The Health Consequences Of Smoking CHRONIC OBSTRUCTIVE LUNG DISEASE a report of the Surgeon General 1984 U.S. DEPARTMENT Of HEALTH AND HLMAN SERVICES P&tic Health Sewiie Offlce on Smckll end Heelth Rockvlile, Maryland 20857 For sale by the Supermtendent of Documents. U.S. Government Prmtmg Office Washmgtan, D.C 2040`2 It 15 a plP.sIIrP to tr2TSlnlt to the congress the surgeon General's Report on the Health Consequences Of Smoking, a5 mandated by Section R(a) of the Public Health Cigarette Smoking Act of 1969. This is the Public Health Services' 16th report on this topic ?nd, likp 211 of the earlier Reports, it identifies cigarette smoking as the chief preventable cause of death and dlsahllity in our SOClety. The enclosed report deals with the relationship between smok- ing and those disease cond~tlons described as chronic obstructive 1unp dlSCPSP, particularly chronic bronchitis and emphyseme. These diseases significantly increase patient loads in hospitals and other health care facl!lties and escalate this Nztion's health care costs. including expenditures under the Medicaid and MedIcare programs. This Department has a strong and ongoing comnitment to Its Pr `ogrnmmatlc and research effor*s I" the field Of disease prever.- ti on. In our view, it is essential to apprise ~ndlviduals of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage indl"ld"alS, particularly the youth of this country, not to kgin smoking. Enclosure FOREWORD The 1984 Report on the Health Consequences of Smoking consti- tutes a state-of-the-art review of the information currently available regarding the occurrence and etiology of chronic obstructive lung diseases. Traditionally, chronic bronchitis and emphysema have been subsumed under the term chronic obstructive lung diseases (COLD). It is now recognized that COLD comprises three separate, but often interconnected, disease processes: (1) chronic mucus hypersecretion, resulting in chronic cough and phlegm production; (2) airway thickening and narrowing with expiratory airflow obstruction; and (3) emphysema, which is an abnormal dilation of the distal airspaces along with destruction of alveolar walls. The last two conditions can develop into symptomatic ventilatory limitation. Although there were scientific reports of a link between cigarette smoking and respiratory symptoms as early as 1870, it was not until the comprehensive review in the first Report of the Advisory Committee to the Surgeon General in 1964 that the nature of the observed association was officially recognized by the Public Health Service. At that time the committee concluded that Cigarette smoking is the most important of the causes of chronic bronchitis in the United States and increases the risk of dying from chronic bronchitis and emphysema. A relationship exists between cigarette smoking and emphysema, but it has not been established that the relationship is causal. On the basis of the evidence reviewed in this volume, we are now able to reach a much stronger conclusion: Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidity and mortality far outweighs all other factors. The Importance of Chronic Obstructive Lung Disease Previous Reports on the health consequences of smoking empha- sized the impact of cigarette smoking on mortality from smoking- related disease. It is estimated that more than 60,000 Americans died last year owing to chronic obstructive respiratory conditions vii (chronic bronchitis, emphysema, and COLD and allied conditions). From available epidemiologic and clinical evidence, it may be reasonably estimated that approximately 80 to 90 percent of these are attributable to smoking. Over 50,000 of the COLD deaths can therefore be considered preventable and premature because these individuals would not have died of COLD if they had not smoked. While smoking-related COLD mortality is less than estimates for smoking-related deaths due to coronary heart disease (170,000) and those due to cancer (130,000), it nonetheless represents a significant number of excess deaths. COLD morbidity has a greater impact upon society than COLD mortality. Death from COLD usually occurs only after an extended period of disability, and many individuals with disability from COLD will die from other causes before the disease progresses to a degree of severity likely to cause death. The progressive loss of lung function that characterizes COLD can lead to severe shortness of breath, limiting the activity level. In recognizing the morbidity associated with these diseases, it is important to realize that the frequency of activity limitation with COLD exceeds that reported for any other major disease category. In 1979, 52 percent of individuals with emphysema reported that it limited their activity; 27 percent said it resulted in one or more bed days that year; and 73 percent reported at least one visit to a doctor during the preceding year due to emphysema. Forty percent more people with emphysema than with heart conditions reported limitation of activity. More recently, the National Center for Health Statistics has estimated that over 10 million Americans suffer from either chronic bronchitis or emphyse- ma. The Changing Pattern of Mortality The 1980 and 1982 Surgeon General's Reports (The Health Consequences of Smoking for Women and The Health Consequences of Smoking: Cancer) reported a rapidly increasing rate of lung cancer among women compared with the rate for men. As this Report documents, the mortality ratio between men and women for COLD is also narrowing. In just 10 years, while total deaths from COLD increased from 33,000 in 1970 to 53,000 in 1980, the male-to-female ratio narrowed from 4.3:1 in 1970 to 2.3:1 in 1980. This epidemic increase in COLD among women reflects their later uptake of smoking when compared with men. Findings of the 1984 Report The mortality ratios for COLD in cigarette smokers compared with nonsmokers are as large as or larger than for lung cancer, the . . . Vlll disease most people usually associate with smoking. In heavy smokers, this risk can be as much as 30 times the risk in nonsmokers. Perhaps even more important, in studies of cross- sections of U.S. populations, cigarette smoking behavior is often the only significant predictor for COLD. Even after 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency have been established as being able to cause COLD in the absence of other agents. The decline in lung function with age is steeper in smokers than in nonsmokers, and the rate of decline increases with an increasing number of cigarettes smoked per day. This excess decline in lung function in smokers reflects the progressive lung damage that can eventually lead to symptoms of COLD and ultimately death. Therefore, it is not surprising that the risk of death from COLD increases with an earlier age of smoking initiation, number of cigarettes smoked per day, and deep inhalation of the smoke. Abnormal lung function can be demonstrated in some cigarette smokers within a few years of smoking initiation. These changes initially reflect inflammation in the small airways of the lung and may reverse with cessation. Beginning in their late twenties, some smokers start to develop abnormal measures of expiratory airflow, an excess decline in lung function that continues as long as they continue to smoke. Some of these smokers will develop enough functional loss to become symptomatic, and some of those who become symptomatic will develop enough functional loss to die of COLD. When the smoker quits, the rate of functional decline slows, but there is little evidence to suggest that the smoker can regain the function that has been lost. We are also beginning to understand that the impact of cigarette smoke on the lung is not limited to the active smoker. Children of smoking parents have an increased risk of bronchitis and pneumonia early in life, and seem to have a small, but measurable, difference in the growth of lung function. One of the major advances described in this volume is in the understanding of the mechanisms by which cigarette smoking causes COLD, particularly emphysema. There is now a clear, plausible explanation of how emphysema might result from cigarette smoking. The inflammatory response to cigarette smoke results in an in- creased number of inflammatory cells being present in the lungs of cigarette smokers. These cells can increase the amount of elastase in the lung, and elastase is capable of degrading elastin, one of the structural elements of the lung. In addition, cigarette smoke is capable of oxidative inactivation of a,-antiprotease, a protein capable of blocking the action of elastase. The net result is an excess of elastase activity, degradation of elastin in the lung, destruction of alveolar walls, and the development of emphysema. ix Research scientists continue to expand our understanding of the process by which cigarettes damage the lung, but the important public health focus must shift to how to prevent children from becoming cigarette smokers and how to help those who now smoke to quit. Helping Smokers Quit Smokers can realize a substantial health benefit from quitting smoking, no matter how long they have smoked. As this Report states, sufficient evidence now exists to document lung function improvement in smokers who have quit. Ex-smokers can look forward to improved future health, avoiding long-term and possibly severe disability, or even death, from COLD. Two chapters in this Report summarize research studies using two vastly different cessation approaches. One focuses on the role of physicians in assisting patient populations to quit smoking; the other looks at communitywide intervention programs. Both can have a significant impact on reducing the number of smokers in our population. In January of this year, the Food and Drug Administration approved a nicotine chewing gum that physicians can prescribe for their patients as an aid to cessation. Studies have shown encouraging results when the gum is used as part of a complete behavior modification program. It must be cautioned, however, that nicotine chewing gum is not a magic cure. Smokers must be strongly motivated to quit or they are unlikely to meet with long-term success. Public Attitudes and Knowledge In 1981, a Federal Trade Commission staff report on cigarette advertising revealed that a sizable portion of the population is not aware of the link between cigarette smoking and chronic bronchitis and emphysema. The report cited a 1980 Roper survey finding that 59 percent of the population, including 63 percent of smokers, did not know that smoking causes most cases of emphysema. Over a third of the general population and almost 40 percent of smokers do not know that smoking causes many cases. It is quite clear that physicians and other health professionals must redouble their efforts to persuade more smokers to quit. As in previous years, I call upon all segments of the health care communi- ty to provide assistance and encouragement in whatever way possible to reduce the health impact of cigarette smoking on our society, by helping their patients to quit smoking and by encouraging our young people not to take up the habit. It is only through efforts X such as these that we can reduce our country's terrible burden of disability and death due to cigarette smoking. Edward N. Brandt. Jr., M.D. Assistant Secretary for Health xi PREFACE This Report The Health Consequences of Smoking: Chronic Ob- structive Lung Disease completes an examination by the Public Health Service of the three principal disease entities associated with cigarette smoking. In 1982, the Service presented an indepth review of tobacco's relationship to cancer, and in 1983, a review of its relationship to cardiovascular disease. This 1984 Report evaluates the contribution that tobacco makes to the suffering and premature deaths due to the chronic obstructive lung diseases, including emphysema and chronic bronchitis. Cigarette smoking is causally related to chronic obstructive lung disease, just as it is to cancer and coronary heart disease; severe emphysema would be rare were it not for cigarette smoking. The evidence presented in this Report supports my judgment and the judgment of five preceding Surgeons General that cigarette smoking is the chief, single, avoidable cause of death in our society and the most important public health issue of our time. This Report, as were all previous Surgeon General's Reports dealing with cigarette smoking, is the work of many experts both within and outside the Federal establishment. To these authors, editors, and reviewers I again express my great respect and sincere thanks. C. Everett Koop, M.D. Surgeon General . . . Xl,, ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag- ing Editor was Donald R. Shopland, Technical Information Officer, Office on Smoking and Health. Senior scientific editor was David M. Burns, M.D., Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, Califor- nia. Consulting scientific editors were John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medi- cal Center, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Prevention Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. The editors wish to acknowledge their grateful appreciation to the National Heart, Lung, and Blood Institute, Claude Lenfant, M.D., Director, for the Institute's invaluable assistance in the compilation of this volume. The following individuals prepared draft chapters or portions of the Report: Brenda E. Barry, Ph.D., Research Associate, Environmental Science and Physiology, Harvard School of Public Health, Boston, Massa- chusetts Richard A. Bordow, M.D., Associate Director of Respiratory Medi- cine, Brookside Hospital, San Pablo, California, and Assistant Clinical Professor of Medicine, University of California at San Francisco, San Francisco, California Joseph D. Brain, Sc.D., Professor of Physiology and Director, Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts A. Sonia Buist, M.D., Professor of Medicine, department of Medicine, Oregon Health Sciences University, Portland, Oregon Louis Diamond, Ph.D., Professor and Dire&or- of the Pharmacody- namics and Toxicology Division, University of Kentucky College of Pharmacy, Lexington, Kentucky xv Terence A. Drizd, Statistician, Medical Statistics Branch, Division of Health Examination Statistics, National Center for Health Statis- tics, Public Health Service, Department of Health and Human Services, Hyattsville, Maryland Millicent W. Higgins, M.D., Professor of Epidemiology and Professor of Internal Medicine, Department of Epidemiology, The University of Michigan School of Public Health, Ann Arbor, Michigan Gary W. Hunninghake, M.D., Director, Pulmonary Disease Division and Professor, Department of Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, Iowa Philip Kimbel, M.D., Chairman, Department of Medicine, The Graduate Hospital, Philadelphia, Pennsylvania Edgar C. Kimmel, Pharmacodynamics and Toxicology Division, University of Kentucky College of Pharmacy, Lexington, Ken- tucky Charles Kuhn, M.D., Department of Pathology, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Alfred L. McAlister, Ph.D., The University of Texas Health Science Center at Houston, Houston, Texas John McCarren, M.D., Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, California Linda L. Pederson, Ph.D., Department of Epidemiology and Biosta- tistics, University of Western Ontario, London, Ontario, Canada John A. Pierce, M.D., Department of Medicine, Washington Univer- sity Medical Center, St. Louis, Missouri Jonathan M. Samet, M.D., Associate Professor of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico Robert M. Senior, M.D., Professor of Medicine, Respiratory and Critical Care Division, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Frank E. Speizer, M.D., Associate Professor of Medicine, Harvard Medical School, and Associate Chief, Charming Laboratory, Brig- ham and Women's Hospital, Boston, Massachusetts Ira B. Tager, M.D., M.P.H., Division of Infectious Disease, Beth Israel Hospital and Channing Laboratory, Brigham and Women's Hospi- tal, and Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts William M. Thurlbeck, M.D., F.R.C.P.0, Professor of Pathology, Department of Pathology, The University of British Columbia, Vancouver, British Columbia, Canada Martin J. Tobin, M.D., M.R.C.P.I., Assistant Professor of Medicine, Division of Pulmonary Medicine, Department of Internal Medi- cine, The University of Texas Health Science Center at Houston, Houston, Texas xvi Adam Wanner, M.D., Professor of Medicine and Chief, Division of Pulmonary Diseases, University of Miami School of Medicine, Miami Beach, Florida Scott T. Weiss, M.D., M.S., Associate Chief, Pulmonary Division, Beth Israel Hospital, and Assistant Professor of Medicine, Har- vard Medical School, Boston, Massachusetts 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. Oscar Auerbach, M.D., Senior Medical Investigator, Veterans Ad- ministration Medical Center, East Orange, New Jersey John Bailar III, M.D., Ph.D., Office of the Assistant Secretary of Health, Office of Disease Prevention and Health Promotion, Washington, D.C. David V. Bates, M.D., F.R.C.P.0, Professor of Medicine, Department of Health Care and Epidemiology, The University of British Columbia, Vancouver, British Columbia, Canada Benjamin Burrows, M.D., Division of Respiratory Science, University of Arizona College of Medicine, Tucson, Arizona Jacqueline Coalson, Professor of Pathology, School of Medicine, University of Texas at San Antonio, San Antonio, Texas Allen B. Cohen, M.D., Ph.D., Executive Associate Director and Professor of Medicine, The University of Texas Health Center at Tyler, Tyler, Texas Manuel G. Cosio, M.D., Director, Pulmonary Laboratories, Royal Victoria Hospital, Montreal, Quebec, Canada Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Public Health Service, Department of Health and Human Services, Hyattsville, Maryland Benjamin G. Ferris, Jr., M.D., Professor of Environmental Health and Safety, Department of Physiology, Harvard School of Public Health, Boston, Massachusetts Gareth M. Green, M.D., Professor and Chairman, Department of Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland Clarence A. Guenter, M.D., F.R.C.P.(C), Professor and Head, Depart- ment of Medicine, The University of Calgary Foothills Hospital, Calgary, Alberta, Canada Ian T. T. Higgins, M.D., Professor of Epidemiology, Department of Epidemiology, The University of Michigan School of Public Health, Ann Arbor, Michigan John R. Hughes, M.D., Assistant Professor, Department of Psychia- try, University of Minnesota, Minneapolis, Minnesota xvii Suzanne S. Hurd, Ph.D., Director, Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Roland H. Ingram, Jr., M.D., Director, Respiratory Division, Brig- ham and Women's Hospital, and Parker B. Francis Professor of Medicine, Harvard Medical School, Boston, Massachusetts Aaron Janoff, Ph.D., Professor and Experimental Pathologist, De- partment of Pathology, School of Medicine and University Hospi- tal, State University of New York at Stony Brook, Stony Brook, New York Lynn T. Kozlowski, Ph.D., Scientist, Clinical Institute of the Addic- tion Research Foundation, Toronto, Ontario, Canada Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Peter T. Macklem, M.D., F.R.S.C., Physician-in-Chief, Royal Victoria Hospital, and Professor and Chairman, Department of Medicine, McGill University, Montreal, Quebec, Canada James 0. Mason, M.D., Director, Centers for Disease Control, Atlanta, Georgia Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at San Diego, San Diego, California C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol- ogy, School of Public Health, University of Minnesota, Minneapo- lis, Minnesota Solbert Per-mutt, M.D., Professor of Medicine, Department of Medi- cine, Division of Pulmonary Medicine, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland Cheryl L. Perry, Ph.D., Assistant Professor, Division of Epidemiolo- gy, School of Public Health, University of Minnesota, Minneapolis, Minnesota Richard Peto, M.A., M.