performed in this study did take respondent status into consideration, and it was determined that this factor could not account for the relationship with husband's smoking status (Garfinkel et al. 1965). It is not clear if the colorectal cancer controls were diagnosed in the same years as the lung cancer cases. Because the response patterns of relatives who are interviewed after the recent death of a subject may differ from responses obtained long after the subject has died, another source of bias may have been introduced. A United Kingdom Study In an ongoing hospital-based cas+control study of lung cancer, chronic bronchitis, ischemic heart disease, and stroke, Lee and dIeagues (1986) examined the role of involuntary smoking in a group of inpatients interviewed after 1979, when, to cover involun- tary smoking, the questionnaire was extended to married patients. An attempt was also made to interview the spouses of the married nonsmoking lung cancer patients and the spouses of the comparison group. The interview on involuntary smoking administered to hospital inpatients included questions on the smoking habits of their first spouse and on FXS exposure at home, at work, during travel, and during leisure, based on a subjective four-point scale. Spouses of nonsmokers were asked about their own smoking habits at the time of interview, during the year of admission of the subject, and during the course of their marriage. A total of 56 lung cancer cases among married lifelong nonsmok- ers was identified, 2 controls were selected for each case and individually matched on nonsmoking status, sex, marital status, age, and hospital. Among the 56 cases and 112 controls, information on spouses' smoking habits was available for 29 (52 percent) cases and 59 (56 percent) controls from an interview conducted while the patient was still in the hospital. Interviews with spouses were obtained for 34 (61 percent) of the cases and 80 (71 percent) of the controls. Using both of these sources of information, the smoking habits of spouses were available for 47 (84 percent) of the cases and 96 (86 percent) of the controls. Nine risk estimates were presented for 8pouses' smoking, for each of the three sources of information (subject, spouse, and both), for men and women separately and for both sexes combined. The researchers concluded that spousal smoking was not associated with lung cancer, because risks were not consistently elevated. When their spouses reported about their own smoking, a RR of 1.60 (95 percent C.I. 0.44, 5.78) was found for lung cancer in the women. In contrast, a RR of 0.75 (95 percent C.I. 0.24, 2.40) was found when the female subjects reported about the smoking habits of their spouses. On the other hand, a RR of l.Ol(96 percent C-1.0.23,4.41) was found for male lung cancer patients when 86 their spouses reported about their own smoking, whereas the risk was 1.53 (95 percent CL 0.37,6.34) when the male patients e~aluat& their spouses' smoking habits. As might be expect&, the combined risk in relation to spouses' smoking for both sexes and both sources of information was near unity, at 1.11 (95 percent C.I. 0.59, 2.39). Using a second group of controls, presumably all of the nonsmokers who had responded to the hospital inpatient interview on involun- tary smoking, the researchers reported no significant case and control differences in exposure to EXS at home, at work, during travel or leisure, from spouses, or for all sources combined. This study has several limitations that must be considered in interpreting its results. Although the study attempted tc verify involuntary smoking from spouses by using two sources of informa- tion, dual reports were obtained for only 16 (29 percent) of the cases and 43 (33 percent) of the controls. The questions on involuntary smoking included exposure from other sources, but they were based on a subjective scale, and different groups of controls were used for the analyses. Information was not presented on the accuracy of the diagnosis of lung cancer or on the histological types included in the study. Moreover, the investigators did not verity the smoking status of the subjects during the interviews with spouses. The study's inconsistent fmdings by source of information and by sex may reflect the absence of an association between involuntary smoking and lung cancer in this population, or may reflect method- ological problems in the design or conduct of the study. The main study was not originally designed to investigate the effects of involuntary smoking. However, because of interest in this issue, the investigators decided to "increase the number of interviews of married lung cancer cases and controls." The representativeness of the cases and the controls cannot be determined because there may have been differential selection factors in enrolling nonsmoking lung cancer cases and controls into the study; thus, selection bias cannot be ruled out. The method for selecting the 112 nonsmoking controls was not adequately described in the report; it is not clear whether they were selected from the pool of all controls for lung cancer or from the pool of controls for the four diseases under study. There is also an apparent discrepancy in the number of nonsmoking cases cited in the text and presented in the results. The report cited 44 never smokers among a total of 792 lung cancer patients who completed the involuntary smoking questionnaires when they were in the hospital. However, the analysis for an involuntary smoking effect based on interviews with subjects in the hospital showed only 29 lung cancer patients. This discrepancy was not explained. The risks in relation to smoking by spouses varied with the source of information. The risk estimates tended to be higher when the respondents were men, either reporting about their own smoking 87 habita or the smoking habits of their spouses. This pattern could result if the male respondents overestimated exposure to environ- ment& tobacco smoke or if the female respondents underestimated exposure. An analysis of the patients (16 cases and 43 controls) for whom data were provided by the spouses and by the subjects themselves showed a 97 percent concordance for spouses' smoking during the year of the interview and 85 percent concordance for spouses' smoking some time during the marriage. Lack of specificity in the question asked regarding spouses' smoking any time during the marriage may partly explain the discrepancy in response. To the extent that there is no consistent pattern in the direction of this discrepancy, it can be assumed that a spouse was a smoker sometime during the marriage if either respondent answered positively. On the basis of this assumption, RRs of 1.47 (spouses of 4 of 7 cases and 7 of 18 male controls smoked) and 1.39 (spouses of 8 of 9 female cases and 16 of 25 female controls) were found for the men and the women, respectively, in relation to their spouses' smoking. The risk estimates were not statistically sign&ant, but the number of subjects was Sldl. The Japanese CaseControl Study The study by Akiba and colleagues (1986) included 426 (264 men, 164 women) incident primary lung cancer cases diagnosed between 1971 and 1980 in a cohort of 110,090 Hiroshima and Nagasaki atomic bomb survivors. Controls were selected among cohort members who did not have cancer. For deceased cases, corresponding controls were selected from among cohort members who died of causes other than cancer or chronic respiratory disease. The controls were individually matched to cases on a number of factors, including age, sex, birth year (f2 years), city of residence, and vital status; a variable number of controls was interviewed, depending on the place of residence. Of the lung cancers, 29 percent were pathologically confirmed, 43 percent were radiologically or clinically diagnosed, and the remain- der were found at autopsy. Subjects or their next of kin were interviewed regarding the subjects' personal smoking, smoking habits of current spouses and parents, and occupation. Less than 10 percent of the interviews with the men and about 20 percent of the interviews with the women were conducted with the subjects themselves. The distributions of the next of kin interviewed were similar for the cases and the controls. Among the cases, 103 (19 men, 64 women) had never smoked, compared with 380 controls (110 men, 270 women). An elevated lung cancer risk associated with smoking habits of spouses was observed for men and women. An OR of 1.8 (95 percent C.I. 0.5,5.6) was found for nonsmoking men married to&ves who smoked and an OR of 1.5 88 (95 percent C.I. 1.0,2.5) for nonsmoking women married to husbands who smoked. Lung cancer risk increased with the amount smoked per day by the husband, with an OR of 2.1 for women whose husbands smoked 30 or more cigarettes per day. The OR was higher (1.8) among women who had been exposed within the past 10 years compared with those who had been exposed before that time (OR 1.3). However, an increasing duration of exposure to husbands smoking was not associated with a monotonic trend of increasing risk. The relation between lung cancer and husbands' smoking was observed regardless of the occupation of wives (housewife, white- collar, blue-collar), but the highest odds ratio was for women who worked in bluecollar jobs and whose husbands were heavy smokers (OR 3.2). Despite a high proportion of proxy interviews, the distribution of informant type was comparable for cases and controls, this compara- bility minimizes the possibility of recall bias. The high concordance between the subjects' reported smoking status in a previous survey and the information from the next of kin is reassuring. Although a high proportion of cases had no histological confirmation, an increased risk was observed regardless of the method of diagnosis. This study also provided an opportunity to test for potential confounding factors, including radiation exposure and occupation, but none were identified. The Swedish Study The study by Pershagen and associates (in press) included 67 incidents of primary lung cancer cases from a cohort of 27,409 nonsmoking Swedish women who were participants in a national census survey or in a twin registry. Two controls were selected from each source and were matched to cases on year of birth, and on vital status if they were selected from the twin registry. Subjects or their next of kin (excluding husbands) were mailed a questionnaire that assessed their exposure to tobacco smoke from parents and the husband with whom the subject had lived the longest time. Information on residential and occupational history was also obtained. Elevated lung cancer risk associated with the smoking habits of spouses was observed. For all lung cancers, ORs of 1.0, 1.0, and 3.2 were observed for women who had no, low ( 5 15 cigarettes/day or < 1 pack of pipe tobacco/week or < 30 years of marriage), and high exposure to their husbands' smoking, respectively. The increased risk was found primarily for squamous and small cell carcinomas (OR 3.3); consistent effects could not be detected for other histologic types. On the basis of the approximately 75 percent of respondents who provided information on parental smoking, there was no effect 89 of parental smoking on risk for all lung cancers, after controlling for the husbands' smoking. The study is similar in design to the Japanese c88e-control study (Akiba et al. 1986), except that the Swedish investigators obtained histologic confirmation for all of the cases under study. Moreover, this study excluded husbands as informants, so a potential bias associated with husbands' reporting their own smoking habits could be eliminated. The investigators contended that the fmding of an association only for squamous cell and small cell carcinomas argues against a spurious finding because it is unlikely that the next-of-kin informers would have been aware of the histologic types diagnosed in the cases. The German Study The last in this description of studies to date based on the cask+ control design is a German study (Knoth et al. 1983), interpreted by the investigators as showing a role for involuntary smoking in the etiology of lung cancer. Of 39 nonsmoking women with lung cancer, 24 (62 percent) had lived with smokers. Although a comparison group was not interviewed, the investigators surmised that this frequency of smokers in the household was about three times higher than expected from census-based smoking statistics for men in the age group 50 to 69. The limitations of this study are evident; the researchers assumed that smoking prevalences for men were indica- tive of smoking prevalences for members of the cases' households and a specific control series was not enrolled. Other Sources of Tobacco Smoke &posure Parental Smoking Recently evaluated as a risk factor for lung cancer, parental smoking is of interest because of the large number of exposed children, the age at which it begins, and its duration. Results of this association are variable, demonstrating no association, association with just mothers' smoking, or association with both mothers' and fathers' smoking. Cmea and colleagues (1983) reported an associa- tion between lung cancer risk and the mothers' smoking in the men, which persisted after adjusting for personal smoking habits (OR 1.5, P l pack/day) in this study. A Swedish case-control study (Stjemfeldt et al. 1986) of aII cancers found a risk of 1.4 (95 percent CL 1.0, 1.9) for maternal smoking during pregnancy. A do-response relationship was dem- onstrated; the risk was highest in the most exposed group, those smoking 10 or more cigarettes per day (RR 1.6, p < 0.01). On the basis of the smoking habits of the parents of subjects up to 10 years of age, Samher, Everson, W&ox, and Browder (1985) reported no significant difference between all cancer cases and controls with respect to the mother's smoking (RR 1.1, 95 percent CL 0.7, 1.6), but the father's smoking was related to an overall increased risk (RR 1.5,95 percent CL 1.1, 2.0). In these three studies, analysis by specific cancer site revealed an increased risk of leukemia associated with parental smoking. Neutel and Buck (1971) found an almost twofold increased risk of leukemia in &i&en of mothers who smoked during pregnancy, but the association was not statisticahy significant. Stjernfeldt and colleagues (1986) reported a sign&ant positive association between maternal smoking and acute lymphoblastic leukemia. The relative risks were 1.0, 1.3, and 2.1 (p for trend, 914-915, October 3,198l. MANTEL, N. Pee&e smoking in adulthood and cancer risk. &ztter). 