&Z., I.C.R.S., Clinical Trial Service Unit, Radcliffe Infirmary, University of Oxford, Oxford, England Thomas L. Petty, M.D., Professor of Medicine, and Director, Webb Waring Lung Institute, University of Colorado Health Sciences Center, Denver, Colorado James L. Repace, Office of Policy Analysis, U.S. Environmental Protection Agency, Washington, D.C. Attilio D. Renzetti, Jr., M.D., University of Utah Medical Center, Salt Lake City, Utah John Repine, M.D., Webb Waring Lung Institute, Denver, Colorado xv111 Eugene Rogot, Statistician, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Marvin A. Sackner, M.D., Director, Medical Services, Mount Sinai Medical Center, and Professor of Medicine, University of Miami School of Medicine, Miami Beach, Florida Roy J. Shephard, M.D., Ph.D., Director of School of Physical and Health Education, University of Toronto, Toronto, Ontario, Cana- da Gordon L. Snider, M.D., Professor of Medicine and Director, Pulmo- nary Center, Boston University School of Medicine, Boston, Massachusetts Donald F. Tierney, M.D., Department of Medicine, School of Medi- cine, Center for the Health Sciences, University of California at Los Angeles, Los Angeles, California Nicholas J. Wald, M.R.C.P., F.F.C.M., Professor, Department of Environmental and Preventive Medicine, The Medical College of St. Bartholomew's Hospital, University of London, London, Eng- land James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Erica W. Adams, Copy Editor, Information Programs Division, Informatics General Corporation, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Richard J. Bast, Medical Translation Consultant, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Charles A. Brown, Programmer, Data Processing Services, Informat- its General Corporation, Rockville, Maryland Clarice D. Brown, B&Statistician and Epidemiologist, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Alicia Doherty, Information Specialist, Clearinghouse Projects De- partment, Informatics General Corporation, Rockville, Maryland Danny A. Goodman, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land xix Kit Hagner, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Rebecca C. Harmon, Publications Manager, Information Programs Division, Informatics General Corporation, Rockville, Maryland Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Douglas M. Hayes, Publications Systems Supervisor, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Margaret H. Hindman, Publications Specialist, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Leena Kang, Data Entry Operator, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Spe- cialist, Office on Smoking and Health, Rockville, Maryland Julie Kurz, Graphic Artist, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Roberta L. Litvinsky, Secretary, Office on Smoking and Health, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Edward W. Maibach, Health Promotion Specialist, Informatics General Corporation, Rockville, Maryland Dixie P. McGough, Publications Specialist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Patricia A. Mentzer, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary land Kurt D. Mulholland, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock- ville, Maryland Sally L. Nalley, Secretary, Office on Smoking and Health, Rockville, Maryland Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland xx Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Anne C. Ryon, Copy Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Data Processing Ser- vices, Informatics General Corporation, Rockville, Maryland Karen Weil Swetlow, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Debra C. Tate, Publications Systems Specialist, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Jerry W. Vaughn, Development Technician, University of California at San Diego, San Diego, California Jill Vejnoska, Writer-Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Dee Whitley, Computer Operator, Data Processing Services, Infor- matics General Corporation, Rockville, Maryland Louise Wiseman, Technical Information Specialist, Office on Smok- ing and Health, Rockville, Maryland Pamela Zuniga, Secretary, University of California at San Diego, San Diego, California xxi TABLE OF CONTENTS Foreword .............................................................. vii Preface ... ................................................................ x111 Acknowledgments ................................................... xv 1. Introduction, Overview, and Conclusions . . . . . . .._... . . . . . 1 2. Effect of Cigarette Smoke Exposure on Measures of Chronic Obstructive Lung Disease Morbidity . . . . . . . . . 17 3. Mortality From Chronic Obstructive Lung Disease Due to Cigarette Smoking . . . . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 4. Pathology of Lung Disease Related to Smoking..... 219 5. Mechanisms by Which Cigarette Smoke Alters the Structure and Function of the Lung . . . . . . . . . . . . . . . . . . . 251 6. Low Yield Cigarettes and Their Role in Chronic Ob- structive Lung Disease . . . . ..**.............................. 329 7. Passive Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 8. Deposition and Toxicity of Tobacco Smoke in the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 9. Role of the Physician in Smoking Cessation ......... 451 10. Community Studies of Smoking Cessation and Preven- tion ............................................................... 499 Index .................................................................. 535 xx111 CHAPTER 1. INTRODUCTION, OVERVIEW, AND CONCLUSIONS CONTENTS Introduction Organization and Development of the 1984 Report Historical Perspective -Overview Conclusions of the 1984 Report COLD Morbidity COLD Mortality Pathology of Cigarette-Induced Disease Mechanisms of COLD Low Tar and Nicotine Cigarettes Passive Smoking Deposition and Toxicity of Tobacco Smoke in the Lung Role of the Physician in Smoking Cessation Community Studies of Smoking Cessation and Prevention Introduction Organization and Development of the 1984 Report Each year the Office on Smoking and Health (OSH), working in close collaboration with scientists, researchers, and others, compiles the annual Surgeon General's Report The Health Consequences of Smoking for submission to the U.S. Congress as part of the Department's responsibility to report new and current information on the topic as required under Public Law 91-222. This Report is the third to examine in detail specific disease entities related to smoking. The 1982 Report was a comprehensive assessment of the relationship between tobacco use and various cancers, and the 1983 Report examined this relationship for cardiovascular diseases. The 1984 volume represents a state-of-the-art comprehensive review of tobacco use and the development of chronic obstructive lung diseases. The scientific content of this Report is the work of experts in the field of chronic obstructive lung disease research both within the Department of Health and Human Services and from outside the Federal Government. Individual manuscripts were written by ex- perts who are nationally and internationally recognized for their scientific understanding of the etiology of chronic obstructive lung diseases, particularly the relationship with cigarette use. Manuscripts received from authors were extensively reviewed by numerous outside experts familiar with these specific areas. The entire Report was then submitted to a broad-based panel of 11 distinguished lung disease experts and to experts within the U.S. Public Health Service for their review and comments. The 1964 Report includes a Foreword by the Assistant Secretary for Health of the Department of Health and Human Services and a Preface by the Surgeon General of the U.S. Public Health Service. The body of the Report consists of 10 chapters, as follows: o Chapter 1. o Chapter 2. 0 Chapter 3. o Chapter 4. o Chapter 5. o Chapter 6. o Chapter 7. o Chapter 8. Introduction, Overview, and Conclusions Effect of Cigarette Smoke Exposure on Mea- sures of Chronic Obstructive Lung Disease Morbidity Mortality From Chronic Obstructive Lung Dis- ease Due to Cigarette Smoking Pathology of Lung Disease Related to Smoking Mechanisms by Which Cigarette Smoke Alters the Structure and Function of the Lung Low Yield Cigarettes and Their Role in Chronic Obstructive Lung Disease Passive Smoking Deposition and Toxicity of Tobacco Smoke in the Lung 5 o Chapter 9. Role of the Physician in Smoking Cessation o Chapter 10. Community Studies of Smoking Cessation and Prevention Historical Perspective The relationship between cigarette smoking and chronic obstruc- tive lung disease (COLD) was among the first recognized and is now the best understood of the diseases caused by smoking. Sigmund reported as early as 1870 that heavy smokers suffered "affections" of the nose, mouth, and throat more frequently and in a more virulent fashion. In 1897, Mendelssohn reported the incidence of "affections" of the respiratory tract to be 60 percent greater in smokers than in nonsmokers, as well as somewhat greater in those who inhaled compared with smokers who did not inhale. Overview Scientists from a variety of disciplines have investigated the role of cigarette smoking in the development of COLD; today we can trace the progressive decline in lung function in smokers with increasing smoke exposure, describe the concurrent pathologic changes, demon- strate that both COLD prevalence and COLD death are limited largely to smokers, and describe in detail a plausible mechanism by which cigarette smoking can lead to the development of emphysema. Some gaps in the understanding of the details of this process may still exist, but the experimental and epidemiologic evidence leaves no room for reasonable doubt on the fundamental issue: cigarette smoking is the major cause of COLD in the United States. The earliest recognized response to cigarette smoke is an increase in airway resistance that occurs with the inhalation of smoke by the smoker. This increase in resistance is a response to the irritants in the smoke, as is coughing, which is more frequent in smokers than in nonsmokers, even among adolescents. By the time smokers become young adults, a substantial proportion of them will have developed pathologic changes in their small airways. These abnormalities are demonstrable using a variety of physiologic tests, and are a result of pathologic changes or inflammation in the airways less than 2 mm in diameter. Part of this small airways response, but perhaps a later manifestation of it, is the development of smooth muscle hypertro- phy, goblet cell hyperplasia, and mild peribronchiolar fibrosis. The prevalence of abnormalities on tests of small airways function increases as these young smokers grow older, and is greater in heavy smokers than in light smokers. While it is clear that changes in the small airways represent an early response to cigarette smoking and that they are a significant finding in the pathophysiology of COLD, it is not clear that abnormal function of the small airways, per se, is 6 useful as a marker for identifying who will progress to develop symptomatic COLD. It may identify a large group of smokers who manifest an irritant response to smoke in the small airways, of whom only a subset actually develop symptomatic airflow obstruc- tion. Measurable differences in tests of expiratory airflow exist between smokers and nonsmokers after age 25. Smokers as a group have a more rapid decline in F'EV, with age than that observed in nonsmokers, and the decline is even greater among heavy smokers. However, this increased rate of decline in lung function is not distributed evenly, even among smokers with similar smoking histories. Some smokers have a far more rapid decline than the average smoker, and clearly those individuals who have developed symptomatic chronic airflow obstruction have had a larger total decline in lung function than the average smoker. This has led to the suggestion that individuals with a particularly rapid decline in FEV, early in life may represent a group especially susceptible to the later development of symptomatic COLD. The nature of this susceptibility remains unclear, but differences in depth or pattern of inhalation, variations in the cellular and biochemical response of the lung to smoke, differences in immune or repair mechanisms, and childhood infections or exposure to environmental tobacco smoke as a child have been suggested as potential factors. The accumulation of lung damage, marked by the excess decline in F'EV, and other measures of expiratory airflow, can lead to shortness of breath and other symptoms that characterize clinically significant COLD. These symptoms can result in disability due to ventilatory limitation and may vary from patient to patient in severity and duration. Many patients with clinically disabling COLD die with the disease rather than because of it. Death from COLD usually results only after extensive lung damage and commonly occurs because of failure of the severely damaged lungs to maintain adequate gas exchange. The cessation of cigarette smoking has a substantial salutary impact on the incidence and progression of COLD. Cigarette smokers who quit prior to developing abnormal lung function are unlikely to go on to develop ventilatory limitation; when the abnormalities are demonstrable only on tests of small airways function, cessation often results in a reversal of these changes and a return to normal function. The presence of significant fixed reduction in measures of expiratory airflow usually reflects the presence of substantial lung damage. Cessation of smoking at this stage of COLD results in a slowing in the rate of decline in lung function with age, in comparison with that in continuing smokers. After a period of cessation, this rate of decline in function may approximate the rate found in nonsmokers, but there is little evidence to suggest that 7 those who quit are able to regain their prior excess functional loss. Therefore, those who quit continue to have reduced lung function when compared with those who have never smoked, but their lung function begins to decline less rapidly with age when compared to the lung function of those who continue to smoke. The importance of cigarette smoking as a causative factor in COLD is emphasized by cross-sectional studies of populations in the United States where often the only major predictor for developing or dying of COLD is smoking behavior. In the absence of cigarette smoking, clinically significant COLD is rare. As the smoker enters the sixth decade of life, pathologically definable pulmonary emphysema begins to become evident. In older age groups, mild to moderate emphysema is present in most smokers and is rare in nonsmokers. Once again, however, only a small percentage of smokers develop severe emphysema; this minority includes a disproportionate number of heavy smokers. A mechanism for smoking-induced emphysematous lung injury has been proposed and continues to evolve as our understanding of cellular and biochemical responses of the lung increases. Emphyse- ma can be produced by the presence of excessive amounts of elastase (an enzyme capable of degrading the structural elements of lung tissue) or by the absence of a,-antiprotease (a protein that inhibits the action of elastase). As part of the inflammatory response to cigarette smoke, an increased number of inflammatory cells are present in the lungs of smokers; these cells may result in an increased amount of elastase being present in the lung. In addition, cigarette smoke can oxidize the a,-antiprotease in the lung, further contributing to the imbalance between levels of elastase and levels of a,-antiprotease. The net result can be excess elastase activity, leading to degradation of elastin in the lung, destruction of alveolar walls, and development of emphysema. The text of this Report discusses in detail the relationship of cigarette smoking to COLD morbidity and mortality, the pathology of smoking-induced COLD, some of the mechanisms by which smoking results in COLD, the impact on the lung of low tar and nicotine cigarettes and of involuntary smoke exposure, the deposi- tion and toxicology of tobacco smoke, and the role of the physician and of community intervention programs in smoking cessation. The overall conclusion of this Report is clear: Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidi- ty and mortality far outweighs all other factors. 8 Conclusions of the 1984 Report COLD Morbidity 1. Cigarette smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. 2. In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. 3. In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- ic defect) are established causes of clinically significant COLD in the absence of other agents. 4. Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the smoking habit, and is greater in heavy smokers than in light smokers. These abnormalities in function reflect inflammatory changes in the small airways and often reverse with the cessation of smoking. 5. Both male and female smokers develop abnormalities in the small airways, but the data are not sufficient to define possible sex-related differences in this response. It seems likely, how- ever, that the contribution of sex differences is small when age and smoking exposure are taken into account. 6. There is, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who will progress to clinical airflow obstruction. 7. Smokers of both sexes have a higher prevalence of cough and phlegm production than nonsmokers. This prevalence in- creases with an increasing number of cigarettes smoked per day and decreases with the cessation of smoking. 8. Differences between smokers and nonsmokers in measures of expiratory airflow are demonstrable by young adulthood and increase with number of cigarettes smoked per day. 9. The rate of decline in measures of expiratory airflow with increasing age is steeper for smokers than for nonsmokers; it is also steeper for heavy smokers thRn for light smokers. After the cessation of smoking, the rate of decline of lung function with increasing age appears to slow to approximately that seen in nonsmokers of the same age. Only a minority of smokers will develop clinically significant COLD, and this group will have 9 480-144 0 - 85 - 2 demonstrated a more extensive decline in lung function than the average smoker. The data are not yet available to determine whether a rapid decline in lung function early in life defines the subgroup of smokers who are susceptible to developing COLD. 10. Clinically significant degrees of emphysema occur almost exclusively in cigarette smokers or individuals with genetic homozygous a,-antiprotease deficiency. The severity of em- physema among smokers increases with the number of ciga- rettes smoked per day and the duration of the smoking habit. COLD Mortality 1. Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. 2. The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. 3. Differences in lifetime smoking behavior are less marked for younger age cohorts of smokers. The ratio of male to female mortality from COLD is decreasing because of a more rapid rise in mortality from COLD among women. 4. The dose of tobacco exposure as measured by number of cigarettes or duration of habit strongly affects the risk for death from COLD in both men and women. Similarly, people who inhale deeply experience an even higher risk for mortality from COLD than those who do not inhale. 5. Cessation of smoking leads eventually to a decreased risk of mortality from COLD compared with that of continuing smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overall lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. 6. Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. Pipe smokers and cigar smokers also experience higher mortality from COLD compared with nonsmokers; however, the risk is less than that for cigarette smokers. 7. There are substantial worldwide differences in mortality from COLD. Some of these differences are due to variations in 10 terminology and in death certification in various countries. Emigrant studies suggest that ethnic background is not the major determinant for mortality risk due to COLD. Pathology of Cigarette-Induced Disease 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of small airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. This lesion may be an important cause of abnormalities in tests of small airways function, and may be involved in the pathogenesis of centrilobular emphyse- ma. The severity of emphysema is clearly associated with smoking, and severe emphysema is confined largely to smok- ers. Mechanisms of COLD 1. Increased numbers of inflammatory cells are found in the lungs of cigarette smokers. These cells include macrophages and, probably, neutrophils, both of which can release elastase in the lung. 2. Human neutrophil elastase produces emphysema when in- stilled into animal lungs. 3. Alpha,-antiprotease inhibits the action of elastase, and a very small number of people with a homozygous deficiency of a,- antiprotease are at increased risk of developing emphysema. The a,-antiprotease activity has been shown to be reduced in the bronchoalveolar fluids obtained from cigarette smokers and from rats exposed to cigarette smoke. 4. The protease-antiprotease hypothesis suggests that emphyse- ma results when there is excess elastase activity as the result of increased concentrations of inflammatory cells in the lung 11 and of decreased levels of a,-antiprotease secondary to oxida- tion by cigarette smoke. 5. Cigarette smokers have been shown to have a more rapid fall in antibody levels following immunization for influenza than nonsmokers. Whole cigarette smoke has been shown to depress the number of antibody-forming cells in the spleens of experi- mental animals. 6. Cigarette smoke produces structural and functional abnormali- ties in the airway mucociliary system. 7. Short-term exposure to cigarette smoke causes ciliostasis in vitro, but has inconsistent effects on mucociliary function in man. Long-term exposure to cigarette smoke consistently causes an impairment of mucociliary clearance. This impair- ment is associated with epithelial lesions, mucus hypersecre- tion, and ciliary dysfunction. 8. Chronic bronchitis in smokers and ex-smokers is characterized by an impairment of mucociliary clearance. 9. Both the particulate phase and the gas phase of cigarette smoke are ciliotoxic. Low Tar and Nicotine Cigarettes 1. The recommendation for those who cannot quit to switch to smoking cigarette brands with low tar and nicotine yields, as determined by a smoking-machine, is based on the assumption that this switch will result in a reduction in the exposure of the lung to these toxic substances. The design of the cigarette has markedly changed in recent years, and this may have resulted in machine-measured tar and nicotine yields that do not reflect the real dose to the smoker. 2. Smoking-machines that take into account compensatory changes in smoking behavior are needed. The assays could provide both an average and a range of tar and nicotine yields produced by different individual patterns of smoking. 3. Although a reduction in cigarette tar content appears to reduce the risk of cough and mucus hypersecretion, the risk of shortness of breath and airflow obstruction may not be reduced. Evidence is unavailable on the relative risks of developing. COLD consequent to smoking cigarettes with the very low tar and nicotine yields of current and recently marketed brands. 4. Smokers who switih from higher to lower yield cigarettes show compensatory changes in smoking behavior: the number of puffs per cigarette is variably increased and puff volume is almost universally increased, although the number of ciga- rettes smoked per day and inhalation volume are generally 12 unchanged. Full compensation of dose for cigarettes with lower yields is generally not achieved. 5. Nicotine has long been regarded as the primary reinforcer of cigarette smoking, but tar content may also be important in determining smoking behavior. 6. Depth and duration of inhalation are among the most impor- tant factors in determining the relative concentration of smoke constituents that reach the lung. Considerable interindividual variation exists between smokers with respect to the volume and duration of inhalation. This variation is likely to be an important factor in determining the varying susceptibility of smokers to the development of lung disease. 7. Production of low tar and nicotine cigarettes has progressed beyond simple reduction in'tobacco content. Additives such as artificial tobacco substitutes and flavoring extracts have been used. The identity, chemical composition, and adverse biologi- cal potential of these additives are unknown at present. Passive Smoking 1. Cigarette smoke can make a significant, measurable contribu- tion to the level of indoor air pollution at levels of smoking and ventilation that are common in the indoor environment. 2. Nonsmokers who report exposure to environmental tobacco smoke have higher levels of urinary cotinine, a metabolite of nicotine, than those who do not report such exposure. 3. Cigarette smoke in the air can produce an increase in both subjective and objective measures of eye irritation. Further, some studies suggest that high levels of involuntary smoke exposure might produce small changes in pulmonary function in normal subjects. 4. The children of smoking parents have an increased prevalence of reported respiratory symptoms, and have an increased frequency of bronchitis and pneumonia early in life. 5. The children of smoking parents appear to have measurable but small differences in tests of pulmonary function when compared with children of nonsmoking parents. The signifi- cance of this finding to the future development of lung disease is unknown. 6. Two studies have reported differences in measures of lung function in older populations between subjects chronically exposed to involuntary smoking and those who were not. This difference was not found in a younger and possibly less exposed population. 7. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and pulmo- nary function changes in patients with asthma. 13 Deposition and Toxicity of Tobacco Smoke in the Lung 1. The mass median aerodynamic diameter of the particles in cigarette smoke has been measured to average approximately 0.46 pm, and particulate concentrations have been shown to range from 0.3 x lo9 to 3.3 X 10' per milliliter. 2. The particulate concentration of the smoke increases as the cigarette is more completely smoked. 3. Particles in the size range of cigarette smoke will deposit both in the airways and in alveoli; models predict that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in alveolar regions and 5 to 10 percent will deposit in the tracheobronchial region. 4. Acute exposure to cigarette smoke results in an increase in airway resistance in both animals and humans. 5. Exposure to cigarette smoke results in an increase in pulmo- nary epithelial permeability in both humans and animals. 6. Cigarette smoke has been shown to impair elastin synthesis in vitro and elastin repair in vivo in experimental animals (elastin is a vital structural element of pulmonary tissue). Role of the Physician in Smoking Cessation 1. At least 70 percent of North Americans see a physician once a year. Thus, an estimated 38 million of the 54 million adults in the United States who smoke cigarettes could be reached annually with a smoking cessation message by their physician. 2. Current smoking prevalence among physicians in the United States is estimated at 10 percent. 3. While the majority of persons who smoke feel that physician advice to quit or cut down would be influential, there is a disparity between physicians' and patients' estimates of cessa- tion counseling, with physician advice being reported by only approximately 25 percent of current smokers. 4. Studies of routine (minimal) advice to quit smoking delivered by general practitioners have shown sustained quit rates of approximately 5 percent. Followup discussions enhance the effects of physician advice. 5. A median of 20 percent of pregnant women who smoke quit spontaneously during pregnancy. That proportion can be doubled by an intervention consisting of health education, behavioral strategies, and multiple contacts. 6. Large controlled trials of cardiovascular risk reduction have demonstrated that counseling on individual specific risk fac- tors, including smoking cessation techniques, can be effective. 7. Studies of pulmonary and cardiac patients indicate that severity of illness is positively related to increased compliance 14 in smoking cessation. Survivors of a myocardial infarction have smoking cessation rates averaging 50 percent. 8. Nicotine chewing gum has been developed as a pharmacologi- cal aid to smoking cessation, primarily to alleviate withdrawal symptoms. Cessation studies conducted in offices of physicians who prescribe the gum have produced mixed results, however, with outcome depending on motivation and intensity of adjunc- tive support or followup. 9. Physician-assisted intervention quit rates vary according to the type of intervention, provider performance, and patient group. In general, quit rates in recent research appear to be lower than in older studies. Community Studies of Smoking Cessation and Prevention 1. Community studies of smoking cessation and prevention are becoming an established paradigm for public health action research. Such studies emphasize large-scale delivery systems, such as the mass media, and include community organization programs seeking to stimulate interpersonal communication in ways that are feasible on a large-scale basis. 2. Although there are methodological limitations to nearly all communitywide studies, the results yield fairly consistent positive results, indicating that large-scale programs to reduce smoking can be effective in whole populations. Person-to- person communication appears to be a necessary part of a successful community program to reduce smoking. 3. Further research is needed, with both improved methodology and more emphasis on low socioeconomic status groups that have not yet shown population trends toward reduced smoking. 4. Several promising directions for research are clear, but the most important future trends will be toward the establishment of smoking reduction programs within existing health services, the combination of chronic disease prevention with mental health promotion via mass media and community intervention, and the development of social policy to establish integrated strategies for smoking cessation and prevention. 15 CHAPTER 2. EFFECT OF CIGARETTE SMOKE EXPOSURE ON MEASURES OF CHRONIC OBSTRUCTIVE LUNG DISEASE MORBIDITY 17 CONTENTS Introduction Early Changes in Response to Cigarette Smoking Acute Response to Cigarette Smoke Chronic Response to Cigarette Smoke Smoking and Tests of Small Airways Function in Population Studies Dose-Response Relationship Between Amount Smoked and Small Airways Dysfunction How Soon Do Changes in Small Airways Function Occur? Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking Effect of Smoking Cessation on Small Airways Function Relationship Between Small Airways Disease and Chronic Airflow Obstruction Summary - Chronic Mucus Hypersecretion Introduction Measurement of Cough and Phlegm in Epidemiologic Studies Prevalence of Cough and Phlegm Relationship of Cough and Phlegm to Smoking Effects of Smoking Cessation Dose-Response Relationships Relationship of Cough and Phlegm to Sex and Age Relationship of Cough and Phlegm to Airflow Obstruction Summary I__.--__-_.~- __-_ - Chronic Airflow Obstruction Introduction Prevalence of Airflow Obstruction Determinants of Airflow Obstruction Introduction Cigarette Smoking and Chronic Airflrlw Obstruction 19 Dose-Response Relationships Factors Other Than Cigarette Smoking ABH Secretor Status Air Pollution Airways Hyperreactivity Alcohol Consumption Atow Childhood Respiratory Illness Familial Factors Occupation Passive Exposure to Tobacco Smoke Respiratory Illnesses Socioeconomic Status Development of Airflow Obstruction Summary Emphysema Introduction Definition of Emphysema Types of Emphysema Detection of Emphysema Quantification of Emphysema Pulmonary Function in Emphysema Mechanical Properties of the Lungs in Emphysema Aging and Lung Structure Emphysema and Cigarette Smoking Observations in People Studies Using Post-Mortem Material Dose-Response Relationships Studies of Alphal-Proteinase-Inhibitor-Deficient Individuals Homozygous Deficient-PiZZ Heterozygous Deficient-PiMZ Observations in Experimental Animals Summary Summary and Conclusions Appendix Tables References 20 INTRODUCTION This chapter describes the sequential development of smoking- induced chronic lung disease, traced from the early structural changes limited to the small airways to the severe and widespread changes involving the small airways, large airways, and lung parenchyma. Chronic obstructive lung disease (COLD) develops relatively slowly, and the progression of lung injury and alterations in function can be followed using an individual smoker's symptoms and performance on a variety of pulmonary function tests. Early in the duration of the smoking behavior, a person may be asymptomat- ic, but often there are abnormalities demonstrable in the small airways that probably represent an inflammatory response to the constituents of cigarette smoke. Later, usually after 20 or more years of smoking, a constellation of symptoms and functional changes may develop, particularly in heavy smokers and in those who will later develop clinically significant COLD. The clinical picture of cigarette- induced chronic lung injury includes three separate, but often interconnected, disease processes. They are (1) chronic mucus hypersecretion (cough and phlegm), (2) airway narrowing with expiratory airflow obstruction, and (3) abnormal dilation of the distal airspaces with destruction of alveolar walls (emphysema). Patients with severe COLD commonly have some degree of all three pro- cesses, but individual patients vary significantly in the relative contribution of the processes to their overall disease state. Some alteration in lung structure or function is demonstrable in the majority of long-term smokers, but only a minority of smokers will develop clinically limiting COLD. In fact, only 10 to 15 percent of smokers will develop moderate or severe airflow obstruction (Bates 1973; Fletcher et al. 1976). This chapter details the relationship between cigarette smoking and morbidity from COLD. The relationship of cigarette smoking to changes in the small airways is described first, followed by discussion of the role of smoking to chronic mucus hypersecretion, chronic airflow obstruction, and emphysema. 21 EARLY CHANGES IN RESPONSE TO CIGARETTE SMOKING The tests of small airways function were developed in the late 1960s and early 19SOs, and grew out of a series of studies calling attention to the functional importance of disease in the small airways. Macklem and Mead (1967) predicted that there could be considerable peripheral airway obstruction that might influence the distribution of ventilation but would have little effect on lung mechanisms; subsequently, Anthonisen et al. (19681 and Ingram and Schilder (1967) demonstrated the existence of early functional changes in smokers. These investigators showed that in a group of patients with clinically mild chronic bronchitis and normal lung function measured by spirometric tests, all had abnormalities of regional gas exchange, as determined by Xenonl"3. They attributed this finding to peripheral airway disease and suggested that the functionally important lesion in chronic bronchitis may be in the small airways. Brown and coworkers (19691, using excised lobes of dog and pig lung, demonstrated that considerable obstruction may be present in the airways smaller than 2 mm with little or no effect on overall pulmonary resistance. Hogg and coworkers (1968), using a retrograde catheter technique, measured central and peripheral airway resistance in excised normal and emphysematous human lungs and found that the peripheral airway resistance (accounting for only 25 percent of total airway resistance in the normal lungs (Macklem and Mead 1967)) was greatly increased in the lungs with emphysema. In an early structure-function correlation study, these investigators correlated the physiologic findings with histologic and bronchographic evidence of mucus plugging and narrowing and obliteration of small airways. Woolcock and coworkers (1969) report- ed that a group of bronchitic subjects with normal responses to routine lung function tests (lung volumes, flow rates, and diffusing capacity) demonstrated a decrease in the dynamic-to-static compli- ance ratio with increasing breathing frequency. These studies provided clear evidence that there can be measurable obstruction in airways 2 mm in diameter or smaller with little or perhaps no detectable influence on total airway resistance, and, therefore, on lung function measured by conventional tests such as lung volumes, spirometry, and diffusing capacity. With the concept of small airways disease firmly established, a number of new tests considered capable of detecting the abnormality were introduced, along with reinterpretation of existing tests. The new measures included frequency dependence of compliance, the single breath NP test for the measurement of closing volumes (closing volume as a percent of vital capacity [CV/VC%] and closing capacity as a percent of total lung capacity [CC/TLC%]), the slope of the alveolar plateau, maximal expiratory flow volume (MEFV) curves using gases of differentdensities, and moment analysis of the forced 22 expiration. The measurements obtained from the MEFV curve, breathing gases of different densities, are (a) the difference in maximal flow at 50 and 75 percent of the forced vital capacity breathing air and breathing a helium-oxygen (He&) mixture (AVrnax50% and AV&, and (b) a measurement of the lung volume at which the air and He02 curves cross, the volume of isoflow (VisoV). Tests already in common use included the volume-time curve (the spirogram) and the MEFV curve breathing air. The measurements obtained from standard tests that were thought to be sensitive to mild airflow obstruction are (a) from the spirogram, the forced expiratory flow between 75 and 85 percent. of the forced vital capacity (FEF75-85~); and (b) from the MEFV curve: maximal flow at 50 and 75 percent of the forced vital capacity, V,, 50% and V,, 75%. The important question of structure-function correlation in tests of small airways function has received much attention over the past 5 years, and has been addressed via a series of attempts to correlate physiologic tests with the actual structural changes observed in lobes or lungs obtained at thoracotomy or post mortem. Fulmer and coworkers (1977) correlated measurements of dynamic compliance with measurements of small airway diameter obtained from lung biopsies in patients with idiopathic pulmonary fibrosis. These investigators demonstrated a highly significant correlation between dynamic compliance and an overall estimate of small airways diameter. Cosio and coworkers (1978) and Berend et al. (1979) did pulmonary function tests before lung resection and correlated the function tests with morphologic abnormalities that divided the subjects into four groups based on increasing degree of pathologic change. They found that an index of overall histologic small airways disease could be related to CC/TLC, Visof, and the slope of the alveolar plateau of the single breath N2 test (Figure 1); inflammation, fibrosis, and squamous metaplasia were the most important lesions. The impor- tant conclusions that can be drawn from this study are that abnormalities of both spirometry and the special tests of small airways function are associated with structural changes in the peripheral airways, and that inflammation is the most important cause of obstruction to flow in small airways dysfunction. Berend and coworkers (1979) noted a significant relationship between narrowing of the peripheral airways and CV/VC and FEFZWSS. In contrast to the study of Cosio et al. (1978), the slope of the alveolar plateau did not correlate with peripheral airway narrowing, and the volume of isoflow was essentially useless because of its high variability. They found that the FEVl was also related to peripheral airway narrowing. Berend (1982) has recently provided new information by reanalysis and expansion of his earlier study. In measurements of small and 23 loo0 800 600 Smoktng Index ag/yr 10 0.7 L- 06 05 I II III IV FEV,WVC MMF RV percent predicted percent predcted 1 1 1 1 2 I II Ill IV 140 100 I II III IV I II Ill IV Pathology groups FIGURE l.--Comparison of increasing small airways disease (Groups I to Iv) to smoking index and various pulmonary diction tests, by mean +: S.E. `P f:`r:ed their limit of normality as the 95th percentile for each of the T~.~;tr~. CC/TI,C and the slope of the alveolar plateau had the highest ~,~~..