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British Joumal of Diseases of the Chest 79(3)%&236, July 1979. 119 CHAPTER 3 ENVIRONMENTAL TOBACCO SMOKE CHEMISTRY AND EXPOSURE OF NONSMOKERS CONTENTS Introduction Laboratory Smoking Human Smoking Sidestream Smoke Formation and Physicochemical Nature Chemical Analysis Radioactivity of Tobacco Smoke Environmental Tobacco Smoke Comparison of Toxic and Carcinogenic Agents in Main- stream Smoke and in Environmental Tobacco Smoke Number and Size Distribution of Particles in Environ- mental Tobacco Smoke Estimating Human Exposure to Environmental Tobacco Smoke Time-Activity Patterns Temporal and Spatial Distribution of Smokers Determinations of Concentration of Environmental Tobacco Smoke Microenvironmental Measurements of Concentration Monitoring Studies Conclusions References 123 Introduction The physicochemical nature of environmental tobacco smoke (ETS) is governed by the type and form of the tobacco product or products burned, by the prevailing environmental conditions, and by secondary reactions. Mainstream smoke (MS) is the complex mixture that exits from the mouthpiece of a burning cigarette, cigar, or pipe when a puff is inhaled by the smoker. Sidestream smoke (SS) is formed between puff-drawings and is freely emitted into the air surrounding a smoldering tobacco product. Sidestream smoke repre- sents the major source for ETS. The exhaled portions of MS and the vapor phase components that diffuse through the wrapper into the surrounding air constitute minor contributors to ETS. In the scientific literature, the terms "passive smoking," "involun- tary smoking," and "inhalation of ETS" are frequently used inter- changeably (US DHEW 1979; US DHHS 19821964). Laboratory Smoking Data on the composition of MS and SS originate from laboratory studies. For such studies, cigarettes, cigars, or pipes are smoked by machines under standardized reproducible conditions. It is a major goal of these measurements to compare the yields of the specific components in the MS or SS or both of a variety of experimental or commercial tobacco products and to simulate, though not to repro- duce, human smoking habits. The most widely used standard conditions for machine smoking cigarettes and little cigars (5 1.5 g) are one 35 mL puff of 2-second duration drawn once a minute to a butt length of 23 mm, or the length of the filter tip plus the over-wrap plus 3 mm (Brunnemann et al. 1976). The annual reports of the U.S. Federal Trade Commission on the tar, nicotine, and carbon monox- ide content of the smoke of U.S. commercial cigarettes are based on these laboratory smoking conditions. For cigars, the standard smoking conditions are a 20 mL puff of l&second duration taken once every 40 seconds, and a butt length of 33 mm CInternational Committee for Cigar Smoke Study 1974). The most frequently used pipe-smoking conditions call for the bowl to be filed with 1 g of tobacco and a 50 mL puff of l-second duration to be taken every 12 seconds (Miller 1964). A number of devices for collecting sidestream smoke have been developed (Dube and Green 1982). The most widely used device is a collection apparatus made of glass and cooled by water circulating through an outer jacket. The air entering the chamber through a distributor has a flow rats of 25 mL per second (1.5 L/min) (Brurmemann and Hoffmann 1974). Under these conditions, the yields of mainstream smoke components from a cigarette approxi- mate those obtained from the same cigarette when it is being smoked 125 in the open air. However, the velocity of the airstream through the chamber has considerable influence on the yields of individual compounds in SS (Klus and Kuhn 1982). To collect the particulate phase of MS and SS, the smoke aerosols are passed through a glass fiber filter (a Cambridge filter with a diameter of 45 mm) that traps more than 99 percent of all particles with a diameter of at least 0.1 pm (Wartman et al. 1959). The portion of the smoke that passes through the glass fiber filter is arbitrarily designated as vapor phase, although it is realized that this separa- tion does not fully reflect the actual physicochemical conditions prevailing in MS and SS. For the analysis of individual components or a group of components, specific trapping devices and methods have been developed (Dube and Green 1982). Human Smoking The standardized machine-smoking conditions used in the tobacco laboratory were set up to simulate the parameters of human smoking as practiced 30 years ago. The examination of current smoking practices suggests that machinesmoking conditions no longer reflect current practices. Human smoking patterns depend on a number of factors, one of which is the delivery of nicotine. Do&retry of smoke constituents has shown that low nicotine delivery (~0.6 to 1.0 m&cigarette) generally induces the smoker to draw larger puff volumes (up to 55 mL per puff), to puff more frequently (three to five times a minute), and to inhale more deeply (Heming et al. 1981). Furthermore, many smokers of cigarettes with perforated filter tips tend to obstruct the holes in these tips by pressing their lips around them; thus, they inhale more smoke than would he expected according to the machine-smoking data (Kozlow- ski et al. 1960). Smokers of cigarettes with a longitudinal air channel in the filter tip compress the tip in a similar manner so that the mainstream smoke delivery is increased over that measured with the laboratory methodology (Hoffmann et al. 1983). These deviations from machin~moking patterns cause a greater ammt of tobacco to be consumed during MS generation. Conse quently, the quantity of tobacco burned between puffs is diminished, and lower amounts of combustion products are released as SS. Because of the proximity to the burning tobacco product, the active smoker usually inhales more of the SS and ETS than a nonsmoker. It is not known to what extent the different constituents of inhaled ETS aerosols can be retained in the respiratory tract of nonsmokers. Studies with MS have shown that more than 90 percent of the volatile, hydrophilic components are retained by the smoker @al- hamn et al. 1968a) and that less than 50 percent of the volatile, hydrophobic MS components are retained by the smoker (Dalhamn et al. 196813). On the basis of these data, it may be assumed that the 126 passive smoker retains a high percentage of the vapor phase components of ETS and significantly less of its hydrophobic volatiles. Sidestream Smoke Formation7 and Physicochemical Nature When nonfilter cigarettes are being smoked under standardized conditions, approximately 45 percent of the tobacco column is consumed during the generation of MS (puff-drawing), whereas the remainder is burned between puffs and under conditions of a strongly reducing atmosphere. In addition, MS and SS is generated at distinctly higher temperatures than SS (Wynder and Hoffmann 1967). Thus, undiluted SS contains more tobaccoderived combustion products than does MS, and contains especially greater quantities of those combustion products that are formed by nitrosation or amination. Consequently, the composition of SS differs from that of MS. The SS of a smoldering cigarette enters the surrounding atmo- sphere about 3 mm in front of the paper burn line, at about 350" C (Baker 1984). In Table 1, the MS and the SS from nonfilter cigarettes are compared. Under standardized conditions, the formation of the MS of a nonfilter cigarette (80 mm, 1,230 mg) is completed during 10 puffs, requires 20 seconds, and consumes 347 mg of tobacco. The formation of SS from the same cigarette during smoldering requires 550 seconds and consumes 411 mg of tobacco (Neurath and Horst- mann 1963). The pH of the MS of a blended U.S. cigarette ranges from 6.0 to 6.2 and the pH of SS, from 6.7 to 7.5. Above pH 6, the proportion of unprotonated nicotine in undiluted smoke rises; at pH 7.9, about 50 percent is unprotonated. Therefore, SS contains more free nicotine in the vapor phase than MS. The reported measurements of the pH of cigars were 6.5 to 8.5 for MS and 7.5 to 8.7 for SS; measurements for the pH of SS from pipes have not been published (Brunnemann and Hoffmann 1974). Chemical Analysis In order to establish reproducible chemical-analytical data, ciga- rette SS is generated in a special chamber. This assures that the cigarettes burn evenly during puff intervals when an air-stream at a velocity of 25 mL per second is drawn through the chamber. At this flow rate in the chamber, MS generation is quantitatively similar to that measured without the SS chamber (Neurath and Ehmke 1964; Brunnemann and Hoffmann 1974; Dube and Green 1982). Through- out this chapter the data refer primarily to MS, SS, and ETS deriving from cigarettes and not from cigars or pipes, because 127 TAEJLE l.-Comparison of mainstream smoke (MS) and sidestream smoke (SS) of a nonfilter cigarette: Some physicochemical data Study Parameter3 MS ss Neurnth and Horstmarm Duration of emoke production (see) 20 660 `1963) Tobaccn burned (m& 347 411 ynder end Hofhann Peak temperature dm formation ("`3 a900 a600 367) Brunnemann and HoEman (1974) pHoft&alaemi3ol a-6.2 6.7-75 sceSaellati-SfOlZOlhli and Savino WE6) Number of partiolen per ckareW1 10.6 x 10" 36 x 10" Carter and Haqawa (1975); Hiller et al. m82) Particle s&a cnm)' Particle meau diameter (rut91 0.1-1.0 0.01-0.8 0.4 0.32 Wynder and Hoffinann Smoke dilution (~01 %I' (I967); K&b and Derrick wo); carbon momxide 3-S 2-3 B&or (1964); Hoffmann, Bnmnemann carbon dioxide 6-11 4-6 et al. w34) 1!&16 1.6-2 cigarette smoke is the major source of EYE3 in public places. Few data are available on the SS and ETS from cigars and pipes. About 300 to 400 of the several thousand individual compounds identified in tobacco smoke have been quantitatively determined in both mainstream and, sidestream smoke. A listing of selected agents iu the MS of nonfilter cigarettes with their reported range of concentration and their relative ratio of distribution in SS compared &ith MS is presented in Table 2. Values greater than 1.0 reflect the greater release of a given compound into SS than intO MS. The grouping of the compounds in Table 2 into vapor phase components and particulate phase constituents refers to the makeup of MS, but does not represent the physicochemical distribution of these corn- pounds in SS. Some of the volatile compounds in MS and SS are compared. On the basis of the amount of tobacco burned in the MS and SS of a nonfilter cigarette (see Table 11, the ratio of SS to MS should be 1.2 to 1.5 if the combustion conditions during both phases of smoke generation were comparable. However, this is not the case, 128 as is indicated by the higher SS to MS ratios for carbon monoxide (2.5-4.7), carbon dioxide W-11), acrolein (3-15), benzene (IO), and other smoke constituents. The high yield of carbon monoxide and carbon dioxide in SS indicates that more carbon monoxide is generated during smoldering than during puff-drawing. After passing very briefly through the hot cone, most of the carbon monoxide gas in both MS and SS is oxidised to carbon dioxide, most likely owing to the high temperature gradient and the sudden exposure to environmental oxygen upon emission., The higher yields of volatile pyridines in SS compared with MS are probably caused by the preferred formation of these compounds from the alkaloids during smoldering (S&melts et al. 1979). In contrast, hydrogen cyanide (HO is primarily formed from protein at temperatures above 700" C (Johnson and Kang 1971), and the smoldering of tobacco at about 690" C does not yield the pyrosynthe- sis of HCN to the extent that it occurs at the higher temperature present during MS generation. The very high levels of ammonia, nitrogen oxide, and the volatile N-nitrosamines in SS compared with the levels in MS is striking. Studies with `6N-nitrate have under- scored that the burning of tobacco results in the reduction of nitrate to ammonia, and that the latter is released to a greater extent during SS formation than during puff-drawing (Johnson et al. 1973). In a blended cigarette, this higher level of ammonia in SS causes its elevated pH to reach levels of 6.7 to 7.5, while the pH of MS is about 6 (Brunnemann and Hoffmann 1974). The increased release of the highly carcinogenic volatile N-nitrosa- mines into SS (20 to 100 times greater than into MS) has been well established (Brunnemann et al. 1977). The carcinogenic potential of SS may also be affected by the levels of the oxides of nitrogen (NO=). Four to ten times more nitrogen oxide (NO) is released into the environment in sidestream smoke than is inhaled with the main- stream smoke. The smoker inhales more than 95 percent of the NO, in the form of NO, and only a small portion is oxidized to the powerful nitrosating agent nitrogen dioxide (NOa). Only a fraction of NO is expected to be retained in the respiratory system of smokers by being bound to hemoglobin. The NO, gases released into the environment are partially oxidized to NO, (Vilcins and Lephardt 1975). Therefore, sidestream smoke-polluted environments are ex- pected to contain the hydrophilic nitrosating agent NO,. Data for particulate matter and some of its constituents in MS and SS are also listed in Table 2. The release of tobacco-specific N- nitrosamines into SS is up to four times higher than that into MS. Whether the distribution of these agents in the vapor phase and the particulate phase of SS is of major consequence with respect to the carcinogenic potential of SS needs to be determined. It is equally 129 t; 0 TABLE `lo-Distribution of constituents in mainstream smoke (MS) and the ratio of sidestream smoke @X3) to MS of noufilter cigarettes Vapor phase constituents ' MS SS/MS range ratio Particulate phase constituents' MS range SSIMS ratio Carbon monoxide Carbon dioxide Carbonyl sulfide Benzene ' Toluene Formaldehyde Acroiein Acetone Pyridine SMethylpyridine S-Vinylpyridine Hydrogen cyanide Hydrazine ' Ammonia Methylamine Dimethylamine Nitrogen oxide 10-23 mg 2.5-4.7 20-40 mg a11 16-42 pg 0.03-0.13 12-46 pg 10 160 PET 6 70-100 Ilg o.k&O 6&m I% 8-16 1w250 pg 2-6 16-40 PB 6.5-20 12-36 p.g 3-13 11-30 w CD-40 4-w 0.1-0.25 32 ng 3 50-130 pg 40-170 11.5-28.7 pg 4.2-6.4 7.610 pg 3.7-5.1 1-W 4-10 Particulate matter * Nicotine Anatabine Phenol C&echo1 Hydroquinone Aniline 2-Toluidine 2-Naphthylamine* 4-Aminobiphenyl * Benz[a]anthracene' Benzo[a]pyrene s Cholesterol y-Butyrolactone' Quinoline I Harman N!