~...:iPtl~r of abnormality among the smokers (47 and 44 percent, respectively), followed by CV/VC% (34 percent), V,,, 75% (33 percent), and V,,, 50% (30 percent). When the indices derived from the single breath Nz test were combined, 60 percent of their smokers had an abnormality in one or more of the measurements obtained from the test, whereas 52 percent had an abnormality in one or more measurements obtained from the forced expiratory maneuver. They pointed out that combining the measurements obtained from a test increases its sensitivity but decreases its specificity. In addition to the studies described above, which involved fairly large population groups, numerous studies have been carried out in smaller groups (McCarthy et al. 1972; Stanescu et al 1973; Gelb and Zamel 1973; Cochrane et al. 1974; Abboud and Morton 1975; Marcq and Minette 1976). These studies have also found the measurements obtained from the single breath NZ test and MEFV curve to be abnormal more often among smokers than among nonsmokers. There have been very few published studies using MEFV curves with air and He02 in reasonably large population groups. This is probably because the test is more difficult to perform than the single breath NB test or the forced expiration maneuver, and because of the wide range of within-individual and between-individual variability associated with these tests. Lam and coworkers (1981) obtained spirometry and MEFV curves with air and He02 in 423 subjects participating in epidemiologic health surveys in British Columbia. The subjects consisted of four groups: nonsmokers and smokers not exposed to air pollutants at work, and nonsmoking and smoking grain elevator workers. Reference values were established from the 78 healthy, asymptomatic nonsmokers who were not exposed to any air pollutant at work. They found that in the subjects not exposed to air pollutants at work, 0 max 50 was the best test for discriminating the effects of cigarette smoking, but &o,, 50 and VisoV were not significantly different between the smokers and the nonsmokers. Interestingly, the FEVl was the best discriminator of the effect of grain dust, and there was poor concordance among the FEV1, V,, 50 and AT,,, 50, and Visoo. They concluded that a comparison of MEFV curves breathing air and He02 is less helpful than the standard MEFV curves in distinguishing the effects of smoking and the effects of exposure to an air pollutant. A careful evaluation of moment analysis in a reasonably large population group of adults has not been published. The limited information in the literature comes from studies of small groups of children (Neuberger et al. 1976; Liang et al. 1979; MacFie et al. 1979) and adults (Permutt and Menkes 1979; MacFie et al. 1979). These preliminary studies look promising, but a more extensive evaluation of the technique in carefully chosen population groups must be carried out before conclusions are reached on the value of this approach. Moment analysis is particularly sensitive to changes in 31 the terminal part of the forced expiratory spirogram, which is particularly sensitive to an artifact in the MEFV curve when volume is measured by a spirometer at the mouth rather than by plethys- mography. This artifact relates to the fact that there are volume changes due to gas compression that are measured by plethysmogra- phy but not by a spirometer at the mouth. The appropriate method to measure volume in moment analysis is by plethysmography, but very few such measurements have been made, most measurements having been made by spirometry. The magnitude of the resulting error has not been assessed. In summary, the prevalence of abnormalities observed in any group of smokers depends on the age and characteristics of the group (how they were selected), on the reference values used (external reference values or reference values obtained from the population under study), and the cutoff used to define abnormality. However, this prevalence is uniformly higher in smoking than in nonsmoking populations. In a randomly selected sample of the general population below age 55, at least a third (and usually more) of the smokers can be classified as having small airways dysfunction. Dose-Response Relationship Between Amount Smoked and Small Airways Dysfunction In general, population-based studies involving adults of all ages with a reasonable range of cigarette consumption consistently show a fairly strong dose-response relationship between the number of cigarettes smoked and the degree of impairment. Burrows and coworkers (1977a1, studying a randomly stratified cluster sample of Tucson, Arizona, households comprised of 2,360 white, non-Mexican-American adults over age 14, found a highly significant quantitative relationship between pack-years of smoking and functional impairment, as measured by v-7546, FEVI percent predicted, and FEVl/FVC percent. The shift in the mean FEVl percent predicted and the distribution of the FEVl percent predicted with increasing cigarette consumption is illustrated in Figure 4. Buist and coworkers found a positive correlation between total cigarette consumption and the frequency of abnormalities in tests of small airways function in 524 smokers attending an emphysema screening center. However, tests of significance were not reported in the description of the relationship between pack-years and CV/VC and CC/TLC (Buist et al. 1973). Tests of significance were reported in the description of the relationship between the slope of the alveolar plateau and cigarette consumption (Buist and Ross 1973b); no clear relationship between daily cigarette consumption and an abnormal slope of the alveolar plateau was found. Among women who smoked more than 20 cigarettes a day, however, the prevalence of an abnormal slope of the alveolar plateau was significantly increased; 32 -1 SD Mean + 1 SD O-20 pack-years (578) 21-40 pack-years (2711 61 + pack-years (1001 40 60 60 100 120 140 160 Percent ore&ted FEV, FIGURE 4.-Percentage distribution of predicted forced expiratory volume in l-second (FEVI) values in subjects with varying pack-years of smoking * Subjects with "respiratory trouble" before age 16 are excluded. NOTE: Means, medians. and * 1 standard deviation of the data for each group are shown m the abscissae. SOURCE Bumws et al. (1977s). among men, a significant increase was found only for those who smoked more than 40 cigarettes a day. Somewhat similar conclusions were reached by Tockman and coworkers (1976) in their study of healthy Baltimore residents. These investigators found that the CC/TLC, the slope of the alveolar plateau, RV/TLC, the steady state diffusing capacity, and respira- tory symptoms were significantly different between smokers and nonsmokers, but there were no significant age-related differences for these variables. In contrast, tests of forced expiration (FEVI/FVC, 0 mm 50, and moment analysis) showed both differences between smokers and nonsmokers and increasing smoker versus nonsmoker differences with increasing age. These investigators interpreted their findings as suggesting that the tests of small airways function measure an all-or-none response that occurs at the onset of smoking but is not affected by duration of smoking. They proposed that the 33 measurements obtained from a forced expiration maneuver probably measure the effects of continued smoking and reflect increasing abnormality associated with longer duration of smoking. In their study of population samples in Manitoba, Manfreda and coworkers (1978) found a significant relationship between the current number of cigarettes smoked per day and the slope of the alveolar plateau and CC/TLC in both sexes and RV/TLC in women. These investigators found that an index of lifetime exposure to smoke had no effect after accounting for the effect of current smoking. Among all the lung function measurements, smoking status accounted for the largest proportion of variance due to the three smoking variables (smoker versus nonsmoker, number of cigarettes smoked per day, and lifetime amount smoked). They interpreted this finding as suggesting that responses on these lung function tests are related more to whether one does or does not smoke than to the amounts smoked. Buist and coworkers, in the three-city collaborative study de- scribed earlier (Buist et al. 1979a), considered the effect of smoking in two ways, first by means of multiple regression analysis using age and cigarette-years data from both smokers and nonsmokers. Using the pooled data from the three cities, they found that cigarette consumption had a significant effect on the CC/TLC, CV/VC, the slope of the alveolar plateau, and FEVI/FVC (only in women). In this analysis, the effect of aging was considerably greater than the effect of smoking. The second approach involved data only from smokers, and a linear regression of the percentage of the predicted value for each variable on cigarette-years was obtained. A significant regres- sion occurred in only one-third of the city/sex groups, and in each case the regression coefficients were very small. They concluded that a dose effect was not apparent when smokers only were considered, using both cigarettes per day and years smoked as indicators of cigarette consumption. They interpreted these findings similarly to Manfreda and coworkers (1978): it could be smoking itself and not the quantity of cigarettes smoked that is the crucial factor in the development of early functional impairment. The researchers sug- gest that absence of a clear-cut dose-response relationship in this study may also have resulted from the limited age range (25 to 54 years) and the relatively few heavy smokers in the study. They also speculate that the single breath NZ test variables, especially the slope of the alveolar plateau, may be so "sensitive" that they reflect an on- off effect of smoking rather than cumulative damage. Dosman and coworkers (1976) looked for a dose-response relation- ship in 49 smokers, aged 28 to 67, of whom 60 percent were attending a smoking cessation clinic. They found a significant relationship between a smoking index (cigarettes per day x years smoked) and VisoV and V,,,, SO. They did not find a significant relationship 34 between symptoms and frequency dependence of compliance, CC/TLC, the slope of the alveolar plateau, or V,,, 50 (Figure 5). Beck and coworkers (1981,1982), in a cross-sectional study of three communities (Lebanon and Ansonia, Connecticut, and Winnsboro, South Carolina) sought a dose-response relationship in 1,209 smok- ers. Dividing the sample into light smokers (1 to 20 cigarettes/day) and heavy smokers (> 20 cigarettes/day!, they found a trend of increasing dysfunction across smoking categories that was evident as early as age group 15 to 24 for both men and women. A difference between men and women occurred in terms of the relationship between residual lung function (observed-predicted FEV,) and pack- years of smoking. In male smokers, the combination of number of cigarettes smoked per day and duration of smoking was the best indicator of loss in lung function, as measured by residual lung function (FEVI, V,,,, XP+, and VX,). For women smokers, pack-years best explained lung function loss as measured by residual lung function. These investigators thus found a very definite dose-re- sponse relationship between the amount smoked and lung function loss. They do point out, however, that smoking variables and age accounted only for up to 15 percent of the variation in residual lung function. In summary, the data suggest a dose-response relationship between number of cigarettes smoked per day and the prevalence of abnormal results on tests of small airways function. That is, heavy smokers are more likely to have abnormal small airways function than light smokers. However, there is only a weak relationship between the degree of abnormality in small airways function and the number of cigarettes smoked per day or pack-years of smoking. In contrast, tests obtained from the forced expiration maneuver have a stronger dose-response relationship. This is consistent with the theory that cigarette smoking induces an inflammatory response in the small airways and that this response is more likely to happen in heavy smokers, as measured by sensitive measures of small airways function such as the single breath nitrogen test. The extent of chronic airway disease that reflects the dose and duration of the smoking habit is better measured by changes in the forced expirato- ry maneuver. How Soon Do Changes in Small Airway Function Occur! The first study to look at the prevalence of abnormalities on tests of small airways function by age in a large group of smokers was reported by Buist and coworkers (1973aJ These investigators found that abnormalities of small airways function could be detected before age 30 by means of the single breath N2 test, with CV/VC discriminating best between smokers and nonsmokers in the age decade of the twenties (Figure 6). 35 160 ' . A 120 Cdyn a 100 Cst (90 BPM) VlS.0~ Percent predacted Slope phase III Percent vreduted cc Percen1 predicted i Illax Percent predIcted symptoms score D . 100 50 0 0 1 2 3 4 Symptoms score FIGURE 5-A composite of six tests plotted against symptoms score SQURCl? Downan et al. (1976). 36 a0 f-J 264 lvonsmohers O 524 Smokers 3 266 Ex-smokers 60 2 E 40 a 20 0 .v= 7 3 4.7 20 30 26 32 51 63 80 66 64 32 21 11 3 7 a1 91 126 143 65 I1 < 20 x-29 30-39 40-49 50-59 6049 70-79 I a0 Age (years) FIGURE 6.-Prevalence of abnormal closing volume/vital capacity ratios in nonsmokers, smokers, and ex-smokers, by age decade SOURCE: Bubr et al. (1973). In their cross-sectional survey of residents in three separate communities in Connecticut and South Carolina, Beck and cowork- ers (1981, 1982) found that the age of onset of abnormalities in lung function may occur as early as age 15 to 24. Their approach used vesidual lung function (observed-predicted value) for FEV1, o,,,, 50%~ and o,, ~SB, with a negative residual indicating an observed value below prediction. Negative residuals for all three measurements began to occur in women in the age group 15 to 24 (Figure 7). Significant differences among smoking categories-nonsmokers, ex- smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers ( > 20 cigarettes/day)-were seen for v,, 50% and o,, 75% in women aged 15 to 24 and for FEVl in age group 25 to 34 (Figure 8). In male smokers, negative residuals began to occur for all three measure- ments in the age 25 to 34 group. Significant differences among the smoking categories were seen for FEVl in the 35 to 44 age group and for e,, 5040 and v,, 76% in the 45 to 54 age group. Seely and coworkers (1971) found lower values for `?,, 50% and `?,, 7590 in a group of high school students with 1 to 5 years of smoking experience. These differences were significant in boys who smoked more than 15 cigarettes per day and in girls who smoked more than 10 cigarettes per day. Significant differences between the smokers and nonsmokers were not found for FEVl. Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59, living in Humboldt, Saskatchewan. Among smokers in the 25 to 29 37 01 0 5 -01 5 E - 2 42 u -03 1 Women (n -2.623) -0 4 0 Nonsmokers a Ex-smokers -05 - Light smokers (l-20 cigarettes/day) E3 Heavy smokers ( ,20 clgaretteslday) 06 o ?? ???????*?*? FIGURE 7.-Mean residual FEV, in women, by smoking status and age SOURCE Beck et al / 1981~ O2 rAge7-14 15-24 2534 35-44 45-54 55-64 65, -0.6 m LaghI smokers (l-20 cigarettes/day) m Heavy smokers ( > 20 agarettes/day) No observations FIGURE 8.-Mean residual FEVl in men, by smoking status and age SOURCE Beck et al. tl9Bli age group, 14.9 percent of the women and 18.5 percent of the men had an abnormal test value for the slope of the alveolar plateau, for CV/VC, or for both. Comparable rates of abnormality for FEVl/FVC 38 were 2.1 percent in women and 5.6 percent in men. For both the slope of the alveolar plateau and CV/VC, the prevalence of abnormal test value increased steadily with increasing age, so that 63.6 percent of the female smokers aged 55 to 59 and 46.2 percent of the male smokers aged 55 to 59 had abnormal values. Comparable rates for an abnormal FEVl/FVC were 4.5 and 19.2 percent in the women and men, respectively. Walter and coworkers (1979) studied 102 Indian male medical students in their late teens and early twenties. Of the 102 subjects, 60 were nonsmokers, 23 were light smokers (lifetime total of < 10,000 cigarettes), and 19 were heavy smokers (lifetime total of > 10,000 cigarettes). The researchers compared mean pulmonary function values obtained from the spirograms across the smoking categories. There was a consistent trend for all the lung function variables examined (FEFZSSOQ, FEFzx,s, FEFKHOS, FEF~~~~i, FEFsx~,, and FEVJFVCLwith the highest mean values being seen in the nonsmokers, intermediate values in the light smokers, and the lowest values in the heavy smokers. There were no significant differences among the three groups in height and weight. No information was given in this report about the type of cigarettes smoked. The consistency of results from the studies attempting to define the age of onset of measurable abnormalities in tests of small airways function is striking. Even though statistical significance was not always found, the trend is clear and provides strong evidence that measurable abnormalities of small airways function do occur in some smokers within a few years of smoking onset. Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking When looking at variations between the sexes in response to cigarette smoking, one must take into account possible differences in the manner in which cigarettes are smoked, in the amount smoked, and in environmental exposures that may interact with smoking. Most investigators have found little or no difference based on sex for the relationship between the various tests of small airways function and age in nonsmokers. Thus, a difference between the sexes in response to smoking, if it exists, probably represents a true biological difference in the effect of smoking on lung function or variations in exposure dose resulting from method of smoking or amount smoked. Unfortunately, the information available in the literature about sex-related differences in small airways response to cigarette smok- ing is scanty and conflicting. Manfreda and coworkers (1978) found a higher prevalence of abnormality in tests of small airways function among male smokers than among female smokers in their study of two communities in Manitoba. The opposite finding has been 39 reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al. 1973, 1979a) in their studies of a screening center population and of population samples and groups in Montreal, Winnipeg, and Port- land. It is quite possible that selection bias in the screening center study limits the ability to extrapolate this study to the general population. The three-cities study, however, did not suffer from that flaw, and showed clear differences (women higher than men) in the prevalence of abnormalities of CV/VC and the slope of the alveolar plateau. The prevalence of abnormality of CC/TLC, on the other hand, was slightly higher in male smokers than in female smokers (32 and 29 percent, respectively). A surprising finding was that the prevalence of FEVJFVC abnormality was considerably higher among women who smoked than among men who smoked (25 and 7 percent, respectively). At this point, a generalization is not yet possible on sex-related differences in the response of the small airways to cigarette smoking. However, it seems likely that the contribution of sex difference is relatively small once age and dose are taken into account. JBfect of Smoking Cessation on Small Airway Function The correlation between abnormalities in tests of small airway function and the pathologic changes of inflammation of the small airways suggests that cessation of smoking may lead to a return toward normal in these tests. A number of authors have examined changes in tests of small airways function in cigarette smokers who have quit. Ingram and O'Cain (1971) examined six smokers with an abnormal frequency dependence of compliance who quit smoking. After 1 to 8 weeks of cessation, values in all six returned to the normal range. Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal FEVl values while they were active smokers and again 6 to 14 months after they had stopped smoking. Static volume pressure curves, slope of phase III, and forced expiratory flow rates on air were unchanged by cessation. However, the maximum expiratory flow rates with helium at 50 and 25 percent of the vital capacity increased, and the volume of isoflow and closing volume decreased. McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who volunteered to attend a smoking cessation clinic. Cessation resulted in a significant reduction in the closing capacity (CC/TLC%) and the slope of phase III within 25 to 48 weeks in the 15 persons who were able to abstain from cigarettes completely. Buist et al. (1976) followed a group of 25 cigarette smokers who attended a smoking cessation clinic and found that cessation resulted in significant improvements in the closing volume (CV,`VC%), closing capacity (CC/TLC%), and the slope of the alveolar plateau (phase III) at 6 and 12 months following cessation. 