-Nitrcsonornicotine' 15-4a mg 1.3-1.9 l-Z.5 mg 2.6-3.3 2-%l% <0.1-0.6 60-140 pg 1.6-3.0 1-w 0.60.9 110-300 pg 0.749 3130 w 30 160 ng 19 1.7 ng 30 4.6 ng 31 2C-70 ng 2-i 20-W 2.5-3.6 22 w 0.9 10-22 pg 3.k5.0 0.5-2 pg a11 1.7-3.1 w 0.7-1.7 200-3,~ ng 0.6-3 TABLE 2.-Continued MS -&SIMS MS Vapor phase constituents' SSIMS range ratio Particulate phase constituents' range ratio N-Nitrusodimethylamine' 1040 ng 20-1cQ NNK' 100-1,006 ng 14 N-Nitrosopyrrolidine' 630 ng 6-30 N-Nitrosudienthanolamine' 20-70 ng 1.2 Formic acid 216-490 ug 1.4-1.6 Cadmium 100 ng 7.2 Acetic acid 33O-SlO l(g 1.9-3.6 Nickel a 20-80 ni3 13-30 ZiiC 624 w 6.7 Polonium-210' 0.64-0.1 pCi 1.0-4.0 Hensoic acid 14-28 pg 0.67-0.95 Lactic acid 63-174 Iig 0.3-0.7 Glycolic acid 37-126 pg 0.6-0.96 Succinic acid 110-140 pg 0.43-0.62 ' Values are given far fresh and undiluted MS and SS. *Human carcinogen (IARC 1936). 3Suspxted human carcinogen (IARC 19%). `Animal carcinogen (IARC 1966). SOURCE: Elliott and Rowe (1975); Hoffmann et al. (1983); Klw and Kuhn (1982); Sakuma et al. Nfl3); Sakuma, Kusama, Ysmaguchi. Mabuki et al. (1984); Sakuma. K-ma, Yamaguchi, Sugawara (1994); Schmeltz et al. (1976). important to examine the significance of the abundant release of amines into SS (levels are up to 30 times higher than in MS), indicated by the data for aniline, Ztoluidine, and the alkaloids. This is of concern because certain amines are readily nitrosated to N- nitrosamines. However, analytical data on secondary reactions of amines in polluted environments are lacking. For a meaningful interpretation of the data on the distribution of the compounds in cigarette smoke presented in Table 2, certain aspects of the methodology should be emphasized. First, the data are baaed on analyses of nonfilter cigarettes that were smoked under standardized laboratory conditions. Second, the standardized ma- chine-smoking conditions were established according to human smoking patterns observed three decades ago and do not reflect the smoking behavior of contemporary smokers. This caveat applies particularly to smoking patterns observed with filter cigarettes designed for low smoke yields. Most consumers of these cigarettes inhale the smoke more intensely than smokers of nonftiter cigarettes (Herning et al. 1981; Hill et al. 1983). This change in smoking intensity affects the delivery of the side&ream smoke. The conven- tional filter tips of cigarettes influence primarily the yield of MS and have little impact on SS yield. However, in the case of cigarettes with specially designed filter tips such as perforations, the yield of SS is also affected (Table 3) (Adams et al. 1985). Radioactlvity of Tobacco Smoke Naturally occurring decay products of radon are found in tobacco and, therefore, also in tobacco smoke. These include the isotopes of lead (Pb-2101, bismuth (Bi-210), polonium (Po210), and radon, which originates from the decay of uranium through radium (Radford and Hunt 1984; Max-tell 1975). Radon and its short-lived daughters (Po- 218, Pb214, Bi-214, Po214), which precede long-lived daughters in the decay chain, are ubiquitous in indoor air and are largely derived from sources other than tobacco smoke. Most of the radon daughters are attached to particles in the air, but a small proportion, referred to as the unattached fraction, is not (Raabe 1989; Kruger and Nijthling 1979; Bergman and Axelson 1983). It has been suggested that the presence of Pb-210 and subsequent decay products in tobacco is dependent upon an absorption of short- lived radon daughters on the leaves of the tobacco plant, especially where phosphate fertilizers that are rich in radium have been used and have caused increased leakage of radon from the ground. These attached short-lived radon daughters then decay to long-lived Pb-210 and subsequent nuclides found in the tobacco (Fleischer and Parungo 1974; Martell 1975). However, the origin of these decay products may 132 TABLE 3.-Distribution of selected components in the sidestream smoke (SS) and the ratio of SS to mainstream smoke (MS) of four U.S. commercial cigarettes components Cigarette A Cigarette B Cigarette ( Cigarette D 85 mm NF 85 mm F 85 mm F 85 mm PF ss SWMS ss SSiMS ss SS/MS ss SSIMS Tar imglgl 22.6 1.1 24.4 1.6 20.0 2.9 14.1 15.6 Nicotine lmgigl 4.6 2.2 4.0 2.7 3.4 4.2 3.0 20.0 C'arbon monoxide cmg/g) 28.3 2.1 36.6 2.7 33.2 3.5 26.8 14.9 Ammonia ImyJgl 524 7.0 8Y3 46 213.1 6.3 236 5.8 (`atecho (pgtgl 58.2 1.4 89.8 1.9 69.5 2.6 117 12.9 Benzolalpyrenv Ingig 67 2.6 45.7 2.6 51.7 42 448 20.4 N~N~trosodlmethyumine tng/gl 735 236 597 139 611 50.4 685 167 N-Nitrosopyrrolidtne cng/g~ 177 2.7 13Y 13.6 233 71 234 11.7 N -Niirosonornlcotme (ng/yi 857 0.85 307 0.63 1x5 0.68 338 5.1 also depend on the general occurrence of radon in the atmosphere and not on the local emanation of radon (Hill 1982). In recent years, it has been shown that relatively high levels of radon and short-lived radon daughters may occur in indoor air, and consistent observations in this regard have been made in several countries (Nero et al. 1985). In the air with a very low concentration of particles, the proportion of unattached radon daughters is increased beyond that found with a higher concentration of particles. The unattached daughters are removed more rapidly than those that are attached by plating out on walls and fixtures. The addition of an aerosol, such as tobacco smoke, increases the attached fraction, elevates the concentration of radon daughters, and reduces the rate of removal of radon daughters (Bergman and Axelson 1983). The dose of a radiation received by the airway epithelium depends not only on the concentration of radon daughters but also on the unattached fraction and on the size distribution of the inhaled particles. The interpIay among these factors as they are modified by KTS has not yet been fully examined. Environmental Tobacco Smoke The air dilution of side&ream smoke, and of other contributors to ETS, causes several physicochemical changes in the aerosol. The concentration of particles in ET'S depends on the degree of air dilution and may range from 300 to 500 mg/mg to a few p&ma. At the same time, the median diameter of particles may decrease as undiluted SS is diluted to form ETS (Keith and Derrick 1960, Wynder and Hoffmann 1967; Ingebrethsen and Sears 1936). Further- more, nicotine volatilizes during air dilution of SS, so that in ET'S it occurs almost exclusively in the vapor phase (Eudy et al. 1985). This is reflected in the fairly rapid occurrence of relatively high concen- trations of nicotine in the saliva of people entering a smokepolluted room (Hoffmann, Haley et al. 1984). Most likely there are also redistributions between the vapor phase and the particulate phase of other constituents in SS due to air dilution, which may account for the presence of other semivolatiles in the vapor phase of KTS. However, evidence of such effects needs to be established. Comparison of Toxic and Carcinogenic Agents in Mainstream Smoke and in Environmental Tobacco Smoke The combustion products of cigarettes are the source of both environmental tobacco smoke and mainstream smoke. Therefore, comparisons of the levels of specific toxins and carcinogens in KTS with the corresponding levels in the mainstream smoke are relevant to an estimation of the risk of E'I'S exposure. Although KTS is a far 134 less concentrated aerosol than undiluted MS, both inhalants contain the same volatile and nonvolatile toxic agents and carcinogens. This fact and the current knowledge about the quantitative relationships between dose and effect that are commonly observed from exposure to carcinogens have led to the conclusion that the inhalation of ET'S gives rise to some risk of cancer (IARC 1986). However, comparisons of MS and ETS should include the consider- ation of the differences between the two aerosols with regard to their chemical composition, including pH levels, and their physicochemi- cal nature (particle size, air dilution factors, and distribution of agents between vapor phase and particulate phase). Another impor- tant consideration pertains to the differences between inhaling ambient air and inhaling a concentrated smoke aerosol during puff- drawing. Finally, chemical and physicochemical data established by the analysis of smoke generated by machine-smoking are certainly not fully comparable to the levels and characteristics of compounds generated when a smoker inhales cigarette smoke. This caveat applies particularly to the smoking of low-yield cigarettes, for which the yields of smoke constituents in machine-generated smoking and human smoking activities may be most divergent (Heming et al. 1981). The levels of certain smoke constituents in the mainstream smoke of one cigarette compared with the amounts of such compounds inhaled as constituents of ETS in 1 hour at a respiratory rate of 10 L per minute are presented in Table 4. Unaged MS does not contain nitrogen dioxide (NO* < 5 &cigarette) because the nitrogen oxides generated during tobacco combustion in the reducing atmosphere of the burning cone are transported in the smoke stream (a10 vol % 0,) to the exit of the cigarette mouthpiece in less than 0.2 seconds, and it takes 500 seconds for half of the nitrogen oxide in MS to oxidize to nitrogen dioxide (Neurath 1972). The relatively low values for nicotine reported in ETS may be explained, in part, by the inefficiency of the trapping devices for collecting all of the available nicotine; the alkaloid is predominantly in the vapor phase, which escapes retention by the filters of such devices. The assignment of benzene as a "human carcinogen," benzo- [alpyrene as a "suspected human carcinogen," and N-nitrosodi- methylamine and N-nitrosodiethylamine as "animal carcinogens" is based on definitions by the International Agency for Research on Cancer (1986). Accordingly, a human carcinogen is an agent for which "sufficient evidence of carcinogenicity indicates that there is a causal relationship between exposure and human cancer." A SUS- petted human carcinogen is an agent for which "limited evidence of carcinogenicity indicates that a causal interpretation is credible, but that alternate explanations, such as chance, bias, or confounding, could not adequately be excluded." An animal carcinogen is an agent 135 E TAFHJZ 4-Concentrations of toxic and carcinogetic agents in notilbr cigarette mainstream smoke and in environmental tobacco smoke (EiTS) in indoor environments Agent . Inhaled ae ETS constituents during 1 hour Mainstream Smoke Range Episodic high values' Weight Concentration Weight Concentration Weight Concentration Carbon monoxide lo-23 mg Nitrogen oxide 100-600M Nitrogen dioxide <5 w Acrolein 60-100 pg Acetone KNJ-260 pg Benzene 1248 pg N-Nitrosodimethylamine' 10-40 ng N-NitrosodiethylemineJ 4-25 ng Nicotine v.3=2,500 Pl? Be@alpyre"e' 20-40 ng 2WXQ-5~,300 rm 23O,ooo-1,400,ooO ppb <7&Q ppb 75,CG+125,000 ppb 120.~,~ ppb 11$00-43,000 ppb s-36 ppb 3-17 ppb 434I,OGC-1,080,000 ppb 5-11 ppb 1.2-22 mg 7-90 pg 24-S7Irg S-72 M 210-720 pg u-190 pg 6-140 ng (6120 ng 0.630 pg 1.7-460 ng l-18.5 ppm 9-120 ppb 21-76 ppb 6-50 ppb 160-500 wb 6-9~ wb 0.003-0.072 ppb <0.00%0.05 ppb 0.15-7.5 ppb 0.0002-0.04 ppb 37 mg 146 w 120 l4z 110 pg 3,500 I% 190 l% 140 ng 120 ng 3cQws 460 ng 32 PP~ 196 ppb 106 wb 8~ wb 2,400 wb 98 wb 0.072 ppb 0.05 ppb 76 wb 0.04 ppb NOTE: Values for inhaled mainstream smoke components were calculated from values in Table 2 and on a respiratory rate of 10 L per minute. Valuea for carbon monoxide and nicotine represent the range in mainstream smoke of U.S. nonfilter cigarettes 88 reported by the U.S. Federal Trade Commission (19%). Data under EIS are derived from Tables 8 through 16, with data fmm the unventilated interior compartmenta of automobiles excluded (Badre et al. 1978). `The designation "episodic high values" was chosen to classify those data in the literature that require confirmation. *Human carcinogen according to the IARC (Vainio et al. 1986) and suspected carcinogen according to the ACGIH (198%. `Animal carcinogen according to the IARC (V&do et al. 1995). 4 Suep&.ed human carcinogen, according to the IARC (Vainio et al. 1985) snd according to the ACGIH (1986). "for which there is sufficient evidence of carcinogenicity in animals but for which no data on humans are available." Polonium-210 is not listed in Table 4 because there are no data on the concentration of this isotope in ETS, although it is a component of both MS and SS. Whereas in clean air the short-lived radon daughters tend to plate out on room surfaces, in the presence of an aerosol such as El's, some of the short&& radon daughters become attached to particles and consequently remain available for inhala- tion. Radon daughter background concentration may more than double in the presence of EYI'S (Bergman and Axelson 1989). Number and Size Distribution of Particles in EnvIronmentsI Tobacco Smoke Environmental tobacco smoke consists of the combined products of both fresh and aged sidestream smoke and exhaled Ilaainstream smoke. Coagulation, evaporation, and particle removal on surfaces occur simultaneously to modify the physical characteristica of the ETS particles; as a result, the "typical" particle size and chemical composition of ETS may vary with the age of the smoke and the characteristics of the environment. Other factors such as relative humidity, particle concentration, and temperature may also tiect the characteristics of EYE. The rapid dilution of SS smoke as it is emitted into a room leads to a number of physical and chemical changes. For example, the evaporation of volatile species as the ETS ages reduces the median diameter of the smoke particles. Several studies have measured the particle distribution of SS under controlled conditions (Table 5), and indicate that the mass median diameter (MMD) of ETS is between approximately 0.2 w and 0.4 v. The differences among the studies reflect the varying analytical methods. EYE3 particles are in the diffusioncontrolled regime for particle removal and therefore will tend to follow stream lines, remain airborne for long periods of time, and rapidly disperse through open volumes. As indicated, a number of factors can produce variation in the mean size of the particles in EYl'S, however, in considering transport, deposition, and removal in the human lung, it is useful to assume that the particle sizes of aged ETS will generally be between 0.1 and 0.4 pm. Although the results presented in Table 5 do not permit the assignment of a single value for the diameter of side&ream smoke particles, the difference in deposition efficiency in the human respiratory tract of 0.2 pm particles and 0.4 w particles is negligible (C&an and Lippmann 1980). Particles in this size range are not efficiently removed by sedimentation or impaction. Although diffu- sion is the major removal mechanism for particles of this size, it is . . mmnnally efficient in the 0.2 to 0.4 v range. The relatively low 137 iii TABLE li.-Summary of sidestream smoke size distribution studies Study Cigarette Method Chamber concentration (pg/m sJ count median diameter Ma.% median diameter Geometric standard deviation Number per cm' Keith and Derrick IlW-ll Blended "Conifuge" Not reported 0.15 Not reported Not reported 38 x 10" PorstendGrfer and Schraub (19721 Not reported CNUdiffusion tube Not reported 0.24 Not reported Not reported 3.3 x 10" Hiller et al. (1982J Not reported SPART analyzer 5@100 0.32 0.41 1.5 Not reported Leaderer et al. (1984) Commercial EAA mcl Not reported 0.225 21 Not reported lngebrethsen and sears (1986) MCICNC 0.2 1.5 particle deposition efficiency for SS particles in human volunteers observed by Hiller and colleagues (1982) is consistent with particles in this size range. Several investigators have measured the size distribution of MS smoke (Table 6). As is the case with SS smoke, the different instruments and methodologies employed yielded differing results. For purposes of comparison, only two sets of studies utilizing similar instruments are discussed. McCusker and colleagues (19831, using a single particle aerodynamic relaxation time @PART) analyz- er to study highly diluted MS smoke particles, found a mass median diameter of 0.42 pm with a geometric standard deviation (GSD) of 1.38. Hiller and colleagues (1982) used the SPART analyzer on SS smoke particles and found a mass median diameter of 0.41 pm and GSD of 1.5. Chang and colleagues (1985) used an electrical aerosol analyzer (EAA) to measure MS for various dilution ratios and reported a MMD of 0.27 pm (GSD 1.26) for the highest dilution. Leaderer and colleagues (1984) used an EAA to determine the size distribution for SS smoke particles in an environmental chamber and determined an MMD of 0.23 urn (GSD 2.08). These results also show that studies utilizing similar instruments provide similar results for the size distribution of both SS and MS particles. As discussed in an earlier section, however, the chemical composition of the MS and ETS particles can be quite different because of the very different conditions of their generation and the subsequent dilution and aging ETS undergoes before inhalation. Estimating Human Exposure to Environmental Tobacco Smoke Human exposure to ETS can be estimated using approaches similar to those used for other airborne pollutants. The concentra- tion of ETS to which an individual is exposed depends on factors such as the type and number of cigarettes burned, the volume of the room, the ventilation rate, and the proximity to the source. These factors, along with the duration of exposure and individual characteristics such as ventilatory rate and breathing pattern, dictate the dosage received by an individual. Ideally, the health effects of exposures to ETS might be assessed by quantifying the timedependent exposure dose for each of the several thousand compounds in cigarette smoke and defining the dose- response relationships for these compounds in producing disease, both as isolated compounds and in various combinations. The magnitude of this task, given the number of compounds in smoke, and the limited knowledge of the precise mechanisms by which these compounds cause disease have led to a simpler approach, one that attempts to use measures of exposure to individual smoke constitu- ents as estimates of whole smoke exposure. The accuracy with which 139 8' TABLE 6.-s ummary of niainstream smoke size distribution studies count MaSa median median Geometric Dilution diameter diameter etadad concentration Study cigarem Method rati0 k-1 (run) deviation (number/cm') Keith and Derrick ma3 Blended "ConIf~" 298 0.23 Not reported 1.6 6.9 I 10 Pomtmdllrfer and Sehraub (1972) Not reported CNC/diffueion tube Not reported 0.22 Not reported Not reported Not regmted Okada and Matmnama (1974) Blended Light e&t.ering Hinds ww Commercial Caecade impactor cascade impactor Cascade @iactor Aerosol certifuge Aeroeol certifuge Aerosol certifuee Aemol CeltitilKe 10 60 100 100 320 Ka 700 0.18 Not reported 0.62 Not reported 0.44 Not reported 0.39 Not reported 0.38 Not reported 0.98 Not reported 0.36 Not reported 0.37 0.29 1.5 1.36 Not reported 1.44 Not reportad 1.43 Not reported 1.33 Not reported 1.37 Not mported 1.35 Not rqmrted 1.31 Not revorkd 3 a 10'" Mdxlsker et al. 2Rl SPAm analmr 1.2611~ 0.36 0.42 1.38 4.2 x t cbang et al. 2Rl EAA 6 0.25 0.30 127 4.2 I 10' mm 10 0.24 0.26 1.18 3.6 x 10' 18 0.22 0.96 1.26 7 a 1w measurements of a single compound reflect exposure to whole smoke is limited by the changes in the composition of M`s with time and the conditions of exposure. For this reason, exposures to E'l'S are often afessed using several measures as markers, including mark- ers of the vapor phase and the particulate phase as well as reactive and nonreactive constituents. Although biological markers show promise as measures of exposure because they measure the absorp tion of smoke constituents, they too have limitations (diecussed ' Chapter 4). An individual's exposure is a dynamic integration of &: concentration in various environments and the time that the individual spends in those environments. In specifying an individual's exposure to specific components of EITS, consideration must be given tc the time scale of exposure appropriate for the response of interest. Immediate exposures of seconds or hours would be most relevant for irritant and acute allergic responses. Time-averaged exposures, of hours or days, may be important for acute contemporary effects such as upper and lowe respiratory tract symptoms or infections; chronic exposures occur ring over a year or a lifetime might be associated with increases prevalence of chronic diseases and risk of cancer. The spatial dimensions or the proximity of the individual to the source of smoke is important in assessing that individual's exposure to ETS. E!lTS is a complex, dynamic system that changes rapidly once emitted from a cigarette. Physical processes such as evaporation and dilution of the particles, scavenging of vapors on surfaces, and chemical reactions of reactive compounds are continuously occurring and modify the mixture referred to as ETS. An individual located a few centimeters or a meter from a burning cigarette may be exposed to a high concentration of ETS, ranging from 200 to 300 mg/m*, and may inhale components of the mostly undiluted smoke plume and of the exhaled mainstream smoke. Ayer and Yeager (1982) reported cigarette plume concentrations of formaldehyde and acrolein in the core smoke stream emitted from the cigarette of up to 190 times higher than known irritation levels. Hirayama, as reported by Lehnert (1984), cites the importance of this "proximity effect" in assewing exposure. llist.anw on the order of a meter tc tens of meters from a burning cigarette are relevant for exposures in offices, restaurants, a room in a how, a car, or the cabin of a commercial aircraft. At these distances, the mixing of ETS throughout the airspace and the factors that affect concentration are of importance in determinin g exposure for people in the space. In many rooms, mixing is not completely uniform throughout the volume, and significant concentration gradients can be demonstrated Wizu 1930). These concentration gradients wilI affect an individual's exposure by modifying the effectiveness of ventilation in diluting or removing pollutants. The airborne mass concentration may vary by 141 a fa&r of 10 or more within a room. Short-term measurements in rooms with smokers can yield respirable particulate concentrations of 100 to 1,000 CLg/mS (Repace and Lowrey 1980). Multihour measurements average out variations in smoking, mixing, and ventilation and yield concentrations in the range of 20 to 200 CLg/mS (Spengler et al. 1981,1985,1986). Finally, on a systems scale, as in a house or building, concentrations are influenced by dispersion and dilution through the volume. Most timeintegrated samples are taken on tbis larger scale. Using a piexobalance, Lebret (1985) found significant variation in respirable suspended particulate (R.SP) levels between the living room, kitchen, and bedroom in homes in the Netherlands during smoking or within onehalf hour of smoking. Ju and Spengler (1981) studied the room-toroom variation in 24-hour average concentra- tions of respirable particles in various residences. Although differ- ences between some rooms were statistically sign&ant, absolute differences were relatively small, with a maximum difference of a factor of 2. Moscbandreas and colleagues (1978) released sulfur hexafluoride, a tracer gas, in the living rooms of several residences and observed uniform concentrations in adjacent rooms within 30 to 90 minutes, RSP, which is slightly reactive, and nonreactive gases would be expected to rapidly migrate through adjacent rooms. Therefore, in a setting such as the work environment, where the duration of exposure is several hours or more, HTS would be expected to disseminate throughout the airspace in which smoking is occurring. Smoke dissemination may be reduced when air exchange rates are low, as may occur when internal doors are closed. Time-Activity Patterns Individual time-activity patterns are a major determinant of exposure to ETS. The population of the United States is mobile, spending variable amounts of time in different microenvironments. Individual activity patterns depend on age, occupation, season, social class, and sex. For example, Letz and colleagues (1984) surveyed the time-activity patterns of 332 residents of Roane County, Tennessee, and found that 75 percent of the person-hours were spent at home, 10.8 percent at work, 8.5 percent in public places, 2.9 percent in travel, and 2.8 percent in various other places. As expected, occupation and age were strong determinants of time-activity patterns. Housewives and unemployed or retired individuals spent 84.9 percent of their time at home, and occupational groups worked 21 to 24 percent of the hours. Students tended to spend the largest percentage of their time in public places, presumably schools, ranging from 14.7 percent for the youngest group to 19.17 percent for the oldest group of students. 142 TABLJZ `I.-Mean percent and standard deviation of time allocation iu various locations by work or school classification subgroup outdoor ofiice/ Indwtrial/ Thl,aU Location HOlIlemaLer student worker ssrvice c4luhuction perticipant.9 Home 84.34 60.91 49.97 63.74 57.23 64.21 (2.02l' (13.92) (12.24) (8.72) c7.05) (13.99) outside 5.52 8.62 19.81 2.47 -10.69 (3-m 6.53 K4.55) (2491 (10.74) (Fi Motor vehicle 4.28 5.11 8.67 (3.19) (3.74) (6.15) 0 (7% 5.51 (4.m other incLmn 6.01 23.61 21.56 24.99 24.80 21.68 (3.27) (10.61) (5.32) (10.241 a28a (11.37) cooking 4.69 0.52 1.24 u.fm (lit (iii (:: @.W cw Near mnokem 2.34 5.!20 275 11.73 (4.32) c1.88) (3.38) (15.19) (12: (!z: Number 8 32 4 12 8 66' `Numbershparentheemarethe~darddeviation. ' `ho unemployed partioipanta - inchded in the total. but not given a mparate catqmy. SOURCE: Data f-mm Quaokerlb et al. (1982). The time allocations for various population subgroups in Portage, Wisconsin, are summarized in Table 7 (Quackenboss et al. 1982). The data are consistent with the findings of Letz and colleagues (1984) and show that the variability of individual nonsmokers' exposure to smokers can be quite marked between the various occupational subgroups. Infants have unique time-activity patterns; their mobility is limited and the locations where they spend their time depend primarily on their caretakers. The time-location patterns for 46 infants is illustrated in half-hour segments in E'igure 1 (Harlos et al. in press). Although infants spend most of their time in their bedrooms, they are in contact with a caretaker while traveling or in the living room or the kitchen for approximately half of the day. These infant time-activity patterns presumably correspond to the family patterns and may significantly influence the infants' poten- tial exposure. Although most people spend approximately 90 percent of their time in just two microenvironments (home and work) (&alai 1972), important exposures can be encountered in other environments. For instance, commuting or being Yn transit" accounts for about 0.5 to 1.5 hours per day for most people. Therefore, additional information 143 -L --M -3 ,aD -a r -9 -Lx -0 FIGURE I.