40 CC/TLC CVNC 140 r 4 \ \ & _____--- --* 120 100 0 20 . 10 . . 30 80 I:; 60 1 1 - O"m3S ---- Smolers FIGURE 9.-Mean values for the ratio of closing volume to vital capacity (W/W), of closing capacity to total lung capacity (CC/TLC), and slope of phase III of the single breath NZ test (ANp/L), expressed as a percentage of predicted value (12, 13) in 15 quitters and 42 smokers, during 30 months after two smoking cessation clinics * A significant difference from the initial value at p< 0.05. N0TF2 Data from amonth followup of the 1973 clinic and 4-month followup of the 1975 clinx have bean combmed. 88 have Gmonth and B-month data for the 1973 clinic. SOURCE: Buist et al. (197%). This study was expanded using a second group of subjects (Buist et al. 1979b) and a 30-month followup. Once again, the three parame- ters of the single breath Nz test showed improvement in smokers who quit; this improvement continued for 6 to 8 months, and then leveled off (Figure 91. In addition, the values for the single breath Nz test in those who quit returned to the levels predicted for nonsmokers, suggesting that the changes in the small airways can be substantial- ly reversed with cessation. Bake et al. (1977) also showed an improvement in the slope of phase III following cessation in a small group who were followed for 5 months. In summary, abnormalities in the small airways are substantially reversible in smokers who have not developed significant chronic airflow obstruction. This suggests that the inflammatory response in the small airways, which may be the earliest change induced by smoking, is also a change that reverses with the cessation of chronic exposure to the irritants in cigarette smoke. 41 480-144 0 - 85 - 3 Relationship Between Small Airways Disease and Chronic Airflow Obstruction There is no question that the information obtained over the past 15 years from studies of small airways function has helped to describe more accurately the natural history of chronic airflow obstruction. The practical question of the place of tests of small airways function in clinical practice has not yet been resolved, and will not be fully answered until longitudinal studies using the tests have been completed. The important issue to be addressed is whether the tests of small airways function can be be used to identify the smoker who will progress to develop irreversible airflow obstruction. This question can be answered satisfactorily only by following a fairly large group of smokers prospectively over a period of time long enough for some of the smokers to develop an abnormal FEVL If the tests of small airways function can be used alone, or in conjunction with other qualitative or quantitative data about risk factors, they will clearly be useful to the practicing physician. If they are too sensitive or have a poor predictive value, their use will be more limited. Buist and coworkers (1984) determined the positive and negative predictive value of tests of small airways function in their study of two cohorts followed prospectively over a `?- to ll-year period. They found that the positive and negative predictive values of the tests of small airways function varied greatly between the cohorts, largely because of the different ages and prevalences of an abnormal FEVl between the cohorts. They concluded that significant associations existed between the single breath Nz test variables and spirometric variables in smokers, but the weakness df these associations and the high misclassification rates suggest that small airways disease does not necessarily lead to clinical airflow obstruction. Over a period of 8 years, Marazzini and coworkers (Marazzini et al. 1977, 1981) followed a group of 69 asymptomatic workers in an iron foundry (49 smokers, 20 nonsmokers) living in the same area. They found that 39 percent of the smokers and 15 percent of the nonsmokers, initially diagnosed as having peripheral airways dis- ease, developed central airways obstruction (defined as 1 or more of the vital capacity WC), FEVl or FEVl/VC being more than 15 percent different from normal) within the ELyear followup. An indirect way to assess the predictive value of the tests of small airways function was proposed by Tattersall and coworkers (1978). These investigators proposed that any valid test of chronic airflow obstruction must yield results that are systematically worse in middle-aged smokers than in middle-aged nonsmokers, and that such a test should also correlate with the FEVl in middle-aged smokers. Using these criteria in a cross-sect.ional study of a sample of working 42 men in West London, they concluded that the most informative and repeatable tests were v max 75% and the slope of the alveolar plateau. Nemery and coworkers (1981) addressed the question of the significance of tests of small airways function in their study of 2,072 blue-collar workers, aged 45 to 55, from a steel plant near Brussels. They found that smokers with an abnormal CC/TLC or slope of the alveolar plateau and a normal FEVJFVC had a significantly lower FEVl/(heightP than subjects with normal CC/TLC and slope of the alveolar plateau. They interpret their data as suggesting that smokers with small airways dysfunction experience a more rapid decline in FEVl than smokers without small airways dysfunction, leading to a higher susceptibility to long-term smoking effects in the former group. The opposite conclusion was reached by Fletcher (1976), who examined the relationship between CV/VC, the slope of the alveolar plateau, and FEVl in 200 male smokers aged 40 to 55. In this group, he found a relatively poor correlation between FEVl and the single breath Nz variables. There is thus, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who is going to progress toward clinical airflow obstruction. The tests of small airways function are probably abnormal for many years before the FEVl becomes abnormal in those smokers who go on to develop airflow obstruction. However, many smokers with abnormal tests of small airways function may never develop clinically significant airflow obstruction. Therefore, functional changes in the small airways may not always be related to the widespread alveolar destruction seen in smokers or to the development of clinical airflow obstruction. It may be that varying degrees of inflammation and fibrosis occur in virtually all smokers, and that there is something very different about the smokers who develop extensive airway or emphysematous changes. Summary A number of tests have been developed that can identify small airways dysfunction in individuals with normal lung volumes and standard measures of forced expiratory airflow. These tests correlate well with the presence of pathologic changes in the airways 2 mm or less in diameter, particularly with peribronchiolar inflammation. Cigarette smokers have a significantly higher frequency of abnormal tests of small airways function. Heavy smokers have a greater prevalence of small airways dysfunction than light smokers, but there is only a weak dose-response relationship between numbers of cigarettes smoked per day or duration of smoking and the extent of small airways dysfunction. This suggests that the response of the 43 small airways may be an "all or nothing" inflammatory response to cigarette smoke irritants rather than a progressive response repre- senting a cumulative injury. Cessation of cigarette smoking results in significant improvement in small airways function, which in those smokers without evidence of chronic airflow obstruction, may return to normal. The relationship between changes in the small airways and the development of chronic airflow obstruction remains unclear. It seems likely that those smokers who will go on to develop ventilatory limitation will have abnormal small airways function before the FEVl becomes abnormal, but many smokers with small airways dysfunction may never progress to significant airflow obstruction. Therefore, the usefulness of tests of small airways function for identifying those who will develop ventilatory limitation remains to be established. 44 CHRONIC MUCUS HYPERSECRETION Introduction The association of cigarette smoking and chronic cough was recognized by the general public in the term "smokers cough" well before the demonstration of this association in epidemiologic studies. Cough is the symptom most frequently experienced by smokers, and it is often accompanied by excess mucus secretion resulting in phlegm production or a "productive" cough. Chronic bronchitis was defined by the Ciba Foundation Guest Symposium report (19591 as "the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree." The position was taken that any production of sputum was abnormal, and chronic was defined as "occurring on most days for at least 3 months of the year for at least 2 successive years." Also, the sputum production could not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. Measurement of Cough and Phlegm in Epidemiologic studies The increasing use of standardized questionnaires in interviews to ascertain the presence of cough, phlegm, or other symptoms of respiratory disease has improved the quality of measurements of prevalence and incidence of these symptoms and the validity of comparisons within and between studies. Similar attention has been given to developing questions about smoking habits, including questions about the type and number of cigarettes used at the time of interview and in the past. The first British Medical Research Council (BMRC) questionnaire published in 1960 (Medical Research Council 1960) had been tested, revised, modified, and extended, and many studies have resulted from its widespread use. However, difficulties in using this questionnaire in epidemiological studies of populations in the United States and the desire to collect additional information led to modification in individual studies and to a loss of comparabili- ty between studies. This motivated the American Thoracic Society and the Division of Lung Diseases of the National Heart, Lung, and Blood Institute to establish the Epidemiology Standardization Project. Extensive methodological studies were done, standardized questionnaires were developed, and techniques for measuring pulmo- nary function and evaluating chest radiographs were proposed (Ferris 1978). Samet (1978) has reviewed the history of the develop ment of respiratory symptom questionnaires. Although many inves- tigators now use the methods advocated by the BMRC or the Epidemiology Standardization Project, several of the studies re- viewed in this chapter of the Report are based on other, nonstandard questionnaires. A comparison between studies of different popula- 45 tions, or the same population studied at different times, must be made cautiously and only after careful consideration of technical and methodological issues. Low rates of participation and use of unrepresentative samples may cause biased estimates of the frequen- cy and distribution of symptoms. Attitudes toward smoking have changed, and comparisons of questionnaire responses and objective measurements of smoking habits indicate that at least in some situations, less reliance can now be placed on answers to questions about smoking habits (MRFIT Research Group 1982). Estimates of prevalence and incidence of respiratory symptoms are imprecise, and too much importance should not be attached to relatively small differences in rates of reporting cough and phlegm. Each author's criteria for detecting the presence of cough or phlegm should be considered, especially when combinations of symptoms or diagnostic labels such as chronic bronchitis or mucus hypersecretion are used. Notwithstanding methodological differences, however, consistent patterns or trends found in many studies indicate that the associa- tions between smoking and chronic mucus hypersecretion are real and that the findings are widely applicable. Prevalence of Cough and Phlegm Unpublished data from the National Center for Health Statistics estimate that there were almost 8 million persons with chronic bronchitis in the United States in 1981 (3.4 million men, 4.5 million women). This is probably an underestimate of the true frequency of cough and phlegm in the population, since people who had these symptoms were not counted as chronic bronchitics unless they responded affirmatively to the question about bronchitis. On the other hand, some cases of acute bronchitis may have been included incorrectly and inflated the estimate. The apparently higher preva- lence rates of chronic bronchitis in women than in men in the National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7 percent for women in 1970 and 1979, respectively, and 3.1 and 3.2 percent for men in 1970 and 1979) are probably due to ascertainment being less complete for men (USDHEW 1980b). Prevalence rates of chronic bronchitis ranged from 4.2 percent at ages under 17 years to 2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent at ages over 65 years. The high rate in the youngest group is presumably because of the inclusion of cases of acute bronchitis. Standard questions about chronic cough were asked in the National Health and Nutrition Examination Surveys (NHANES) of representative samples -of the U.S. population. Some supplementary questions were asked about phlegm and other respiratory symptoms, and these data are presented in the appendix to this chapter. Prevalence rates of diagnosed chronic cough in 18- to 74-year-old participants in NHANES 1(1971-1975) were 3 percent for men and 2 46 0 4 I 31.1 r 16.7 ; 12.0 10.2 Il.6 7.1 r 1 1 1 FIGURE lO.-Percentage of recurring persistent cough attacks by sex and smoking status for adults 25-74, United States, 1971-1975 NOTE. Light smoker: 1-14 cigarettes per day Moderate smoker- l&24 c,garettea per day Heavy smoker 2 25 ngarettes per day SOURCE- Natmnal Canter for Health Statistics. Unpublished data from the first National Health Nutntion and Exammauon Survev lNHANl?S Ia percent for women; they increased with age from 1 percent at 18 to 24 years to 6 percent at 65 to 74 years for men, and from 1 percent at 18 to 24 years to 3 percent at 65 to 74 years for women (National Center for Health Statistics, unpublished data). The prevalence of self-reported recurring persistent cough by smoking status for men and women of different ages is presented in the appendix and in Figure 10 based on NHANES 1. For the entire NHANES population, the prevalence of the persistent cough in- creased threefold in male smokers and twofold in female smokers compared with nonsmokers (Figure lo), and the prevalence of cough increased with increasing cigarette consumption in both men and women. Relationship of Cough and Phlegm to Smoking Relationships between smoking and cough or phlegm are strong and consistent; they have been amply documented and are judged to be causal (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a, 1981). Associations between smoking and cough or sputum are apparent in the recent studies listed in Tables 2 and 3 and are illustrated in Figures 11 and 12. Although cough, phlegm, and 47 chronic bronchitis occur in nonsmokers, prevalence rates are consis- tently higher in cigarette smokers. The excess prevalence of cough and phlegm in cigarette smokers increases with the amount smoked (see below). The frequency of reporting cough and phlegm is at least twice as high for smokers as for nonsmokers except in some groups with minimal exposure. Differences in prevalence rates between smokers and nonsmokers tend to be greater at older ages among men, whereas differences in rates between smoking and nonsmoking women tend to be as great or greater at younger ages (Tables 2 and 3). Rates are not given for pipe or cigar smokers in most of these studies, presumably because the numbers of such smokers were too small for reliable rates; male pipe smokers and cigar smokers in Tecumseh reported cough and phlegm more frequently than nonsmokers or ex-smokers, but less frequently than cigarette smokers (Higgins et al. 1977). Individual studies have evaluated other factors as well as smoking, but smoking has been judged the most important determinant of symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of evidence from many different studies has led to the conclusion that cigarette smoking is the overwhelmingly most important cause of cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz- er and Tager 1979; USDHHS 198Ob). Effects of Smoking Cessation Cross-sectional information on ex-smokers suggests that stopping smoking is followed by a reduction in cough and phlegm because symptoms are less prevalent than in current smokers, but these symptoms are generally mere prevalent in ex-smokers than in lifelong nonsmokers (Huhti et al. 1978; Gulsvik 1979; Park 1981; Schenker et al. 1982). However, the differences between ex-smokers and nonsmokers were either very small or absent in the studies reported by Higgins et al. (1977) and Manfreda et al. (1978). The longitudinal studies cited in Table 3 strengthen the evidence from cross-sectional studies that cigarette smoking causes cough and phlegm. Prevalence rates were higher at followup examinations in persons who started to smoke after being nonsmokers at a previous examination (Kiernan et al. 1976; Leeder et al. 19771. Rates of reporting cough or phlegm decreased in smokers who stopped smoking in two British studies (Kiernan et al. 1976; Leeder et al. 1977) and in populations in the United States (Ferris et al. 1976; Friedman et al. 1980; Beck et al. 1982). Many people who stop smoking report a rapid reduction in cough and phlegm. Although remission of symptoms occurs in some persistent smokers, remission rates are generally higher and incidence rates lower in those who quit than in those who continue to smoke. 48 TABLE 2.-Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and es-smokers (EX), c rossactional studies Author, year, country Poplllation Other Comments Tager and 507 realidetlta, Speizer. esed 15-66+, 1976, U.S. EastBostoll Chronic bmnchitie Men NS 7.0 SM @chars) l-6 8.7 5-10 25.0 10-N 28.6 >20 47.5 Women NS 4.6 SM @uck-years) l-5 14.3 5-10 9.1 10-20 20.8 Chmnic bronchitie (cough and phlegm >3 no&r for 2 years); no sge trend for either eex after adjusting for smoline; prevalence greater for men than women at each a@; significant increase in chronic bronchitis with increased lifetime cigarette consumption for current smokers, but not ex+.mokem g TABLE Z-Continued Author, year, country Population Cwxh Phlegm Other Comments Dean et al.. 1978 United Kingdom 6,277 men and 6,459 women, aged S-67, England, Scotland. and W&S Morning cough NS 12.5 SM (filter) :-7 19.6 6-12 32.8 13-17 36.3 18-22 44.0 23-27 50.6 28-32 56.8 33+ 52.1 NS SM (filter) l-7 a12 l&17 18-22 23-h 9.8 16.9 25.8 29.6 45.1 56.6 NS SM (filter) Il.4 14.4 20.8 25.4 26.9 34.2 34.5 26.4 Women NS 7.5 SM (filter) 13.8 16.6 16.6 25.8 34.3 Bronchitis syndrome NS SM (filter) 3.5 5.1 8.6 9.4 8.5 1.0 8.7 13.8 NS SM (filter) 2.5 3.8 4.2 5.1 10.6 12.0 Bronchitis syndrome (cough and phlegm 3 moe/yr, shortness of breath); significant increase of all symptoms with age; prevalence of mugh, phlegm. and whesze increased with number of cigar&ten smoked; filter vs. nonftiter cigarette effecta small, nonsignificant for most eymPbme TABLE 2.-Continued Author, year, country Population cough Other Commenta Higeins 1977. U.S. et al., 4,699 men and women, aged B-74, Team& Chronic bmnchitii Men NS 5.1 Ex 2.6 SM 4,000; resulta probably not age adjusted Schenker et al., 1962, U.S. 5,686 women, aged 17-74 (mean 44.6), western Pennsylvania, telephone interviewn Chronic cough chronic phlegm Wheeze moat daye or nigh& Cough and phlegm meet strongly NS 5.6 NS 4.5 NS 7.2 related to current cigarettes/day; w 7.5 Ftx 6.7 Ex 8.3 tar content had independent SM SM SM effecte; age effect Been for l-14 9.1 1-14 7.2 1-14 14.4 nonsmokera, but not current 15-24 17.0 15-24 16.7 15-24 16.5 smokers; symptom 25t 31.8 25+ 24.8 St 28.0 prevalencee age adjusted TABLE a.-Prevalence (percent of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and ex-smokers (MI, longitudinal studies Author, year, country Population Smoking habits SYmptoms Comments Ferris et al., 1,201 men and Cwrh Phlegm 72.3% of men, 78.4% of 1976, women, aged 25-74 1973 1967 1973 1967 1973 women followed up; 1973, U.S. in 1961, Berlin Men symptom prevalencea, ege New Hamphire NS 6.0 8.5 8.9 7.6 @usted to compare with 1967, Ex 20.5 9.7 23.3 15.9 showed little change SM l-14 22.2 25.5 17.9 27.5 15-24 35.4 26.5 31.6 30.0 25-34 26.1 26.7 33.8 32.4 St 50.6 56.4 37.1 51.9 Women NS 4.4 6.2 8.1 7.4 Ex 3.2 5.2 7.3 10.1 SM 1-14 10.7 10.0 11.6 9.8 15-24 19.5 16.3 21.8 9.8 2544 27.2 16.1 22.5 21.8 St 44.7 31.0 43.1 41.2 Kieman et al., 2,736 men and Cough day or night in winter Effecta of cheat illnem before age 1976. women, aged 26, born 1966 1971 1966 1971 2, father's vocation, and current Great Britain ill1946,eUIlllin NS NS 5.5 4.9 emokhg r$nikant; air pollution 1966 and 1971 NS SM 7.2 9.6 ' effect not aignif~cant; current SM SM 14.3 18.5 ' smoking had lanpst effects SM Ex 9.2 5.8 `Prevalence, 1966 vs. 1972 P <0.05 TABLE 3.-Continued Author, year, cmntly Population Smoking hahits Comments Leeder et al., 2,130 fathers, Cough/phlegm prevalence range In male ersmokers, prevalence 1977, mean age 31.0rt6.1, Men of cough/phlegm decreased Great Britain 2,146 mothers, let period 2nd period 1st syr period 2nd 3yr period over time; no signiicant mean age 27.9f5.3, NS NS 8.69.6 9.2-11.1 change in prevalence in female children horn NS SM 4.6-16.9 13.3-20.5 er+mokera. but numhera 19634965, SM SM 25.6-30.2 30.W4.0 were amall London, 6 year SM Ex 21.6-25.3 5.b20.7 r0110wup Women NS NS 4% 6.8 5% 7.3 NS SM 8.2-10.2 13.3-18.4 SM SM 16.3-22.4 23.0-28.4 SM Ex 4.1-22.5 12.2-14.3 Woolf and Zamel. 302 women, wed Cough and/or phlegm Breathleesneas 60% followcxl up; all subjects 1960. `E-54 at initial let exam Findexam let exam Finalexam maintained con&ent smoking Canada study. &year NS 10 14 10 5 habita for 5 years followup J%x 3 13 18 8 SM 56 54 25 21 --- ---_.-. -. ___.-__. .~_.. TABLE 3.-Continued Author, year, muntry Population Smoking habits Comments Beck et al.. 1982, U.S. 1,262 white residents, aged 7-55 t , Lebanon, Connect icut, exams in 1972 and 1978 1972 NS NS SM SM FX 1978 NS SM SM Ex Bx NS NS NS SM SM SM SM Ex Ex Ex Usual cowh 1972 1978 Men 5 2 0 0 23 21 25 2' 7 6 7 4 0 0 20 14 26 12 10 3 usual phlegm 1972 1978 7 3 0 4 22 26 18 8 12 15 5 6 0 9 15 11 8 16 4 1 65% followed up; health indiaza of respondents and non- respondents similar; symptom prevalence tended to decline, but few changes were. significant; `Prevalence, 1972 vs. 1978, p of the true popula- tion values. Nevertheless, the figures clearly portray the magnitude of the effect that smoking exerts on expiratorv flow rates in a national population sample. Airflow obstruction is also prevalent outside t.he United States (Table 5). The disease can be identified in both technologically advanced and less developed populations. As in the United States, in other countries the prevalence of airflow oba. 3667 . - Never smokers - - - Current agarette smokers ~_--- .~~~-~~.-~T--- - 25-34 35-44 45-54 Age group .---r..~---.-~--~ 5M4 65-74 3712 -===\y,-.L- 26*3 `. . `. ----._---. 2712 2533 o- i -_.. i.-~-.~ 25-34 3544 4554 Age group 55-64 65-74 FIGURE 23.-Mean forced vital capacity for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE Values udjusti by the direct method to reflect the age distribution of the US populatlan at the midpoint of the survey. SOURCE Kational Center for Health Sttltlstics Unpubhshed data from the first Natuxaal Health Nutrition and Fxamlnstion Surwy fNHANEX lr 91 `CAtiLK 6..--Pusbulat~:d risk factors for airflow obstruction during childhood _" _.~ -.... -.- . ..-_ -I-.-- Actwe clgaret& smokmg :&ir pollubiun. indoor and outdoor Airnajs hypeneartivity A~WY - . . .._- .-LX.. - . I_-.-- -----be-. -......- _ I-~II-. .-__ _.-. ..- .-_. _ .--.. , `3 .& .lSlED iit;+. F.~c'!I;~G FOR AIHF'LOW OFSTRLKTION DL'RIh'G ADULTHOOD _-I- -.---.---m-w-^--. __I_ Actlre cqawtte smoking Alpha,-antltrjpsin deficient) _~_ _._ _.. .----__----- _____- PI'TA iIVE ~1% P.1: IXXS FOR AIHFLGW OBSTRUC'I'ION DURING ADULTHOOD ABH secretor status Air pollution Airways hyperreactivity Alcohol consumption A~PY Childhood respiratory illnesses Familial factors Occupation Passive exposure to t&acco smoke Respiratory illnesses Scciwconomic status occupational groups (Table 10) with exposures that have little or no effect on lung function. The selected studies are all cross sectional in design and thus describe the relationship between cigarette smoking and lung function level at only a single point in time. Investigations in the United States, spanning the time period 1958 to 1977, convincingly demonstrate that cigarette smoking is a strong determinant of FEVl level and the prevalence of airflow obstruction (Table 8). In every population for which prevalence data are available, airflow obstruction is more common among smokers than among nonsmokers (Mueller et al. 1971; Knudson et al. 1976; Detels et al. 1979; Rokaw et al. 1980). In fact, in a multivariate analysis of determinants of airflow obstruction in East Boston, lifetime cigarette consumption was the only statistically significant predictor (Tager et al. 1978). Data from populations outside the United States (Table 9) and from a variety of occupational groups (Table 10) confirm the importance of cigarette smoking. Effects of cigarette smoking on FEVi level have been readily demonstrated in employed populations 92 TABLE &-Association between cigarette smoking and FEV, level in selected U.S. adult populations Author, year of study, Number and type location, reference of population Findings Ashley et al.. 1956. Framingham, Massachusetts, (1975) 1,236 men and women, 37 to 89 years of age By linear regression, significant decline of FEX,/FVC ratio with pack-years of cigarette consumption in men; similar decline demonstrated in women, but not significant for all ab!e mute Higgine and Kjelsberg 19% 1980, Tecumeeh, Mich!gan (1967) - Higgins et al., 1963, Marion County. West Virginia 1196all I_..------ Higgins et al., 1962-1965, l'rcumwh. lIichiian (1977) 5,140 men and women, 16 to 79 yeare of age 926 white men, 20 to 69 years of age 4,669 men and women, 20 to 14 years of age - Age-adjusted mean FEV, Oiters) Men Women Nonsmokers 3.32 2.34 Ex-smokera 3.31 2.34 Current smokers 3.12 2.26 Mean FEV, (liters) Nonsmokers 3.64 Ex+mokers 3.25 Current smokers 1-14/day 3.67 15-2.4lday 3.51 > mday 3.30 Mean normalized FEV, score Men Women Nonsmokers 10.2 10 1 Ex-emokers 9.9 10.0 Current smokers c2O/day 9.8 9.9 2 2oMay 9.5 9.6 -~.__l___-.__l~---- Prevalence of E'E:V : i FVC <: Go% Men Women Mlwl'r" ct n'. 1`W 1 . Glenwood, cid!LI f%)(l :xn and women. Nonsmokers 3 ; %;! to 69 JY'Ul-8 or age Current smokers 19 2 (2971) .- ~.-- Fen% et al., 1967, &rlin, 848 men and women, By multiple r-ion, in men and women, FEV, drops by New Iiampehire (197.3 3OtcW)yearsofage 0.01 liters for each cigarette smoked per day -.-._-- -. _-- _ _----- -~ ___--. .-.---__ Burrowe et al., 1972.-1!?7?. 2369 men and women, By multiple regression analysis, FEV, drops by 0.31 and Tucson, Arizona iI above 14 years of age 0.24 percent of predicted value per pack-year of smoking in men and women, respectively .____ --- ---..---- _- Knudson et al., 19X1973. 2,7.35 men and women, Pravalence (%) of abnormal FEV, and/or FIW,/FVC Tucson, Atiana (f97fJ all ages Asymptomatic nonsmokers 8.3 Asymptomatic smokers 13.3 __-- ---. --.~ Tsger and S+vr, 1973.397!. 633 men and women, By multiple regression, in men and women, significant FM Ftiton. Massachusett 15t years of age reduction of an FJXV, score with increasing lifetime /19707 consumption, and in smokers compared with nonsmokers Tagger et al., 197:%1974. East Boston, Msssarhwe!k !!9,3 1,251 men and woman, By multiple logistic analysis, lifetime cigarette consumption only significant pradictor of airflow obstruction, defmed as FEV, laea than 65% predicted 4.6W men and women, 7t yearsofage By multiple regression analysis, significant dose-response relationships of adjusted residual FJIV, with measurea of cigarette smoking: duration, pack-years. and cigarettes per day TABLE %-Continued Author, year of study, Number and type location, reference of population Findings Ferris et al., 1974-1977, U.S. communities (19791 Detele et al., Rokaw et al., 1973-1975, Burbank, Lan- mater, Long Beech, California (lhtels et al.. 1979, Rokaw et al., 1960) 8,480 men and women, 25to74yeareofage Approximately 8,000 men and women, 18 yeare or older Mean r&dual FEV, (liters) after correction for height and age Lifetime packs Men Women None 0.25 0.06 <3.ooo 0.21 0.04 3.~999 0.01 -0.05 9,ooo-17,999 -0.19 -0.20 2 l&o00 -0.45 -0.28 F'revalence (%Y of FEV, below 75% predicted, age and eex-adjusted Never smoked Current smoker 1859 years old Burbank 6.6 12.5 Lancaster 3.4 6.6 Long Bench 5.3 10.0 260 years old Burbank 15.9 23.5 Lancaster 13.4 21.7 TABLE 9.-Association between cigarette smoking and lung function in sele&ed non-U.S. populations Author, year of study, Number and type location, reference of population Findings Hi, 1956, VaIe of GlamorgaIl, wales mm 661 men and women, 25 to 74 yearn of age lr men, reduced peak tlow rates and indirect maximum v&ntary ventilation in smokers compared with nonsmokers; no effect of smoking in women Higgins et al., 1957 Stavely, England (1959l 776 men, aged 25 to 34and55to64 Mean indirect maximal breath capacity (liters) 25ta34yrE 55ta64yl-n Nonsmokers 145 101 Exsmokers 143 89 Current smokers Light 140 87 HWVY 133 80 H&inn et al., 1966, Rhondda 537 men, aged 36 to 64, Mean indimct maximal breathinx canacit~ titers). men Fa& -. - Walea (1961) and 173 women, aged55to64 Miners Nonminers Nonamokern 93.1 114.6 Ex+mokern 93.6 106.9 Current smokers Light 89.0 104.1 HeavY 88.3 99.4 No effect of smoking in women TABLE 9.-Continued Author, year of study, Number and type location, reference of population Findings College of General Practitioners, 787 men and 762 Age-adjusted mean PEFB' flitera/minute) 1966, Britain (1961) women, aged 40 to 64 Men Women Nonsmokers 448 316 Ex-nmokern 417 300 Current smokers 1-lllday 412 314 15-24/day 399 310 > 25lday 398 265 SluisCremer and Sichel, 533 men, 36 yearn Reduced FEV, and PEFR' with increased tobacco mnsumption 1962-1963, Carletonville, or older South Africa (1Si!7~ Huhti, 1961. Harjavalta, 420 men, 608 women, All women, nonsmokers; in men, reduced FEV, and PEFB ' in Finland (1967~ aged4ot.oe4 smokers mmpared with nonsmokers Wilhelmsen et al., 1963. 339 men. aged 50 Gi5teborg, Sweden (1969) Mean FEV, (liters) Nonsmokers 3.72 &-smokers 3.71 Current smokers 1-14 g/day 3.58 > 15 g/day 3.36 Huhti et al., 1968-1970, 1,162 men, aged 25 to Reduced FEV, in smokera compared with nonsmokers; increased Hankaaalmi. Finland (1978) 69 prevalence of FEV,/FVC ratio lese than 60% in smokers TABLE 9.-Continued Author, year of study. Iwatinn. reference Number and type of population Findings MimIca, 1969. Croatia, 4,214 men and women, Yugoslavia (1979 35 to 54 years of age Nonsmokers Ex+mokers Current smokers Light H-V Mean FEV, (liters) Men 3.56 3.57 3.42 3.42 Women 2.62 2.70 2.64 2.66 Neri et al, 19691973. Sudbury and Ottawa. Canada 11975 Manfreda et al, 1974, Portage la Prairie and Charleswoo& Canada (197x) --- -- Andemon. year not stated, Karkar Island. Papua New Gtinm 11976-I Anderson, year not stated, Lufa, Papua New Guinea (2979) 5,466 men and women, 14 years of age or older 502 men and women, 25toXiyearsofage 548 men and women, 25 years of age or older 733 men and women 25yearsofageor older Declining ratio of FEV!/FVC with number of cigarettes smoked MY Significant regression of FFV,/FVC ratio on number of cigarettes smoked daily Age and heightadjusted mean FEV, (liters) Men Women Nonsmokers 2.56 2.13 Smokers 2.40 2.01 Age and heighta&sted mean FEV, (liters) Men Women Nonsmoker 2.58 2.36 Exsmoker 2.62 2.27 Occasional 2.57 2.29 R@idw 2.63 243 TABLE IO.-Association between cigarette smoking and lung function level in selected occupational groups Author, year of study, Number and type location, reference of population Findings Sharp et al., 1960-1961, 1.667 men, aged 43 to Chicago, U.S. (1965) 56 years. employed at an electronics plant ..-_ --~___ Fletcher et al., 1961. 1,136 men aged 30 London, England (2976) to 59, employed at bank or in maintenance of transportation equipment f, --__ i- -- Goldsmith et al. 1961 San Francisco. U.S. ima' 3,311 longshoremen Mean FEV, (liters) Nonsmokers Smokers 40 cigarettes/day 3.15 3.02 2.90 3.28 3.16 2.81 3.05 2.99 2.94 100 97 93 93 94 E TABLE IO.-Continued Author. year of study, Number and type location, reference of population Rndinga Bidchum et al.. 1961, La 1,456 men employed in Prevalence (per 100) of FTV,/FVC ratio less than 70 percent Angeles, U.S. (I96ZI various induetrien Nonsmokers 1.6 Smokers 18.8 Coata et al.. 1962. Detroit, 1,584 male and female Reduced FFX, and FFX,/F'VC ratio in smokers of 25 or more U.S. (1965) pcwtal employees, cigarettes daily compared with nonsmokers aged 40 or older Deneen et al., 1961-1983, New York City, US. (2969) 12,500 males employed 88 postal or transit workers Age- end heightadjusted FJW, W..ere) Pcetal workers Transit workers Band6 et al., 1980-1975. Belgium (1980) 7.123 male military personnel, * few over age 45 white Nonwhite White Nonwhite Nonsmokers 3.29 3.05 3.39 3.08 Cigarette smokers <25gperday 3.14 2.95 3.15 3.00 2% B per &Y 3.06 2.93 3.02 2.95 By multiple regression, in crcesaxtional analyeie, signiiiwnt effect of smoking on FEV, level after age 35 Cornstock et al.. 1962-1963 and 1967. U.S. and Japan (19731 Three cme+eectional Mean FJW, level as percent predicted studies of men working U.S. Jaw for telephone company; Study 1 Study 2 U.S.-l,302 and Cigarettea per day 1,194 subjects, aged None 106 103 99 40 to 65. 6% in 1-14 104 101 100 study; Japan--592 15-24 98 92 98 subjecta, aged 40 to 60 2% 95 93 99 `I'ABLE l&--Continued Author, year of study, Number and type location, reference of p0pu1at10n Fmdings Khmla. 1964. Port Talbot, United Kingdom (1971) Schlesinger et al., 1966. 7,701 males employees Adjusted mean FEV, level (liters) in the ateel industry Never amokem /- Current smokers i 15 cigarettealday lb24 cigarett&day 25-34 cigar&tea/day 2 35 cigarettes/day 4.331 male civil servants, Mean value of the FEV,/FVC ratio Israel (1972) aged 45 or older Nonsmokera Jhmokem Current smokers 1-19 cigarettes/day - 3.70 3.57 3.48 3.41 3.37 - 76.0 74.3 73.9 2 20 cigarettes/day 72.7 Keateloot et al., 1968-1969, Belgium (2976) O'Donnell and de Hamel. 1969- 1970, New Zealand (1976) Linn et al., 1973, San Fran- cisco and Los Angeles, U.S. (1976) Rndelman et al.. year not stated. Baltimore. U.S. (1966) 4,961 males in the Belgian military, aged 15 to 59 1.079 male public sewante, up to age 65 644 male and female office workem aged 17 to 60 410 male volunteers, aged2otQ103 By multiple regression, FEW, reduced by 0.14 liters in smokers of 1-19 cigarettes daily and by 0.23 liters in smokere of 20 or more daily Beduoed mean FEV, in smokers of 10 or more cigarettes daily; increaeed prevalent of FEX, below 80 percent of predicted in smokers of more than two pa& daily By analysis of covariance, significant reduction of FJXV, in smokers compared with nonsmokers By partial regression analysis, significant reduction of FEW, in current and former cigarette smokem c 0 e TABLE 10.~-Continued Author. year of study, Number and type location, reference of population FlllilllgS Woolf and Suero, year not stated. Toronto (1971) Krumholz and Hedrick. year not steti, Dayton. U.S. (1973l 298 female volunteers employed at commercial film, aged 25-54 227 male executives. aged 3.544, selected to include nonsmokers (n = 136) and long- term smokers (n=91) Adjwted mean levels Nonsmokers Exsmokers Current smokers 70 cigarettes/week 71-140 cigarettes/week 2 140 cigarettes/week Mean values Nonsmokers Smokers EV, FEV,/FVC ratio 2.65 a.7 2.64 85.0 2.63 86.2 2.50 85.1 2.45 84.1 ___- EV, FEV,IFvC 3.80 71.3 3.42 73.6 Grimes and Hanes. year not stated, Los Angeles, U.S. (1973) Lefcoe and Wonnacott. year not stated. western Ontario, Canada ( 1974 1,059 male and female insurance company employees 1,072 males in four occupational groups By multiple regression, significant reduction of FEV, level in male smokers but not in female smokers By multiple regression. significant reduction of FEY, in current cigarette smoken Higgenbottam et al.. year not stated, London. England (1980) 18.403 male civil sewants. aged 4ota64 Reduced FEV, io cigarette smokers compared with nonsmokers, increased effect with increasing daily amount in current smokers (Table lo), even though people with symptomatic airflow obstruction may be likely to retire from their jobs. Recently, predictors of the incidence of airflow obstruction have been examined with multivariate techniques in data from popula- tion samples in Tecumseh, Michigan (Higgins et al. 19821, and in Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest predictors of airflow obstruction (defined as an FEVl less than 65 percent of predicted) were age, the number of cigarettes smoked daily, changing smoking habits, and the initial FEVl level (Higgins et al. 1982). The addition of other variables to the predictive model did not greatly improve its validity. In Tucson, these same variables, along with certain symptoms and illnesses, and skin test reactivity were significant predictors (Lebowitz et al. 1984). During the 10 years of followup of a population sample in Finland, incidence cases of chronic airflow obstruction (defined as FEV1/FVC ratio less than 60 percent) were observed only in those who continued to smoke (Huhti and Ikkala 1980). These studies of incidence highlight the importance of cigarette smoking in t.he etiology of airflow obstruc- tion; new cases are rare among nonsmokers. Dose-Response Relationships Dose-response relationships between FEVl level and the amount of cigarette smoking have been described with simple descriptive statistics and further characterized by multiple regression analysis. In cross-sectional data, the FEVl level varies inversely with the amount smoked. Although the variation in mean FEVl levels among strata of smoking appears clinically unimportant, the distributions of values in smokers and nonsmokers are quite different (Figure 4). Cigarette smokers more often have abnormal lung function, regard- less of the criteria applied to the population (Mueller et al. 1971; Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw et al. 1980; Beck et al. 1981). This increased prevalence of abnormal function is a result of the skewed distribution of function in smokers, with a subgroup of the smokers showing a large decline rather than the entire group shifting by a small amount (Figure 4). As noted in this reference, however, there are decreasing numbers of smokers with FEVI above the mean for nonsmokers as pack-years increase, suggesting that all smokers are probably somewhat affected, even though only a minority eventually develop clinically significant airflow limitation. In several populations, the relationship between cigarette smoking and FEVl level has been examined in greater detail. Burrows et al. (1977a) used linear multiple regression analysis to examine the relationship between cigarette smoking and ventilatory function in a population sample in Tucson, Arizona. Pack-years, a cumulative- dose measure, was the strongest predictor of FEVi level among the 103 smoking variables considered. In currently smoking men and women, the FEVi declined by approximately 0.25 percent of the predict.ed value for each pack-year of cigarette smoking; the effect was of a similar magnitude in ex-smokers. Using data from three separate U.S. communities, Beck and colleagues (1981) assessed the importance of six separate smoking variables: amount smoked daily, use of filters, inhalation, age started, age stopped for ex-smokers, and cumulative pack-years. For the FEVi, the strongest predictors in male current smokers were the duration of smoking and the amount smoked; in female current smokers, only pack-year was statistically significant. The number of years of cessation was associated with FEVl in male but not in female ex-smokers. However, in both the multiple regression analysis reported by Beck et al. (1981) and that reported by Burrows et al. (1977a), the measured cigarette smoke variables accounted for only about 15 percent of the variation of age- and height-adjusted FEVi levels. Unmeasured aspects of cigarette smoking, other environmental exposures, and the characteristics of the smokers must contribute to the unexplained variation. A role for the type of cigarette smoked has not yet been established (USDHHS 19811, and the impact of differences in depth or pattern of inhalation