-Time location patterns for 46 infants SOURCE: HarIm et al. (in prem). on the time spent and the EZS concentration in various microenvi- ronments may be useful in defining exposure. This exposure information can be obtained by questionnaire and validated by personal monitoring programs. The characterization of concentra- 144 tions or exposures or both in microenvironments should use time scales appropriate for the health effect of interest. These variations in location -and time-activity patterns can make the reconstruction of detailed ETS exposure difficult in studies of long-term health effects. The limitations in utilizing this timeactivity approach in charac- terizing exposures to other environmental pollutants also apply for ETS exposures. They include the following: the extent to which overall population estimates can be generalized to individual pat terns is poorly understood; concentrations in various microenviron- ments are only partially characterized, the variation in time and activity patterns and their effects on concentration levels are not established; extrapolation to longer time scales either prospectively or retrospectively has not been validated; the differences within structures, i.e., room to room ~variations, are not well established. Temporal and Spatial Distribution of Smokers Exposure to ETS can occur in a wide variety of public and private locations. Approximately 30 percent of the U.S. adult population currently are cigarette smokers. Nationwide, 46 percent of homes have one or more smokers (Bureau of the Census 1985). In a survey of more than 10,000 children in six U.S. cities, the percentage of children living with one or more smoking adults varied from a low of 60 percent to a high of 75 percent (Ferris et al. 1979). Lebowitx and Burrows (1976) reported that 54 percent of children in a study in Tucson had at least one smoker in the home; Schilling and colleagues (1977) reported that 63 percent of homes in a Connecticut study had a smoker in the home. These data indicate that the population potentially exposed to ETS in the home is greater than might be inferred from aggregated national statistics on the prevalence of smoking. A variation in the percentage of homes with smokers may be observed among different regions. Furthermore, within house holds, smoking does not take place uniformly in time or space. Smoking patterns may change with activity, location, and time of day. These variables all serve to modify a nonsmoker's exposure to ETS. Exposure to ETS at home may also correlate with ETS exposures outside the home, possibly because nonsmokers married to smokers may have a greater tolerance for ETS-polluted environments or may be in the company of more smokers because of the spouses' tendency to associate with other smokers. Wald and Ritchie (1984) used a biological marker and questionnaires to show that nonsmokers married to smokers reported a duration of exposure to ETS greater outside the home than was reported by nonsmokers married to nonsmokers (10.7 hours and 6.0 hours, respectively). Smoking prevalence varies widely among different groups (e.g., teenage girls, nonworking adults, and adults employed in VICIOUS 145 occupations); this variation modifies the exposure of nonsmokers to EEL Smokers are present in nearly all environments, including most workplaces, restaurants, and transit vehicles, making it almost impossible for a nonsmoker to avoid some exposure to ETS. The number of cigarettes consumed per hour by the smoker may vary at different times in the day, and the rate and density of smoking will also differ by the type of indoor environment and activity in such hales as schools, autos, planes, offices, shops, and bars. Although there have been numerous measurements of ETS concentrations in various indoor settings, these data do not repre- sent a comprehensive description of the actual distribution of ETS exposures in the U.S. population. Spengler and colleagues (1995) and Sexton and colleagues (1984) demonstrated by the personal monitor- ing of respirable particles and the use of time-activity questionnaires that exposures to EZS both at home and at work are significant contributors to personal exposures. However, additional data on the distribution of smokers in the nonsmokers' environment, as well as the distribution of ETS levels in that environment, are needed in order to characterize the actual E!CS exposure of the U.S. population. Determinations of Concentration of Environmental Tobacco Smoke Environmental tobacco smoke is a complex mixture of chemical compmmds that individually may be in the particulate phase, the vapor phase, or both. ETS concentration varies with the generation rate of its tobacco-derived constituents, usually given as micrometer per hour. The generation rate for ETS has been approximated by the number of cigarettes smoked or the number of people present in a room who are actively smoking. Room-specific characteristics such as ventilation rate, decay rate, mixing rate, and room volume also modify the concentration. Because ETS particles have MMDs in the 0.2 to 0.4 Frn range, convective flows dominate their movement in air, they remain airborne for long periods of time, and they are rapidly distributed through a room by advection and a variety of mixing forces. Under many conditions, the ventilation rate of a space will dominate chemical or physical removal mechanisms in deter- mining the levels of ETS particles. Nonreactive ETS components distribute rapidly through an air- space volume, and their elimination depends almost solely on the ventilation rate. For example, Wade and colleagues (1976) simulta- neously measured carbon monoxide, a nonreactive gas, and nitrogen &oxide, a reactive gas, in a house and determined their half-lives to be 2.1 and 0.6 hours, respectively. This study demonstrates the need for caution in extrapolating from one vapor phase compound to another. Reactive gases and vapors may be rapidly lost to surfaces or 146 may react with other chemical species. Their removal may be dotted by their reactiOn Or absorption rates. Furthermore, the decay of ETsderived Substances can be a function of the chemical as well as the physical characteristics of room surfaces. For example, Walsh and colleagues (1977) found that sulfur dioxide removal was greater for rooms with neutral and alkaline carpets than for rooms bving carpets with acidic PH. Reactions with furnishings and other materials may occur for some M`s components as well. ~tx-c-tenvjronmental Measurementa of Conce&r&ion As was discussed earlier, the complex chemical tieup of ETS makes the measurements of individual levels for each compound present in JWS impossible with existing resources; thus, some individual constituents have been measured as markers of overall smoke exposure. Because many of these constituents are also emitted from other sources in the environment, the contribution of El% to the levels of these constituents is quantified by determining &e enrichment of specific compounds found in smoke-polluted environments relative to the concentration measured in nonsmoking areas. Various ETS components have been measured for this purpose, including acrolein, aldehydes, aromatic hydrocarbm, carbon monoxide, nicotine, nitrogen oxides, nitrosamines, phenols, and respirable particulate matter. A summary of the levels found and the conditions of measurement are presented in Tables 8 through 15. The major limitation of using most of these gases, vapors, and particles is their lack of specificity for ETS. The presence of sources, other than tobacco smoke, of these compounds may limit their utility for determining the absolute contribution made by EITS to room concentrations. Levels of nicotine and tobacco-specific nitrosamines, however, are specific for ETS exposure. Obviously, no single measurement can completely characterize the nonsmoker's exposure to ETS, and many studies have measured several of these components in order to characterize the exposure. Markers should be chosen both because of their accuracy in estimating exposure and because of their relevance for the health outcome of interest. One widely reported marker of ETS is respirable suspended particulate (RSP) matter. Although lacking specificity for tobacco smoke, the prevalence and number of smokers correlates well with RSP levels in homes and other enclosed areas. A study of the RSP levels in 80 homes in six cities (Figure 2) (Spengler et al. 1981) showed that indoor concentrations were higher on average and had a greater range than the outdoor concentrations. From these data, it is evident that even one smoker can SigllifiCiUltig elevate indoor R+SP levels. 147 TABLE EL-Acrolein measured under realistic conditions Study Badre et al. wm c%fee &Ken Hospital lobby 2 train compartment9 car F&her et al. (1978) and Weher et al. (1979) lleataurant Rataurant Bar Cafeteria Varied Not &em 18 smokers Not given 12 to a0 amokem Not given 2to3mokera Not given 3 smokers Natural, open 2 mnokem Natural, cloned F&80/470 m' 6@-m/440 m* 30 -40/&l ma NJ-l&Y674 ma Mechanid Natural Natnral, open 11 changeanu loo n&L. sampled 100 mL eamplen loo mL mmpla 100 mL .mulplea loo mL m.mpled 1OOmLsampla 27 x 30 mic samplea 29X3Odlumpla 28 x 30 min analplea 24 x 30 min 8anlpla 0.03-0.10 m&n' 0.195 m&n* 0.02 mglm' 0.0!&0.12 &In' 0.03 tag/m* 0.20 mg/m' 7PPh 8 Ppb 10 ppb 6 ppb (5 Ppb non8moking eecticad TABLE 9.-Aromatic hydrocarbons measured under realistic conditions Study Type of premises Levele Ncmemcha aatde Monitwing Ventilation mnditiona Mean Ranec-w Badre et al. (1978) cafes Room Train compartmente car cf&a Varied Not given loo mL sampled Room 18 amokem Not @en loo mL Eamplee Train wmpartmente 2 to 3 emokem Not &en loo mL namplw car 2 maokern Natural, clcued loo mL samples FXllott and Rowe (1976) Arena Galuakinova ww Ileetaurant Varied Not given 100 mL Blrmplen 18 smokera Not given loo mL Mmples 2 ta 3 amokere Not given loo mL amnples 3 nmokera Natural, open loo mL Bamph 2 amokere Natural, clod loo mL samples s,647-10,7S9 people 12,00&4S44 people 13,ooO-l4Xl7 people Not given Not @en Not given Not given Not &en Separate non- =Ktif,Y dsJrs 7.1 9.9 21.7 ~dweineummer 6.2 18 daya in the fall 2aHU Benzene b&m*) 0.102 0.04 0.16 O.W.16 0.oM.10 Toulene (mg/ms) 0.04-1.04 0.216 1.87 0.60 Beinclabymae (M/m*) 0.69 TABLE 9.-Continued Study Just et al. (1972) Coffee houses Not given Not given 6 hr wntinuoue 02610.1 4.0-9.3 (outdoola) Jhzde~yrone (ng/m") 3.3-23.4 3.0-5.1 (outdoola~ Benmkhihmrylene (ng/m*) W-10.6 6.9-13.6 (outdoors) Perylene bglm*) o-7-1.3 0.1-1.7 (outdoola) F%mne (s&m') 4.1-9.4 2%?.O (outdoom) Anthanthrene (&ma) 0.61.9 0.5-1.8 knltdooE3) Coronene (rig/d 05-1.2 1.0-2.8 Phenols b/m') 7.4-11.6 Beruda$yreae (r&m') Peny (1973) ' 14 public placea Nat piven Not given samples, 6 outdoor IoCatiOllE < 20460 (20-43 ' The correctn~ of the data ia doubtful (Grimmer et al. 1977). TABLE lO.-Carbon monoxide measured under realistic conditions Study Ventilation Monibrlng CWditiOM Levela (ppm) Mean Nonsmoking contmle @Pm) Mean Eadre et al. (1978) Bcafea Varied Not given 20 mill sempleu 2-23 (outdoore) O-15 Room 18 emokma Not given 20 mln snmplea 60 0 (0ukJoonl) Hospital lobby 12 to 90 amokem Not given 20 mln samples 5 2train 2 to 3 smokers Not given 20 min namplea 44 wmpartmenta car 3 amokera Natural, open 20 min aample 14 0 (0utdooIu) 2 Bmokera Natural, cloeed 20 min samples !?a 0 (outdoore) Can0 et al. (1970) Submarines 68 ma 157 c;sarettes per&Y 94-103 cigarettea w* &Y YeS Ye0 <40 mm <40 mm Chappell and Parker wl7) 10 offices 16 resteurant3 14 nightclubs and taverns Tavern Not given Not given Not 9iven Not given value4 not given valuea not given valuea not glven Arti&ial None of!?@ 1440 ft.' Natural, open 17x2-3min samples 17X29min -Pl- 19 x 2-3 min mamplm 18XMmiJJ anmplee 2x2-3min BEUUPlW 2-3mlnaamplee 3omlnafter amaking 2.5 f 1.0 1.5-4.6 2.5 f 1.0 1.5-4.5 butdoors) 4.0 f 2.5 1.0-9.6 2.5 f 1.6 1.0-6.0 (outdwm) 13.0 f 7.0 3.0-29.0 3.0 f 2.0 1.06.0 bladom~ 8.5 =tPW 10.0 (peak) 1.0 t; RI TABLE 10.4ntinud Study Coburn et al. ~oorrm Not given Not given (lssa) Not &en 4.9-9.0 N-oked roome 2.2 f 0.96 oA-4.6 Cuddeback Tavern 1 16-294 people 6 changedhr 8 br continuous 11.6 10-l-12 Et) 2 wdwd 2hrafteremoking -1 Tavern 2 Not given l-2 cbangen/br 8 hr amtiauoun 17 -CM?2 valua not given 2brefterMokblg -12 valum not given U.S. Dept. of 18 military 165-219 people Mecbwlcal 6-7 hr contlnuoue l smoker/ms (mean 2.2 smokers/mJ) 18 f 7 persons/lo0 ma, with 1 smoker/l00 ma ,202 120 38 f 16 38 f 16 242 f 176 m-697) 406 * 188 (187-697) Subtracted from TSP Same Not done 36 + 10' (4 locations) 47 f 13' (13 locations) 53 f 8' TSP measured with pieeoefectric balance (see above) All samples colfected using pieroelectric balance with very high collection efficiency at 3.6 pm and 10% at 4 (cm; sample the l-60 min, outdoom 6-16 min z TABLE 4.