and other aspects of the pattern of smoking remains to be investigated; they are discussed in more detail in the chapter on low tar and low nicotine cigarettes. Further studies of these aspects of cigarette smoking are needed to monitor the consequences of changing cigarettes. Factors Other Than Cigarette Smoking A number of risk factors other than cigarette smoking have been postulated as contributing to the development of airflow obstruction (Table 7). Of these, a definite role for a,-antitrypsin deficiency has been established, but only the small number of persons with homozygous deficiency incur markedly increased risk (Morse 1978). The current hypotheses on susceptibility to cigarette smoke postu- late roles for childhood respiratory illnesses (USDHEW 1979; Burrows and Taussig 1980; Samet et al. 19831, for endogenously determined hypersensitivity of the lung, and for other genetic and familial factors (Speizer and Tager 1979; USDHHS 1980aJ At present, these hypotheses remain largely untested. The data are similarly incomplete at present for the other factors listed as putative risk factors in Table 7. The status of each is briefly reviewed below. ABH Secretor Status Secretion of ABH antigens is a genetically determined trait that follows an autosomal dominant inheritance pattern; approximately 104 70 to 80 percent of the population excrete antigen into the body fluids (Cohen et al. 1980a). In a genetic-epidemiology study in Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had lower levels of FEVJFVC ratio and a higher proportion with FEVJFVC ratio below 69 percent. Studies in France (Kauffmann et al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed reduced expiratory flow rates in ABH nonsecretors. In contrast, ABH secretor status did not predict the development of obstructive airways disease in the Tecumseh, Michigan, population (Higgins et al. 1982). Air Pollution Although exposure to air pollution at high levels may exacerbate the clinical condition of persons with chronic lung disease, a causal role for air pollution in the development of airflow obstruction has not been established (Tager and Speizer 1979; USDHHS 1980b). However, smoking is the major predictor for chronic airflow obstruction in areas of high as well as low atmospheric air pollution. Airways Hyperreactivity Orie and colleagues in the Netherlands (Orie et al. 1960) speculat- ed that bronchial hyperreactivity and allergy may predispose to asthma and chronic bronchitis. Findings from two small longitudinal studies have suggested that airways reactivity may influence indi- vidual susceptibility to cigarette smoke. Barter and colleagues followed 56 patients with mild chronic bronchitis during a 5-year period (Barter et al. 1974; Barter and Campbell 1976). The rate of decline of FEVl increased with the degree of airways reactivity, as measured by reversibility with isoproterenol or responsiveness to methacholine. Britt et al. (1980) measured change of FEVl in 20 young adult male relatives of patients with chronic obstructive pulmonary disease. The decline of FEVl was approximately five times larger in the nine subjects with a positive methacholine challenge test. In patients with clinically diagnosed airflow obstruc- tion, airways reactivity is also associated with more rapid decline of lung function (Kanner et al. 1979). Because airway reactivity would affect the FEV, directly as well as possibly influence the susceptibili- ty to smoke, it is difficult to ascertain from these data whether the relationship between airway reactivity and COLD is direct or spurious. Alcohol Consumption The epidemiological data on alcohol consumption are conflicting. A study of former alcoholics demonstrated an excess prevalence of lung function abnormalities, including airflow obstruction (Emergil 105 480-144 0 - 85 - 5 and Sobol 1977). In the Tucson population, alcohol consumption was a significant predictor of ventilatory function after the effect of smoking was controlled (Lebowitz 1981). The findings of an investiga- tion in Yugoslavia were similar (Saric et al. 1977). However, two large U.S. investigations did not demonstrate adverse effects of alcohol intake (Cohen et al. 1980b; Sparrow et al. 1983a). Cross-sectional data from the Tucson population suggest increased susceptibility to cigarette smoke in atopic people (Burrows et al. 1976). In subjects aged 15 to 54, the prevalence of an FEVAWC ratio below 90 percent of predicted value increased with skin test reactivity among both smokers and nonsmokers. Subsequent reports from this same study have not confirmed an overall relationship between FEVl level and atopy, but indicate that atopy may predis- pose to airfIow obstruction in a subset of the population (Burrows et al. 1977a, 1983). Burrows and coworkers (1981) also reported an increased level of IgE in smokers independent of their allergy skin test reactions, and the interrelationship of these factors is currently being examined. Childhood Respiratory Illness In a longitudinal investigation of 792 English working men, Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional association between childhood illness history and FEVl level. The decline of FEVl level during the study's longitudinal phase was not correlated with childhood illness variables. In contrast, a.nalyses of cross-sectional data from a population sample in Tucson suggested that childhood respiratory illnesses may increase susceptibility to cigarette smoke (Burrows et al. 1977b). In this population, people with a history of respiratory trouble before age 16 demonstrated excessive decline of ventilatory function with increasing age and with increasing cigarette consumption. Familial Factors Familial aggregation of lung function level, adjusted for age, height, and sex, has been demonstrated in populations in the United States and elsewhere (Higgins and Keller 1975; Tager et al. 1976; Schilling et al. 1977; Mueller et al. 1980). However, a recent report suggests that the familial aggregation of lung function may be a reflection of the familial aggregation of body habitus (Lebowitz et al. 1984). Relatively modest correlations of FEVI level have been demonstrated between siblings and between parent-child pairs. The role of familial factors is further supported by investigations demonstrating increased prevalence of airflow obstruction in rela- 106 tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978; Cohen 1980). This familial factor cannot be explained by familial resemblance of a,-antitrypsin phenotype or of ABH secretor status (Kueppers et al. 1977; Cohen 1980). In the Tecumseh population, however, family history of airflow obstruction did not predict the incidence of this disease. The results of twin studies are also consistent with genetic influences on FEVl level and suggest that genetic factors may influence susceptibility to cigarette smoke (Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982). Occupation Several population-based investigations suggest that occupational exposures other than those recognized as causing lung injury may have some effect on lung function level. In Tecumseh, mean age and height-adjusted FEVl scores in men were highest in farmers and lowest in laborers; the differences were not explained by smoking and were present in nonsmokers (Higgins et al. 1977). Similarly, in Tucson, men reporting employment in certain high risk industries or exposure to specific harmful agents had a higher prevalence of abnormal lung function (Lebowitz 1977a). In a Norwegian case- control study, men employed in workplaces characterized as polluted were at increased risk for clinically diagnosed emphysema (Kjuus et al. 1981). Longitudinal studies of industrial populations also show that occupational exposures may increase the rate of decline of FEVl (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982). For example, Kauffmann et al. (1982b) found that FEVl change during a 12-year period varied with job exposures in an employed industrial population. Effects of dust, gas, and heat were present, as was evidence for a dose-response relationship between increasing exposure and a greater rate of decline. In these studies, however, smoking effects were generally much greater than the occupational effects. Passive Exposure to Tobacco Smoke Passive exposure is discussed in detail elsewhere in this Report. Respiratory Illnesses In an 8-year followup study of London men, chest infections were not associated with a rate of FEVl decline (Fletcher et al. 1976). The findings of several smaller longitudinal studies were similarly negative with regard to respiratory infection (Howard 1970; John- ston et al. 1976). It is now apparent that mucus hypersecretion and airflow obstruction are separate pathophysiological entities that have a common cause-cigarette smoking (Fletcher et al. 1976; Peto et al. 1983). 107 Socioeconomic Status Weak effects of socioeconomic status on lung function level have been demonstrated in community samples in Tecumseh (Higgins et al. 1977) and in Tucson (Lebowitz 197713). In both populations, lung function appeared to be influenced independently by socioeconomic status indicators, even after controlling for cigarette smoking. In the Tecumseh study, FEVI increased slightly with increasing income and education level (Higgins et al. 1977); in the Tucson study, the proportion of people with an abnormal FEVl varied in a similar pattern with these indices (Lebowitz 1977al. Effects of socioeconomic status were present in nonsmokers in both investigations. Stebbings (19711, in a sample of nonsmokers in Hager&own, Maryland, also demonstrated an association between lung function level and socioeconomic status. In summary, there is evidence that a number of factors other than cigarette smoke may influence lung function, but the influence of these factors is small relative to the effect of smoking, and the major question is whether they can influence susceptibility to cigarette- induced lung injury rather than whether they, of themselves, result in lung disease in nonsmokers. Development of Airflow Obstruction At this time, the natural history of airflow obstruction has been only partially described; a population has not yet been followed from childhood to the development of airflow obstruction during adult- hood. However, the available data from separate investigations cover the entire course of the disease and support the conceptual model proposed in Figure 15. With aging, measures of function begin to deteriorate after age 25 to 30. In nonsmokers without respiratory disease, cross-sectional data generally show that the FEVl declines by 20 to 30 ml per year (Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al. 1981). Longitudinal data have been confirmatory (Tables 11 and 12). For example, Tockman (19791 measured the FEVi loss during an 8 year period in 399 male nonsmokers. In most, the FEVl declined at 25 ml annually; a few, with an initial FEVl lower than 2.5 1, lost 34 ml annually. Sufficient excessive loss leads to the development of airflow obstruction. However, many questions remain unanswered concern- ing this process of functional deterioriation. It is unclear whether the loss always occurs uniformly or if it develops in stages with intermittent and relatively steep declines (Bates 1979; Burrows 1981). The concept that the decline is nearly always gradual receives strong support from the findings of the &year longitudinal study conducted by Fletcher and coworkers (1976). In this investigation of 108 TABLE IL-Association between cigarette smoking and longitudinal change in lung function in selected population samples Author, years of study, Number and type location, reference of population Findings Higgins and Oldham, 1954-1959 Rhondda Fach. Wales (196.9~ 253 male miners, ex- miners, and nonmining controls Annual decline of indirect maximal breathing capacity (liters/min) Miners, ex-miners controls without pneumoconiosis Nonsmokers 1.6 0.8 Es-smokers 0.7 1.8 Current smokers 1-14 g/day 1.3 1.7 115g/day 1.6 2.2 Ashley et al.. 195S1968, Framingham. U.S. 11975) 399 men and 636 women. aged 37 to 69 in 1958 lo-year change in FEV,IFVC ratio (agestandardized to overall distribution for each sex) Men Nonsmokers 0.21 Gmtmued smokers -1.3 stopped. 1953-1963 0.51 Women -3.6 -4.1 -4.6 Higgins et al.. 1957-1966. 594 men, aged 25-34 Annual decline of FEVw, (ml/year) bv age and smoking in 1957 &ely. -- England (1968b) or 55-64 in 1957 2534 ;rs 5Gl yrs Nonsmokers 21 32 Exsmokem 29 44 Current smokers 1-14glday 37 54 2 15gida.v 38 37 E TABLE 1 l.-Continued Author, years of study. Number and type location, reference of population Huhtl and Ikkala. 196-1971. Harjavalta. Finland (1980) Wilhelmsen et al.. 1963-1967. Goteborg. Sweden (1969) 492 men and 671 women, aged 40 to 64 in 1961 313 men, aged 50 in 1963 Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Continued smokers Stopped. 196-1971 Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Current smokers I-llg/day 2 15glday StQDDd. 1963-1967 Men 33 45 44 51 43 33 70 70 40 Women 27 27 39 35 _ -- _ -. .,"II***.u~u Author. years of study. Number and type locatlon. reference of population Findings Oxho] et al.. 1963-1973, 269 men. aged 25 ctgslday 54 Annual decline of FEV, iml/year). adjusted for initial level Nonsmokers 40 Ex-smokers 44 Current smokers c 15 g/day 46 ? 15 g/day 51 5-year decline of FEV, as percent of mean, by 1973 smoking Nonsmokers 3 Ex-smokers 5 Current smokers 7 Annual decline of FEV, (ml/year) I.9821 - Nonsmokers Ex-smokers Continued smokers stopped, 1967-1977 37 39 49 48 E TABLE 12.-Continued Author. years of study, Number and type locatton. reference of population Findings Woolf and Zamel. years not gtven. Toronto. Canada r IY8O)xoI BOW et al, lYfxLlY68 to 1YtwlY74. Boston. II s ( I.WII 302 female volunteers, aged 25 to 54 at entry H50 male volunteers 5.year change m FEV, as percent of initial value Nonsmokers 15 Rx-smokers 0 8 Smokers <. 70 clgslweek 0.4 71-140 ctywveek `): 3.t,, 140 cigs! week 48 Annual declme of FEV, imllyearr. adjusted for age and mtttal level Nonsmokers 0.053 Ex-smokers 0.057 Current smokers 0085 Love and Mtllcr. 1957 to 1973 1.677 male coalmmers II-year declme tn FEV, Ilttersl Iaverage followup. 1 I years). UnIted Ktngdom ~l.Y&?b Nonsmokers 0.41 b-smokers 0.48 IntermIttent smokers 0.52 Current smokers 0.53 792 employed men, the individual patterns of temporal change of the FEVl were strongly variable, but the loss generally occurred gradually. Fletcher et al. further demonstrated that FEVl levei correlated with FEVl slope, a finding that they termed the "horse- racing effect." Correlation between slope and level would be antici- pated, if functional loss occurs gradually. This correlation has important implications for intervention; those losing FEVl more rapidly should become identifiable early as they develop a reduced FEVl level. Other studies, however, do not agree with either the pattern of FEVl decline or the "horse-racing" effect. Rapid declines to levels compatible with clinical disease or followed by a prolonged plateau have been described (Howard and Astin 1969; Howard 1970; Johnston et al. 1976). In a followup study of Canadian men with chronic bronchitis, steep declines of FEVl without subsequent improvement were frequently observed (Bates 1973). Additionally, correlation of FEVl level and slope has been. found in most other longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne 1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974; Krzyzanowski 1980). Another unanswered question concerning functional deterioration is whether gradual decline occurs in a linear or a nonlinear fashion (Fletcher et al. 1976). Sufficient numbers of people have not yet been followed to distinguish alternative patterns, although the available data indicate acceleration of the decline with aging (Emergil et al. 1971; Fletcher et al. 1976). In spite of these uncertainties concerning the development of airflow obstruction, the available data indict cigarette smoking as the primary risk factor for excessive loss of FEVl (Tables 11 and 12). The findings in both general population samples (Table 11) and occupational and volunteer cohorts (Table 12) have been similar. Recent reports from Belgium (Bande et al. 1980; Clement and van de Woestijne 1982) and from Connecticut (Beck et al. 19821, not readily summarized in tabular form, also described a strong effect of smoking on FEVl decline. A few studies have not shown increased loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek 1971). Even in people with clinically diagnosed airflow obstruction, continued smoking maintains the excess decline of FEVl (Hughes et al. 19821, although not all findings are consistent (Ogilvie et al. 1973; Johnston et al. 1976). Dose-response relationships have been found in many investiga- tions between the amount smoked during followup and the FEVl decline (Tables 11 and 12). The reported increases from the lowest to the highest smoking categories range up to 10 to 15 ml annually. Although this additional loss in heavier smokers appears small, if sustained for long periods of time it would shorten the time interval 115 Never smoked or not suscepbbk? Its effects - Stopped at 45 Death 25 50 75 Age (years) FIGURE X-Risks for men with varying susceptibility to cigarette smoke and consequences of smoking cessation NOTE: + = death. SOURCE: Fletcher and Pet0 (1977). to the development of functional impairment. So far, favorable effects of filter tip smoking and declining tar content on the rate of decline have not been shown (Fletcher et al. 1976; Sparrow et al. 1983b). Generally, sustained smokers experience a greater loss than those who stop during followup. In the study by Fletcher et al. (1976) of London men, subjects who stopped smoking at the beginning of the followup period lost FEVI at the same rate as never smokers. The results of two U.S. studies of ex-smokers are similar (Bosse et al. 1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes the importance of active smoking and the immediate benefits of smoking cessation (Figure 24). Smokers with reduced FEVI may be protected from developing clinically significant loss by timely smoking cessation (Fletcher and Peto 1977). The distribution of FEVI decline has been characterized and described for some populations, including patient groups (Burrows and Earle 1969; Howard 1974; Barter et al. 19741, population samples (Milne 19781, and occupational cohorts (Howard 1970; Fletcher et al. 1976). Similar data are also available for the mid-maximum expira- tory flow, another measure of ventilatory function (Bates 1973; Woolf and Zamel 1980). In each of these investigations, the distribu- tion of FEVI decline is unimodal (Figure 25); that is, a distinct population with more rapid decline is not sharply separated from those with lesser rates. The modes and medians of the distributions 116 60 70 Mean 60 Nonsmokers and Q a-smokers ii 50 e 6 i 40 30 1 20 10 0 -160 -140 -120 -100 -60 -60 40 -20 0 +20 FIGURE 25.-Distribution of &year FEVl slope in 792 London men SOURCE: Fletcher et al. (1976). are generally negative, but some subjects have had positive slopes during the relatively brief followup period of investigations conduct- ed up to this time. The distributions tend to be skewed by subjects losing FEVl more rapidly. The proportion of cigarette smokers is increased among those in the tail of excess loss (Figure 25). For example, Clement and van de Woestijne (1982) examined subjects with excess FEVl decline in a prospective study of 2,406 members of the Belgian Air Force. Losses beyond those expected from nonsmokers affected 6 percent of nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and 12 percent of heavy smokers ( > 20 cigarettes/day). The shape of the distribution of FEVl decline has important implications for the development of airflow obstruction. Smokers are not sharply separated from nonsmokers (Figure 251, but more often lose FEVl at a rapid rate. Because of this spectrum of severity, not all smokers develop significant airflow obstruction. Although the fac- tors that lead to excessive loss in individual smokers remain uncertain, they may include differences in the pattern of smoking. It is apparent, however, that this susceptible minority can be protected by smoking cessation. 