-Continued Study Location Conditions of location, occupancy, smoking 6% nonsmoking (NS) TSP pmhn' I fsD Background pm/m' Comments Spengler et al. (1981) 35 homes 16 homes 5 homes 1 home* No smokers 1 smoker 2 smokers 2 smokers, tightly sealed, central air conditioning 24.4 f 11.6' 36.6 f. 14.6 70.4 f 42.9 144 21.1 zlz 11.9 all 55 homes Annual mean: respirable ma8s collected on filters after removal of nonrespirable fraction; `24-hr sample collected every 6 days ' Ambient prticulate concentration at site, but outdm~~. `This home is one of the !ive homes above. TABLE &-Indoor concentration of total suspended particulates (TPM) generated by smoking cigarettes under laboratory conditions chamber Cigarette TPM Study Test conditions Ventiition Size consumption mg/m' Comment.9 Penkala and Well mixed None 9.2 ma 3 simultan~usly, 2 q 3.0 de Oliveira (19'76) puffs Hoegg Sealed chamber; Portable fans 25 ma 24 simultaneously by 16.66 (1972) experimenter and test circulated air TPM measured gravimetrically machine after collection of suspended equipment in chamber; particulatea on fdten; measured 18 min sidestream smoke mlIected in pcetamoking chamber; mainstream smoke dischaqp?d Same, 150 min Same 4 simultaneously by 1.61 wetsmokina machine Hugod et al. (1978) Sealed room Unventilated 68 mJ 20 simultaneously by machine 6.76 TPM measured gravimetrically from 3hr collection on filter; mainstream smoke in chamber Cain et al. (1983) Muramahm 4-12 occupants Climata-controlled chamber Climatec0ntr0lled 11 ft3/min/oceupant 11 ma 4/hr (by occupants) 0.350 66 ft'lminloccupant 11 mJ 4/hr fby occupants) 0.16 11 ft'/min/occupant 11 ma 16/hr (by occupants) 1.26 68 ft'/min/occupant 11 mJ 16/hr (by GCGU~MW 0.40 16.4 air changes/hr 34 ms l/8 min to 60 min 0.19-0.26 F5ezoelectric balance messwed total mass over 0.01-20 pm Pieaoelectric balance et al. (1963) chamber Climate-controlled chamber 16.4 air changeslhr 30 ma 3 simultaneously, then 2/8 min 0.47-0.622 and a deposition fraction of 11 percent (Hiller, McCusker et al. 1982), mass deposition over an &hour work shift would be 0.317 mg. The Concept of "Cigarette Equivalents" Many investigators have attempted to estimate the potential toxicity of involuntary smoking for the nonsmoker by calculating "cigarette equivalents" (C.E.). To inhale one C.E. by involuntary smoking, the involuntary smoker would inhale the same mass quantity of ETS as is inhaled from one cigarette by a mainstream smoker. This approach has led to estimates from as low as 0.001 C.E. per hour to as high as 27 C.E. per day (Hoegg 1972; Hinds and First 1975; Hugod et al. 1978; Repace and Lowrey 1980). These differences of up to three orders of magnitude seem illogical when most reports of measurements of environmental concentrations of smoke, from the most clean to the most polluted with environmental tobacco smoke, are within tenfold to fiftyfold of each other. The following discussion demonstrates why the C.E. can vary so greatly as a measure of exposure. The calculation of C.E. is as follows: PMIw = TSP (mg/m') x Ox; where PM&,) equals the particulate mass inhaled by passive smoking, TSP equals the total suspended particulate, and VE equals the inhaled volume. C.E. = PMI&PML); where C.E. equals cigarette equivalent and PML) equals the mass inhaled by (mainstream) smoking one cigarette. (This is taken to be the tar content of a cigarette as reported by the U.S. Federal Trade Commission.) Cigarette equivalents can be calculated for any time interval chosen, i.e., per hour, per day. Although the example given is for particulate mass, C.E. can be calculated for any component of cigarette smoke, such as carbon monoxide and benzo[a]pyrene. The following calculations illustrate the different results from two different approaches to the calculation of C.E. Example 1 Example 2 SIB 0.36 mg/hr 20 ma/day PMIw 16.1 mg tar/@ 0.55 mg tar/cig TSP 40 CLg/mS 700 pg/m9 Example 1 PMIcp, = TSP x Ox = 40 P /m9 x 0.36 ms/hr = 14. CLg/hr C.E. = PMI&PM&ms, = (0.0144 mg/hr)/(l6.1 mg/cig) = 0.001 cig/hr 198 Example 2 PM&PI =TSPxOr = 700 w/ma x 20 ma/&y = 14,990 p&day C.E. = PMldwIk4 = (14 mgklay)/(O.65 mghig) = 245 &g/day These caktitiOn8 of C-E. approximate the approach- d h ho ~~rts-Exanw~e 1 by Kinds and Pi.& (1975) and Example 2 by Repace and Lowrey (198O)-and the results are similar. The exam- ples are the extremes used in the two studies, and are at the extremes Of CommOmy cited rep&a of C.E. Even if the Tsp concentration used in the two examples were the me, the multx would differ 24-fold because Example 1 is calculated per hour and Example 2 is calculated per day; 2%fold because of the aerence in inhaled minute volume; and 29-fold because of the difference in what is considered to be a `Wandard" cigarette. Even using the same TSP concentration, the results would be 1.6 x 10" different. If C.E. is to be calculated, all of the factors used in the calculation should be Standardized. The calculation of C.E. is deficient in several other ways. The deposition fraction of the total inhaled particulate mass in the respiratory tract from mainstream smoke is higher than from involuntary smoking. The deposition fraction for involuntary smok- ing is approximately 11 percent for mouth breathing (Hiller, Mazumder et al. 1982). The deposition from mainstream smoke has been reported to vary from 47 to 90 percent (Table 3). The cigarette equivalent calculation considers only the quantity inhaled, and if mm dose depoeited is considered, one C.E. from passive smoking will cause several times less mass to be deposited than the mainstream smoke of one cigarette. The differences in the chemical composition between sidestream smoke and mainstream smoke make the C.E. concept misleading unless C.E. is calculated for each smoke constituent. This has been accomplished (Hugod et al. 1973) using measured levels of various smoke co&ituente in a chamber filled with sidestream smoke. The redts indicate that one C.E. for carbon monoxide could b i&&j 5.5 times faster, and for aldehyde, 2.9 times faster, than for particulate mass. Measurements of total particulate matter and benxc(a]pyrene taken in an arena with active smoking revealed a fivefold rise in TSP above background and an eighteenfold increase in benzo[ajpyrene over background. Using the measured ben- zo[alpyrene concentration of 21.7 ng/ms, an inhaled volume of 2.4 ma, and 3.2 ng benxo[ajpyrene per cigarette, the occupant of such an environment would consume 6.4 C.E. for benzo[ajpyrene (IARC 1986, p. 87). The C.E. TSP would be 1.7. Therefore, a C.E. for the 199 carcinogen bedabyrene would be inhaled 3.6 times more rapidly w a C.E. for `JSP moth and Rowe 1975). me *de latitude h the results of C.E. calc~ations demonstrates the &pen&n= of the C.E. c.ahhtiOn On the numerical VahleS of the variables chosen, and correspondingly demonstrates the marked lotion of &e use of C.E. as an atmospheric measure of exposure b the wnb h en&m&d MOROCCO smoke. When the quantifica- con of an w ia needed, it is far more precise to use terms that defiae &e a of exposUre t0 the agent Of interest per unit he. However, the term cigarette equivalent is frequently used, not &ply 88 a mwure of exposure, but 88 a unit of disease risk that ~~them~ured~uresintoatikofdiseaseusingthe known daeresponse relationships between the number of ciga- re#es~~perdayandtheriskofdiseaee.IfC~.istobeusedasa tit of risk, the variables used to convert atmospheric measures into levels of rid for the active smoker need to be determined on the basis of the depcsition and smoke exposure measures for the average smoker. The deposition fraction of individual smoke constituents in t&e population of active smokers is needed rather than the range ob~rved in a few individuals. In addition, the actual average yield of the cigarettes smoked by the subjects in the prospective mortality studies would be needed to compare the dose-reeponse relationships accurately. The yield using the Federal Trade &nmission (Fl'c method may dramatically underestimate the actual yield of a cigarette when the puff volume, rate of draw, or number of puffs is increeeed; therefore, calculations using the Fl'C numbers may be inaccurate, particularly for the low-yield cigarettes. These limita- tions make exlxapolation from atmospheric measurea to c&are* equivalent units of disease risk a complex and potentially meanin- BleseP~. lAaiwa of Absorption In contrast, measuma of absorption of environmental tobacco smoke, particularly cotinine levels, can potentially overcome some of the limitations in translating environmental tobacco smoke expc+ sure3 into expected d&ease risk. Urinary cotinine levels are a reLatively accurate dosage measure of exposure to smoke; they have been measured in populations of smokers and nonsmokers, and are not subject to emrs in estimates of the minute ventilation or yield of the average cigarette. Potential differences in the half-life of cotinine in smokers and nonsmokers, differences in the absorption of nicotine relative to other toxic agents in the smoke, and differences in the ratio of nicotine to other toxic agents in mainstream smoke and sidestream smoke remain sources of error, but the accuracy with which active smoking and involuntary smoking exposure can be 200 compared is almost certainly substantially greater with measures of absorption than with atmospheric measures. Tobacco smoke contains many substances, but only a few have been measured in human biological fluids. of the g-w compo- nents, markers include carbon monoxide and thiocyanate. The latter is not a gas but a metabolite of gaseous hydrogen cyanide. Concentra- tions of nicotine and its metabolite cotinine are markers of nicotine uptake. In mainstream smoke, nicotine uptake reflects exposure to particulates. In environmental tobaccc smoke, nicotine becomes vaporized and therefore reflects gas phase expcsure @udy et al. 1985). Quantitating tar consumption is more difficult urinary mutagenic activity has been used as an indirect marker. The relative exposures of nonsmokers to various tobacco smoke constituents differs from that of smokers. Assuming that exposure to a single tobacco smoke constituent accurately quantifies the expo- sure of both smokers and nonsmokers to other constituents is inaccurate because mainstream smoke and environmental tobacco smoke differ in composition (see Chapter 3). To understand the usefulness and limitations of various biochemi- cal markers, it is important to appreciate the factors that influence their absorption by the body and their disposition kinetics within it. Carbon Monoxide Carbon monoxide is absorbed in the lungs, where it dZfuses across the alveolar membrane (Lawther 1975; Stewart 1975). It is not appreciably absorbed across mucous membranes or bronchioles. Within the body, carbon monoxide binds, as does oxygen, to hemoglobin, where it can be measured as carboxyhemoglobin. Carbon monoxide may also be bound to myoglobin and to the cytochrome enzyme system, although quantitative details of binding to the latter sites are not available. Carbon monoxide is eliminated primarily by respiration. The amount of ventilation influences the rate of elimination. Thus, the half-life of carbon monoxide during exercise may be less than 1 hour, whereas during sleep it may be greater than 8 hours (Castleden and Cole 1974). At rest, the half-life is3to4hour-s. The disposition kinetics of carbon monoxide explain the temporal variation of carbon monoxide concentration in active smokers during a day of regular smoking. With a half-life averaging 3 hours and a reasonably constant dosing (that is, a regular smoking rate), carbon monoxide levels will plateau after 9 tc 12 hours of cigarette smoking. This has been observed in studies of circadian variation of carbon monoxide concentrations in cigarette smokers (Benowitx, Kuyt et al. 1982). Smoking is not a constant exposure source, but results in pulsed dosing. There is a smsll increment in carboxyhemoglobin level immediately after smoking a single cigarette, which then 201 declines mta tie next, cig~tt.e is smoked. But after several hours of smou, the m@t&e of rise and faR is small compared with the trough vahres. For this reason, carboxyhemoglobm levels at the end of a day of smoking are satisfactory indicators of carbon monoxide exposure during that day. &bn monoi& e-m may be more'constant during environ- mental ~~CCCB m&e exposure than during active smoking. The major limitation m using carbon monoxide as a means of measuring hrvohmtary smoke exposure is its lack of specificity. Endogenous carbcn monoxide generation from the metabolism of hemoglobin results in a low level of carbo~hemoglobin (up to 1 percent) (Lawther 1975; Stewart 1975). Carbon monoxide is generated by any source of combustion, including gas stoves, machinery, and automo bile exhaust. Thus, nonsmokers in a community with moderate home and industrial carbon monoxide sources may have carboxyhemogb bin levels of 2 or 3 percent (Woebkenberg et al. 1981). A carbon monoxide level of 10 in room air results in an increment of 0.4 and 1.4 percent carboxyhemoglobin at 1 and 8 hours of exposure time, respectively (Lawther 1975; Stewart 1975). Thus, small increments of carhcn monoxide due to environmental tobacco smoke may be indistinguishable from that due to endogenous and non-tobacco related sources. Measurement of carbon monoxide is straightforward and i,nexpen- sive. &dar carbon monoxide pressures are proportional to the concentration of carhoxyhemoglobin in blood, therefore, end&~ carbon monoxide tension accurately reflects blood carboxyhemoglo bin (Jti and Russell 1980). Expired carbon monofide - & measured Using an instrument (Ecolyzer) that measures the rate of conversion of carbon monoxide to carbon &&de 88 it pm over a catalytically active electrode. Blood carboxyhemoglobin - b xm~~ured ~~1~ ad quickly wing a differential spectropho~m~ ter. Hydrogen cyanide is metabolized by the liver to thiooyanate. In addition to tobacco smoke, certain foods, particularly leafy vegeta- bles and some nuts, are sources of cyanide. Cyanide is also present in beer. Thiocyanatc is distributed in extracellular fluid and is eliminated slowly by the kidneys. The half-life of thiocyanate is long, about 7 to 14 days. Thiocyanate is also secreted into saliva, with salivary levels about 10 times that of plasma levels (Haley et al. 1983). The long half-life of thiocyanate means that there is little flu&ration in plasma thiocyanate concentrations during a day or from day to day. Thus, the time of sampling is not critical. On the other hand, a given level of thiocyanate reflects exposure to hydrogen cyanide over several we&~ ~mceding the time of sampling. When a smoker stops smoking, it takes an estimated 3 to 6 weeks for thiocyanate levels to reach that individual's nonsmoking level. Because of the presence of cyanide in foods, chiocyanate is not specific for exposure to cigarette smoke. Although active smokers have plasma levels of thiocyanate two to four times those of nonsmokers (vogt et al. 1979, Jacob et al. 1981), light smokers or involuntary smokers may have little or no elevation of thiocyanate. When thousands of subjects are studied, involuntary smokers have been found to have slightly higher thiooyanate levels than those without exposure (Friedman et al. 1983). Other studies of smaller numbers of subjects have shown no difference in thiocyanate level between exposed or nonexposed nonsmokers (Jarvis et al. 1984). Serum or plasma thiocyanate levels can be measured using spedrophotometric methods or, alternatively, gas chromatography. Nicotine Nicotine ia absorbed through the mucous membranes of the mouth and bronchial tree as well as across the alveolar capillary mem- brane. The extent of mucosal absorption varies with the pH of the smoke, such that nicotine is absorbed in the mouth from alkaline (cigar) smoke or buffered chewing gum, but very little is absorbed from acidic (cigarette) mainstream smoke (Armitage and Turner 1970). With aging, environmental tobacco smoke becomes less acidic; pH may rise to 7.5, and buccal or nasal absorption of nicotine by the nonsmoker could occur (see Chapter 3). Nicotine is distributed rapidly to body tissues and is rapidly and extensively metabolized by the liver. Urinary excretion of unmetabo- lized nicotine is responsible for from 2 to 25 percent of total nicotine ehnrination in alkaline and acid urine, respectively; nicotine excre- tion also varies with urine flow (Rosenberg et al. 1980). Exposure to environmental tobacco smoke, active smoking, and use of smokeless tobacco markedly elevate salivary nicotine transiently out of propor- tion to serum and urinary levels (Hoffiann et al. 1984). Nicotine is present in breast milk (Luck and Nau 1985), and the concentration in the milk is almost three times the serum concentration in the mother (Luck and Nau 1984). The rate of nicotine metabolism varies considerably, as much as fourfold among smokers (Benowitz, Jacob et al. 1982). There is evidence that nicotine is metabolized less rapidly by nonsmokers than by smokers (Kyerematen et al. 1982). A given level of nicotine in the body reflects the balance between nicotine absorption and the metabolism and excretion rates. Thus, in comparing two persons with the same average blood concentration of nicotine, a rapid metabolizer may be absorbing up to four times as much nicotine as a slow metabolizer. To determine daily uptake of nicotine directly, 203 both the nicotine blood concentrations and the rates of metabolism and excretion must be known. These variables can he measured in experimental studies (Renowitz and Jacob 1984; Feyerabend et al. 1985), but are not feasible for large-scale epidemiologic studies. The time course of the decline of blood concentrations of nicotine is multiexponential. Following the smoking of a. single cigarette or an intravenous injection of nicotine, blood concentrations of nicotine decline rapidly owing to tissue uptake, with a half-life of 5 to 10 minutes. If concentrations are followed over a longer period of time or if multiple doses are consumed so that the tissues are saturated, a longer elimination half-life of about 2 hours becomes apparent (Renowitz, Jacob et al. 1982; Feyerabend et al. 1985). Because of the rapid and extensive distribution in the tissues, there is considerable fluctuation in nicotine levels in cigarette smokers during and after smoking. As predicted by the Z-hour half-life, nicotine blood concen- trations increase progressively and plateau after 6 to 8 hours of regular smoking (Renowitz, Kuyt et al. 1982). Nicotine concentra- tions have been sampled in the afternoon in studies of nicotine uptake during active cigarette smoking (Renowitz and Jacob 1964, and similar timing might be appropriate in assessing the plateau levels that result from continuous ETS exposure, such as during a workday. Russell and colleagues (1965) quantitated nicotine exposure by comparing blood nicotine concentrations during intravenous infu- sions (0.5 to 1.0 mg over 60 minutes) in nonsmokers to the blood nicotine concentrations in nonsmokers exposed to environmental tobacco smoke. The data suggest that nicotine uptake in a smoky bar in 2 hours averaged 0.20 mg per hour. .. The presence of nicotine in biologic fluids is highly specific for. tobacco or tobacco smoke exposure. Nicotine concentration is sensi- tive to recent exposure because of nicotine's relatively rapid and extensive tissue distribution and its rapid metabolism. Urinary nicotine concentration has been examined in a number of studies of environmental tobacco smoke exposure. Although influenced by urine pH and flow rate, the excretion rate of nicotine in the urine reflects the concentration of nicotine in the blood -over the time period of urine sampling. In other words, nicotine excretion in a timed urine collection is an integrated measure of the body's exposure to nicotine during that time. When timed urine collections are not available, nicotine excretion is commonly expressed as a ratio of urinary nicotine to urinary creatinine, which is excreted at a relatively constant rate throughout the day. Urinary nicotine excretion is highly sensitive to environmental tobacco smoke expo -sure (Hoffmann et al. 1984; Russell and Feyerabend 1975). Saliva levels of nicotine rise rapidly during exposure to sidestream smoke and fall rapidly after exposure has ended (Hoffmann et al. 1984). 204 Presumably, this the course reflects local mouth contamination, followed by absorption or the swallowing of dcotine. Blood, urine, or saliva concentrations of nicotine can be measured by gas chromatography, radioimmunoaaeay, or high pressure liquid chromatography- sample preparation is problematic in that contam- ination of samples with even small amounts of tobacco smoke c8n substantially elevate the normally low concentrations of nicotine in the blood. Thus, careful Precautions against contamination during sample collection and processing for analysis are essential. &cause the concentrations are so low, the measurement of nicotine in blood has been difficult for many laboratories in the past, but with currently available assays, it is feasible for largescale epidemiologic StUdiM. C&nine Cotinine, the major metabolite of nicotine, is distributed to body tissues to a much lesser extent than nicotine, Cotmine is eljmmated primarily by metabolism, with 15 to 20 percent excreted unchanged in the urine (Benowitz et al. 1983). Urinary pH does affect the r-end elimination of cotinine, but the effect is not as great as for nicotine. Since renal clearance of cotinine is much less variable than that of nicotine, urinary cotinine levels reflect blood coti.&e levels better than urinary nicotine levels reflect blood nicotine levels. Plasma, urine, and saliva cotinine concentrations correlate strongly with one another (Haley et al. 1983; Jarvis et al. 1984). The elimination half-life for cotinine averagea 20 hours (range, 10 to 37 hours) (Benowitz et al. 1983). Because of the relatively long half-life of cotinine, blood concentrations are relatively stable throughout the day for the active smoker, reaching a maximum near the end of the day. Because each cigarette adds relatively little to the overall cotinine level, sampling time with respect to smoking is not critical. Assuming that smoke exposure occurs throughout the day, a midafterrmcm or late afternoon level reflect8 the average wtinine concentration. The specificity of cotinine as a marker for cigarette smoking ie excellent. Because of its long -half-life and its high specificity, cotinine measurements have become the most widely accepted m&hod for assessing the uptake of nicotine from tobacco, for both active and involuntary smoking. Gotinine levels can be used to generate quantitative estimates of nicotine absorption. Galeazzi and colleagues (1985) defined a linear relationship between nicotine uptake and plasma cotinine levels in six healthy volunteers who received several i.v. doses of nicotine ( 5 480 &kg/day) for 4 days. The ability to extrapolate from this model to levels in nonsmokers is limited, however, because the elimination half-life of cotinine may be shorter in smokers than in nsmokers, as is the elimination ha&life of nicotine (Kyerematen 1; al. 1982). Cotinine can be assayed by radioimmunoassay, gas chromatogra- phy, and high pressure liquid chromatography. Urinary Mutagenicity TO&~ smoke condensate is strongly mutagenic in bacterial test s-m (ties test) (Kier et al. 1974). A number of compourids, j&u&g polycyclic aromatic hydrocarbons, contribute to this mutagenicity. The urine of cigarette smokers has been found to he mutagenic, and the number of bacterial revertants per test plate is r&ted to the number of cigarettes smoked per day Wamasaki and Ames 1977). Urinary mutagenicity disappears within 24 hours after smoking the last cigarette &do et al. 1986). For several reasons, the measurement of mutagenic activity of the urine is not a good quantitative measure of tar absorption. Individu- als metabolize polycyclic aromatic hydrocarbons and other mutagen- ic substances differently. Only a small percentage of what is absorbed is excreted in the urine as mutagenic chemicals. The bacterial system is differentially sensitive to different mutagenic compounds. The urine of smokers presumably contains a mixture of many mutagenic compounds. In addition, the test lacks speciEcity, in that other environmental exposures result in urinary mutagenicity. The test may also be insensitive to very low exposures such as mvobmtary smoking. However, one study, by Bos and colleagues (1983), indicated slightly increased mutagenic activity in the urine of nonsmokers following tobacco smoke exposure. The presence of bedalpyrene and 4-amino biphenyi covalently bound to DNA and hemoglobin in smokers (Tannenbaum et al., in press) suggests other potential measures of carcinogenic exposure. Whether such measures will be sensitive to HIS exposure is unknown. The development of specific chemical assays for human exposure to componenta of cigarette tar remains an important researchgoal. Populations in Which Exposure Has Been Demonstrated Absorption of tobacco smoke components by nonsmokers has been demonstrated in experimental and natural exposure conditions. Experimental Studies Nonsmokers have been studied after exposures in tobaccosmoke- Clled rooms. The smoke may be generated by a cigarette smoking machine or by active smokers placed in the room by the investigator, or the location may be a predictably smoke-filled environment such as a bar. The level of environmental smoke has most often been quantitated by measuring ambient carbon monoxide concentrations. In nonsmokers exposed for 1 hour in a test room with a carbon monoxide level of 33 ppm, carboxyhemoglobin levels increased by 1 percent and urinary nicotine increased about eightfold (Russell and Feyerabend 1975). Seven subjects in a similar study sat for 2 hours in a public house (bar) with a carbon monoxide level of 13 ppm; their expired carbon monoxide increased twofold and their urinary nicotine excretion increased ninefold (Jarvis et al. 1983). In a study exposing eight nonsmokers to a smoke-filled room for 6 hours, a small increase in urinary mutagenic activity was measured (Bos et al. 1983). Nonexperimental Exposures Exposure studies performed in real-life situations have compared biochemical markers of tobacco smoke exposure in different imiivid- uals with different self-reported exposures to tobacco smoke. Absorp tion of nicotine (indicated by urinary cotinine levels) was found to be increased in adult nonsmokers if the spouse was a smoker (Wald and Ritchie 1934). In another study (Matsukura et al. I984), urinary cotinine levels in nonsmokers were increased in proportion to the presence of smokers and the number of cigarettes smoked at home and the presence and number of smokers at work. Blood and urinary nicotine levels were increased after occupational exposure to ETS such as a transoceanic flight by commercial airline flight attendants (Foliart et al. 1983). Nicotine absorption, documented by increased salivary cotinine concentration, has been shown in schoolchildren in relationship to the smoking habits of the parents (Jarvis et al. 1985), and using plasma, urinary, and saliva measures, in infants in relation to the smoking habits of the mother (Greenberg et al. 1934; Luck and Nau 1985; Pattishall et al. 1935). Quantification of Absorption Evidence of Absorption in Different Populations One questionnaire survey indicated that 63 percent of individuals report exposure to some tobacco smoke (Friedman et al. 1983). Thirty-four percent were exposed for 10 hours and 16 percent for 40 or more hours per week. The distribution of cotinine levels in a few populations has been reported. In men attending a medical screening examination, there was a tenfold difference in mean urinary cotinine in nonsmokers with heavy exposure (20 to 80 hours per week) compared with those who reported no ETS exposure (wald et al. 1984). The median and 90th percentile urinary cotinine concen- trations for all nonsmokers who reported exposure to other people's smoke were 6.0 and 22.0 ng/mL, respectively, compared with a median of 1645 ng/mL for active smokers, In 569 nonsmoking 207 schoolchildren, salivary cotinine concentrations were widely distrib- uted. Values were strongly influenced by parental smoking habits (Jarvis et al. 1985). The median and 25 to 75 percent ranges (in ng/mL) were 0.20 (O-0.5), 1.0 (O&1.8), 1.35 (0.7-2.71, and 2.7 (l.M.4) for children whose parents did not smoke or whose father only, mother only, or both parents smoked, respectively. Quantification of Exposure Expired carbon monoxide, carboxyhemoglobin, plasma thiocya- nate, plasma or urinary nicotine, and plasma, urinary, or salivary cotinine have been used to evaluate exposure to ETS. However, successful attempts to quantify the degree of exposure have been limited largely to measurements of nicotine and cotinine. Expired carbon monoxide and carboxyhemoglobin have been found to be increased up to twofold after experimental or natural exposures (Russell et al. 19731, `but not in more casually exposed subjecta. Thiocyanate was slightly increased in one very large study of heavily exposed individuals (Friedman et al. 1983), but most studies report no differences as a function of involuntary smoking exposure. The most useful measures appear to be nicotine and cotinine. The data on nicotine and cotinine measurements are presented in Tables 6 and 7 and suggest the following: (1) Both nicotine and cotinine are sensitive measures of environ- mental tobacco smoke exposure. Levels in body fluids may be elevated 10 or more times in the most heavily exposed groups compared with the least exposed groups. (2) The tune course of change in the levels of biochemical markers depends on which marker is selected and which fluid is sampled. There ia a lag between peak blood levels of nicotine and peak blood levels of cotinine, owing to the time required for metabolism (Hoffmann et al. 1984). Salivary levels of nicotine, because of the local deposition of smoke in the nose and mouth, peak early and decline rapidly. (3) With nicotine, salivary levels increase considerably after environmental tobacco smoke exposure, but decline rapidly follow- ing the end of exposure. Blood nicotine levels are too low to be very useful in quantitating environmental nicotine exposure. Urinary nicotine is a sensitive indicator of passive smoke exposure, but because of its relatively short half-life, urinary nicotine levels decline within several hours of the time of exposure. (4) Cotinine levels are less susceptible than nicotine to transient fluctuations in smoke exposure. Blood or plasma, urine, and saliva concentrations correlate strongly with one another. Because of the stability of cotinine levels measured at different times during an exposure and the availability of noninvasive (i.e., urine or saliva) 203 TABLE 6,Nicotine measurea in nonsmokers with environmental tobacco smoke (EIB) sxponve and comparisons with active smoking Numberof Smoking eubjecta et&Ii Rxposum level BefOr After Mom After Before Ahr Ruassll and Feyerebend U~6) Feyerabend et al. (1982) Foliart et al. M89) 12 NS 14 NS 13 NS 18 S 26 NS 90 NS 8 S 16 S 32 S 27 5 6 Ns 18 min in enlokem2d room Hoepad ~~~lw=u Averege 24 cigdday No S eqxnum Work expmum Nonlnhelem slight inhalere Medium bIbden Dwp inhdm Flight attendNIb 0.73 0.90 - - - - - - - - (1E.S) - 80 w-2rs) - - 12.4 (O&64.3) - - 8.9 (o-26) - - - 1236 (104-2799) - - - 1.5 lb.9 21.6 10.1 w ls2 1261 421 1949 (64 1527 o(# lb.2 (8.Sr.4) - - . JAetal. 7 NS s&m, 1Mo can. 0.8 2.6 10.6. 92.6 1.9 49.6 After, public houm x 2hr HolTmann et al. 10 NS Rxpimental chamber (1980 2cigaburned 1.1 1.1 24' Sl' 0 427 3cigebumed ND 1.3 20 94 1 ma 4 cigc burned 0.2 0.5 17 loo 3 790 E TABLE i&fhntinued 0 Mean or median conoentration and range Study Number of Smoking subjects etatus Expmure level Plasma nicotine ht/mL, Before After Urine nicotine Saliva nicotine bf+u WmL, Before At& EdOR After Jarvia et al. ww Greenberg et al. (1984) Luck and Nau (1986) 48 27 20 7 94 32 19 10 10 10 9 Hospital clinic patients NS No expmure - 1.0 - 3.9 - 3.8 NS Little expceure - 0.8 12.2 4.8 NS Some expcmm - 0.7 - 11.9 4.4 NS Lot of exposure - 0.9 - 12.2 12.1 S - 14.8 1760 - 872 NS Infanta, mother S - - as' (O-370) 12.7 (O-188) NS infant, mother NS - - 0 o-89) - 0 (O-17) NS, neonates No exposure - - 0' @14) - - NS, neonates Nuraad by S mother: - 14 (&llO) - - no Em expomre NS, infants S mother, not nursed - - 36 (4-218) - - NS, infants Nureed by S mother; - - 12 (s-42) - - Em exposure 1 nglmg creatinins. TABLE V.-Cotini.ne measures in nonsmokers with environmental smoke exposure and comparisons with active smoking ban or median concentration and - Plaema &hine Number Urine cutinine WmL) salivaootin& Of Smoking WmL) WmL) Study eubjecta atatw Expoeure level Before After Before After More After Jarvis 7 NS Before, 1150 a.m. 1.1 7.3 et al. 4.8 12.9 1.6 8.0 After, public houae x 2 hr GBw Jarvis Hcepital clinic patients et al. 48 NS No expmure 0.8 ww 27 NS 1.6 0.7 Litie expmum - - 1.8 - 20 NS 6.6 2.2 Some expoeure - - 2.6 - 8.6 7 NS 2.8 Lot of expmure - 1.8 - 9.4 94 S 26 - 276 - 1391 - 810 Hoffmann 10 NS Rperlmental chamber et al. 2 ciga burned 1.7 2.6 (peak 14 21 1.2 28 ww Scignburned 1.0 3.0 chenge) 14 88 1.7 2.6 4eigsburned 0.9 9.9 14 66 1.0 1.4 Wald and 101 NS Wife abstinent - - 8.6 (median 6.0) Ritchie 20 NS Wife uaoker - - 26.2 (median 9.0) TABLE `I.--continued Number of Smoking Study subjecte etatue Ekpceure level M~I or median amcantration and raage Urine wtinine sdh mtininc b6ld.J WmL) BdOl-fJ After hf0m After Wald et al. (1984) 221 NS 43 NS 47 NS 43 NS 43 NS 46 NS 131 S 69 S 42 S Mataukura 200 NS et al. 272 NS ww 25 NS 67 NS 99 NS 38 NS 28 NS 472 NS 392 S Med scraening clinic patients - ch colleeguex O-l.6 hr JTTS expaeurejwk 1.6-4.6 hr El?3 exposumlwk 4.5-8.6 hr El% expumlwk 8.6-20 hr ~3% expwlwk XI-W hr E%?J expmlwk cigarettes wm Pips No home exposure All home exposure Home expmure: l-9 &/day lo-19 CigldaY 20-29 CisldaY So-39 ciglday > 40 ciglday All All 76 NS 201 NS No workplace exposure Workplace exposure - 11.2 - 2.8 3.4 6.3 14.7 29.6 - 1646 (637-3326) - 398 (613139) - 1920 MmS-46@) - 610 ' 790 310 4m - 870 - 1030 1680 - 880 - 8620 - 220 720 TABLE 7.-Continued Mean or median concentration and range Study Number of aubjocta Smoking etatua Expmure level Plasma cotinine (nghL) Before After Before urine c&nine ww After Saliva cotinine b&IlL) Before ARer Greenberg 32 et al. 19 (1984) NS, infants S mother 361 (41-1885) - NS mother 9 @-261 - 4 0-125) - 0 6x3) Jarvie et al. 269 (1965) 98 76 128 Luck and 10 Nau 19 NW 10 9 Children aged 11-16 NS Neither parent SM - 0.4 (median 0.2) NS SM father 1.9 (1.0) NS SM mother 2.0 (1.7) NS Both parents SM - 3.4 (2.4) NS, neonates No exposure - - - 0' @-w - NS, neonates Nursed by S mother; - - loo Qo-666) - no Fps exposure NS, infants S mother, not nursed - - 327 (117-780) NS. infants S mother, nursed; - - 660 (226870) - ITS exp&ure Serum mtinine Pattishall 20 et al. 18 NS, children Smokers in home 4.1 - - NS, children No smokers in home 1.0 - E TABLE CI.-Continued Mean or median concentration nnd range Study Number of subjects Smoking statue Expoeure level PI- cotinhe b&W Before After Before Urine cotinine wmu After coulta8 88 NSaBed (6 No emokera in home et al. 41 NS aged (6 1 smoker in home w66) 21 NS aged <6 2 or more smokera in home 200 NS aged Cl7 No smokers in home 98 NS aged 6-17 1 smoker in home 26 NS aged 617 2 or more mnokem in home 316 NSaged >17 No smokers in home 80 NSaged >17 1 emoker in home 12 NSaged >17 2 or more smokers in home - - - - 0, 1.7' - - 7 - 3.8, 4.1 - - - - 6.4, 6.6 - - 0, 1.3 - - - 1.6, 2.4 - - - - 6.3, 6.8 - - - 0, 1.6 - - - - - 0.6. 2.8 - - - - - 0, 3.7 `rag/me creatinine. *median. mean. meats-men% &i&e appears to be the short-term marker of choice for epidemiological studies. (6) Mean levels of urinary nicotiue and of cotinine in body fluids increase with an increasing seKreported E!l'S exposure and with an increasing number of cigarettes smoked per day. There is consider- able variability in levels among individuals at any given level of self- reported exposure. Comparison Of Abeorption From Environmental Tobacco Smoke and From Active Smoking &idemiologic studies show a dose-responss r&tiomGp between number of cigarettes smoked and lung cancer, coronary artery disease, and other smoking-related d&eases. Aseuming that dose- response relationships hold at the lower dose end of the expoeure- respome curve, risks for nonsmokers can be estimated by using measures of absorption of tobacco smoke constituenta to compare the relative exposures of active smokers and involuntary smokers. As diSCUSStd PreviOuSly, measures Of nicotine uptake (i.e., r&&&e or cotinine) are the most specific markers for El% exposure a& provide the best quantitative estimates of the dose of expoeum. Although the ratio of nicotine to other tobacco smoke constituents differs in mainstream smoke and sidestream smoke, nicotine uptake may still be a valid marker of total ETS exposure. Nic@ne uptake in nonsmokers can be estimated in several ways. Russell and colleagues (1965) infused nicotine intravenously to nonsmokers and compared resultant plasma and urine nicotine levels with those observed iu nonsmokers with E'l'S exposure. An infusion of 1 mg nicotine over 60 minutes resulted in an average plasma nicotine concentration of 6.6 ng/mL and an average urinary mcotine concentration of 224 ng/mL. Using these data in combina- tion with measured plasma and urinary nicotine levels in nonsmok- ers after 2 hours in a smoky bar, nicotine uptake was estimated as 0.22 mg per hour. Since the average nicotine uptake per cigarette is 1.0 mg (Renowitz and Jacob 19&i, Feyerabend et al. 1965), 0.22 mg of nicotine is equivalent to smoking about onefifth of a cigarette per hour. In m&.ng these calculations, it is assumed that the disposition ~etics of inhaled and intravenous nicotine are similar and that the rate of nicotine expowre from ETS ifs constant. Steady state blood cotinine concentrations can also be used to estimate nicotine uptake. Galeazzi and colleagues (1985) measured c(ginj.ne levels in smokers receiving various doses of intravenous nicotine, simulating cigarette smoking, for 4 days. They described the relationship: [steady state plasma cotinine concentration] (ng/mL) = (0.783) x [daily nicotine uptake] (w/kg/day). With such data, a 70 kg nonsmoker with a plasma cotinine concentration of 2.5 ng/mL would have an estimated uptake of 3.2 )~g nicotine/kg/day, or 215 0.22 mg nicotine/day, equivalent to one-f* of a cigarette. This approach assumes that the half-life for cotinine and nicotine ewt,iom is similar in smokers and nonsmokers, an assumption that may not be correct Wyerematen et al. 1982). A third approach is to compare cotinine levels in nonsmokers with those in smokers. Jarvis and colleagues (1984) measured plasma, saliva, and urine nicotine and cotinine levels in 100 nonsmokers selected from outpatient medical clinics and in 94 smokers. Ratios of average values for nonsmokers compared with smokers were as follows: plasma cotinine, 0.6 percent; saliva cotinine, 0.6 percent; urine &nine, 0.4 percent; urine nicotine, 0.6 percent; and saliva nicotine, 0.7 percent. These data suggest that, on average, nonsmok- em absorb 0.5 percent of the amount of nicotine absorbed by smokers. Assuming that the average smoker consumes 30 mg nicotine per day (Benowitx and Jacob 1984), this ratio predicts an exposure of 0.15 mg nicotine, or onesixth of a cigarette per day. The most heavily exposed group of nonsmokers had levels almost twice the overall mean for nonsmokers, indicating that their exposure was quivslent to one-fourth of a cigarette per day. Most studies (see l'ables 6 and `7) report similar ratios when comparing nonsmokers with smokers. The exception is Matsukura and colleagues (1984), who reported urine cotinine ratios of. nonsmokers to smokers of 6 percent. The reason for such high values in this one study is UllhOWIl. Personal air monitoring data for nicotine exposure can also be used to estimate nicotine uptake. For example, Muramatsu and colleagues (1984) used a pocketable personal air monitor to study environmental nicotine exposures in various living environments. They reported air levels of from 2 to 48 cog nicotine/ma. Assuming that respiration is 0.48 ms per hour and exposure is for 8 hours per day, nicotine uptake is estimated to range from 8 to 320 w per day. The average values are consistent with other estimates of onegixth to onethird cigarette equivalents per day in general populations of nonsmokers exposed to ETS. Aa noted before, these estimates must be interpreted with caution. Rddh absorption of nicotine in smokers and nonsmokers may substantially underestimate exposure to other components of ETS. Conclusions 1. Absorption of tobacco-specific smoke constituents (i.e., nicotine) from environmental tobacco smoke exposures has been docu- mented in a number of samples of the general population of developed countries, suggesting that measurable exposure to environmental tobacco smoke is common. 216 2. Mean levels of nicotine and c&nine in body fluids increase with self+ep0rted EXS exposure. 3. 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