117 summary During the 20 years that have elapsed since the 1964 Surgeon General's Report, the relationship between cigarette smoking and airflow obstruction has been intensively investigated. Surveys of community samples and other groups have established that airflow obstruction is a common condition in the United States and elsewhere. In some populations, as high as 10 percent of adults are affected. Determinants of lung function level and of the prevalence of airflow obstruction have now been examined in many populations throughout the world. Cigarette smoking is the strongest predictor of abnormal measures of ventilatory function. A causal relationship between cigarette smoking and airflow obstruction is supported by the consistency of the many published reports, the strength of the association, and the evidence for dose-response. Many risk factors for airflow obstruction other than cigarette smoking have been postulated, including other harmful environmen- tal exposures and the inherent susceptibility of the smoker. Homozy- gous a,-antitrypsin deficiency can explain only a minute proportion of the disease burden. The development of airflo-w obstruction by only a minority of smokers indicates that the interaction of smoking with other factors may influence the risk for specific smokers. Current research emphasizes the potential roles of childhood respira- tory illness and airways hyperresponsiveness. Longitudinal studies have now partially described the prolonged natural history of airflow obstruction. Excessive loss of ventilatory function, beyond that expected from aging alone, results in the development of disease in cigarette smokers. Only a susceptible minority of cigarette smokers lose function at a rate that will eventually cause clinically significant impairment. For this group, timely smoking cessation can prevent the development of disease. 118 EMPHYSEMA JA-oduction Pulmonary emphysema is frequently present in the lungs of individuals with chronic obstructive lung disease. This section has three purposes: (1) to review the definition, types, and quantification of emphysema; (2) to summarize the physiological and radiographic feature of emphysema; and (3) to discuss critically the relationship of smoking to emphysema, based upon observations in people and in experimental animals. Current concepts of the pathogenesis of emphysema are reviewed elsewhere. Definition of Emphysema The generally accepted definition of emphysema is an anatomic condition of the lung characterized by abnormal dilation of air spaces distal to the terminal bronchioles accompanied by destruction of air space walls (American Thoracic Society 1962; Heard et al. 1979). Difficulties with this definition have been discussed by Thurlbeck (1983). Normal air space dimensions have not been determined, and criteria of destruction have not been defined. These limitations hamper attempts to investigate the earliest lesions of emphysema and the subtle effects of environmental agents on lung structure. Types of Emphysema British pathologists pointed out in the forties and fifties that emphysematous lesions in certain people involved the respiratory bronchioles, which appeared as grossly enlarged airspaces in the center of the primary lung lobules surrounded by normal lung. In other individuals, the alveolar ducts were involved early, and even mild involvement appeared grossly as a coarsening of the architec- ture of the entire lobule. They designated the two polar patterns of emphysema as centrilobular emphysema (CLE) and panlobular emphysema (PLE) (Heppleston and Leopold 1961). Many lungs either show both types of emphysema or are unclassifiable. Of 122 lungs with emphysema examined by one pulmonary pathologist, 73 were -considered mixed or unclassifiable and 49 were clearly CLE or PLE (Mitchell et al. 1970). When the agreement of three pathologists was required, only 27 of the original 122 lungs remained classifiable and 95 were mixed or could not be classified. There were no statistically significant differences between the groups classified as PLE or CLE in any clinical variables. The only nonsmokers in either group had CLE, and the proportion of light smokers (less than 25 pack-years) was very similar between groups. In this study and others (Anderson and Foraker 19731, CLE was most severe in the upper lobes and PLE was uniformly distributed. According to Thurlbeck (19761, a common 119 combination is CLE in the upper lobes and PLE in the lower lobes; where lobectomies are used for correlation, typing of emphysema is therefore a particularly empty exercise. When emphysema is far advanced, it is often impossible to recognize the site of the initial involvement. Thus, it is not clear whether the differences in prevalence of CLE and PLE are real or represent differences in interpretation by different observers. Several localized types of emphysema occur in areas around scar tissue (paracicatricial), along interlobar and interlobular septa (paraseptal), and as bullous lesions (which represent the most advanced and extreme distortion of normal lung structure). Bullous deformities occur with any type of emphysema, including CLE and PLE. Occasionally, bullous lesions occupy huge intrapulmonary volumes. Detection of Emphysema The detection of emphysema requires suitably prepared lung specimens. At a minimum, this means the lung must be fued in inflation (Thurlbeck 1964). Fume fixation or fixation by instillation of liquid fixative through the airways is satisfactory, but for optimal evaluation of the latter group, barium impregnation or paper- mounted whole-lung sections should be used. Because lungs with emphysema frequently also have some degree of intrinsic airways disease, the severity of emphysema and the clinical state of the patient may not correlate directly. Pathologists can easily recognize mild degrees of emphysema that are rarely associated with clinical disability. Quantification of Emphysema There are a number of techniques for quantifying the volume of lung involved with "obvious" emphysema that are adequately reproducible and correlate well with one another (Thurlbeck 1976; Bignon 1976). Semiquantitative or subjective scoring methods as well as point counting have been used. These approaches all require lungs inflated to a relevant volume, usually one approximating total lung capacity during life. This can be achieved by a distending pressure of 25 cm H& (Thurlbeck 1979; Berend et al. 1980). In the scoring method, the lung is divided into a number of units and the severity of emphysema in each unit is scored (mild, moderate, or severe receive 1,2, or 3 points, respectively). The scores for each unit are summed to give a total score for the lung (Ryder et al. 1969). Alternatively, lung slices may be matched by visual comparison to a set of graded standards to achieve an emphysema score (Thurlbeck et al. 1970). These methods include both severity and extent of emphysema, and although they involve subjective judgments, they have proved to be remarkably reproducible. 120 In the point counting approach, regularly spaced points are superimposed on a lung slice. Each point is recorded as falling on normal parenchyma, emphysematous parenchyma, or nonparenchy- ma (conducting airways or vessels). The volume proportion of emphysematous lung is recorded. This method can be objective (e.g., if an emphysematous space is taken to be one greater than 1 mm in diameter), but it includes only extent and not severity of emphyse- ma. Morphometric methods carried out on histologic sections, exempli- fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are strictly objective, but they require careful attention to problems of sampling and are time consuming and insensitive to focal disease. For measurements of the Lm, histologic sections are made of blocks selected by stratified random sampling. The average distance between alveolar walls is determined from the number of intersec- tions of alveolar walls with a line of known length. The internal surface area of the lung can be calculated when the volume of the lung is known (Hasleton 1972). Pulmonary Function in Emphysema Because unequivocal proof of the presence of emphysema requires direct examination of lung tissue, the strategies used to characterize the pulmonary function abnormalities associated with emphysema have either involved comparison of functional data collected during life with autopsy or surgical material or have used measurements made exclusively on post-mortem specimens. Two important conclu- sions from these studies should be noted at the outset. First, impaired air flow during maximal expiratory maneuvers, as reflect- ed in reduced values for the FEV1, FEVIS, and FEF~~s, is neither sensitive nor specific for emphysema. It is possible to have severe emphysema without clinical obstructive lung disease (Thurlbeck 1977). It is also possible to have severe chronic obstructive lung disease without having emphysema, even though most patients with advanced chronic obstructive lung disease have some degree of emphysema (Mitchell et al. 1976). Second, none of the tests used to identify early obstructive lung disease, such as closing volume, the single breath NZ curve, or frequency dependence of compliance, distinguish diminished elastic recoil that may be related to emphyse- ma (see below) from increased resistance in small airways (Buist and Ducic 1979). Even the determination of density dependence of maximum expiratory airflow, once felt to be specific for detecting abnormalities in the caliber of small airways, is not immune to the effects of lung elastic recoil. A decreased effect on maximal expiratory air flow of using low density gas can be caused by decreased elastic recoil (Gelb and Zamel 1981). 121 Pulmonary function testing of individuals with proven emphyse- ma often shows increases of residual volume, functional residual capacity, and total lung capacity and decreases of maximal expirato- ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in Kidokoro et al. 1977). However, because individuals with emphysema commonly also have intrinsic airway disease (Casio et al. 1978) affecting the results of these pulmonary function tests in the same direction as emphysema, it is clear that these tests are not specific for emphysema. Accordingly, there has been interest in other, more distinctive tests. Among readily applicable tests, the diffusing capacity has proved to be directly related to the extent of emphyse- ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 19791, presumably reflecting a diminution of internal surface area avail- able for gas exchange. The usefulness of the diffusing capacity to identify and estimate emphysema is limited, however, because the measurement is not sensitive to low grades of emphysema (Symonds et al. 1974) or specific for emphysema. Moreover, the results must be interpreted carefully in smokers because the values for diffusing capacity are lower than in nonsmokers, and the difference extends even to young smokers who are not likely to have emphysema (Enjeti et al. 1978; Miller et al. 1983). Mechanical Properties of the Lungs in Emphysema Measurements of the pressure-volume characteristics of the lung have generally been regarded as a reliable means of physiologically detecting and quantifying emphysema because (al patients with emphysema often have increased lung distensibility and correspond- ingly low transpulmonary pressures (loss of elastic recoil) and (b) the severity of emphysema has seemed to correlate with the change in elastic recoil. It has also been assumed that the regions of lung with emphysema are the cause of the decreased lung elastic recoil, an assumption that appears reasonable because elastic recoil results in part from surface forces at the air-liquid interface and there is less surface area in emphysema. Recent observations challenge these concepts. Berend and Thurl- beck (19821, using lungs obtained post mortem, could not demon- strate a relationship between indices of lung elasticity and the grade of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of 100), and observed (Berend et al. 1981) in emphysematous lungs that the relative increase in compliance of the lower lobes was greater than the upper lobes, even though the emphysema was worse in the upper lobes. Others have also reported poor correlations between emphysema and elastic recoil. Silvers et al. (1980) found decreased elastic recoil and increased total lung capacity in excised human lungs with minimal emphysema, and Schuyler et al. (19781 noted in hamsters given small doses of elastase intravenously that there was 122 decreased lung elastic recoil at low lung volumes, although the lungs did not show morphometric changes. Guenter et al. (1981) noted that mild emphysema produced by pepsin caused greater changes in lung elasticity than similar degrees of lung destruction produced by endotoxin-induced repetitive leukocyte sequestration. They suggest- ed that these differences may be due to differences in the location of the connective tissue injury within the lung. Even among those who have reported an association between emphysema and elastic recoil, the correlations have been best when the emphysema was severe (Greaves and Colebatch 1980). Pare et al. (1982) found a correlation between emphysema grade and elastic properties of the lungs in 55 persons; however, in 5 whose surgically removed lung tissue received emphysema scores between 20 and 70 (out of a maximum of lOO), the elastic properties of the lungs tested preoperatively were indistinguishable from normal. While such discrepancies probably reflect the limitations of relating the overall elastic properties of both lungs to the morphology of a single lobe, it must also be recognized that the sensitivity of the pressure-volume diagram is limited, since a narrow range of pressure (to 20 cm HzO) depicts the average retractive force from millions of air spaces and the connective tissue network of the lung. From these recent findings it must be concluded that the relationship between elastic recoil and morphologic measures of emphysema is not highly predictable, and that the decrease of elastic recoil and increase of total lung capacity commonly seen in emphysematous lungs may not result entirely from abnormal mechanical properties in the areas showing emphysema. The mechanical abnormalities may also derive from areas that appear normal, although the possible reasons for this are obscure (reviewed by Thurlbeck 1983). An alternate explanation for this discordance between elastic recoil and morphologic emphysema may be the problems of sampling and grading intrinsic to these morphologic measures. The work of Michaels et al. (1979) introduces a further complexity to the use of pressur*volume curves as an indicator of emphysema. They found that inhalation of a bronchodilator shifted the curve of smokers in the direction of increased compliance, but had no effect in nonsmokers (Figure 26). Cessation of smoking had the same effect as a bronchodilator. These results were interpreted as indicating that smoking causes some peripheral airway units to constrict and become effectively closed. Thus, pressure-volume studies to detect early changes compatible with emphysema in smokers may give false negative results unless accompanied by studies with bronchodi- lators. 123 90 60 70 60 50 0 / I - .smoken p 6.0. [3--o Ncrwnckers M Nonsmokers p B.D I I I 1 4 6 12 16 P(stat)cmH& FIGURE 26.-The effect of nebulized bronchodilator on the pressure-volume characteristics of the lungs in 19 smokers (6 men and 13 women) and 16 nonsmokers (9 men and 7 women) NOTE: The mean age was approximately 40 years (range. 19 to 66) and smokers wed approximately 30 cigarettes per day. Male amoken, showed borderline significant differences in indicea of expiretory airflow and single breath Nz test data as mmpsred with the male nonsmokers. but there was no diRerace in these testa between female smokers and nonsmokers. As shown. smokers had significantly laes elastic recoil than nonsmokers. After the bronchcdiletor, the difference between smokers and nonsmokers increased further. particularly at high lung volume. B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity: Rstat) = transpulmonary preeeure. *p SOURCE. Auerbach et al (1972) TABLE 16.-Means of the numerical values given lung sections at autopsy of female current smokers, standardized for age SubJects who never smoked regularly Current cigarette smoken Number of subjects Emphysema Fibrosis Thickening of arterioles Thickening of arteries 252 0.05 0.37 0.06 001 10 years stopped l Pack l Pack 66 51 131 0.70 1.08 1.69 1.74 2.44 3.30 0.93 1.25 1.59 0.16 0.36 0.61 NOTE: Numeneal values for each finding were determined by rating each lung section on scales of S4 for emphysema and thrckenmg of the arterioles, CL7 for librosis, and C-3 for thickenmg of the arteries. SOURCE Auerbach et al (1974) proteinase inhibitory activity and the demonstration of the frequent early development of emphysema in such subjects (Ore11 and Mazodier 1972) called attention to the critical step of fibrous tissue proteolysis in the remodeling of lung structure. It also pointed to at least one potential explanation for the variability in extent of emphysema among smokers. Together with data from animal experiments, the discovery of the PiZZ defect and its association with emphysema has led to general acceptance of a theory of imbalance between the extracellular levels of proteinase and proteinase inhibitor in the lung as the cause of panacinar emphysema in subjects with this deficiency. The patho- genetic lessons learned from a,-proteinase-inhibitor deficiency also afford plausible explanations for other forms of emphysema, espe- cially emphysema associated with cigarette smoking. Homozygous Deficien t-Pi22 In his classic description of the severe (PiZZ) deficiency of the aI- proteinase inhibitor, Eriksson (1965) did not indicate an effect of cigarette smoking on the development of emphysema. Later studies, however, did recognize smoking as a potential aggravating factor (Kueppers and Black 1974; Larsson 1978) and reported that PiZZ persons who smoked cigarettes were destined to experience shortness of breath 10 to 15 years earlier (Figure 27) and to die sooner than PiZZ persons who did not smoke (Figure 28). 130 I Men I Smokers Nonsmokers T women Smokers . 81. . . i 11. . . . . . . . . . T . . . . . Nonsmokers . . . . . . . i 0 o FIGURE 27.-Age at onset of dyspnea in 169 PiZZ individuals separated according to sex and smoking history NOTE The hormntal lines show the me&an values. The difference between nonsmokers and smokers was highly s~gnrficant for both sexes and was 13 and 15 years for men and women. respezt~vely SOURCE: Larsson /1978, More recent studies, however, have shown considerable variation in the rate of decline of lung function among middle-aged PiZZ adults (Buist et al. 19831. In a comparison of 22 persons with PiZZ phenotype who had never smoked with 36 PiZZ smokers, Black and Kueppers (1978) found variability in symptoms and lung function abnormalities in both groups. Smokers generally sought medical attention earlier, and those who reached the older age groups, such as 60 to 69, had smoked less and started to smoke later in life. There was overlap in these characteristics between the age groups, however, and some smokers did live into the 50 to 69 age range. In this analysis, the correlations between pulmonary function test abnormalities and pack-years of cigarette smoking were small. The British Thoracic Society, in a multicentered study of PiZZ individuals (Tobin et al. 19831, reported an association between 131 0 Nonsmokmg PiZ men and women A All Swedish women All Swedish men 20 30 40 60 60 70 60 90 100 Age (IIT yeam) FIGURE 28.-The cumulative probability of survival, given that 20 years of age is reached, in smoking and nonsmoking Swedish PiZZ individuals, compared with all Swedish men and women NUI'E Surv~al was tugher for PlZZ nonsmokers than for PiZZ smokers in both exe8 above age 35 SOURCE. Lamson (19781 cigarette smoking and the onset of pulmonary symptoms and deterioration of lung function, but demonstrated no significant correlation between the quantity of tobacco consumed and the extent of pulmonary dysfunction. A notable finding in this study, applicable to other studies of the natural history of disease related to a1- proteinase-inhibitor deficiency, was the impressive difference be- tween individuals found because of medical complaints (index cases) and those detected by surveys (nonindex cases). Nonindex cases had better pulmonary function and survived longer than index cases, irrespective of other variables such as age and smoking history. The distinction between these two categories of subjects suggests the importance of factors besides the PiZZ phenotype in the development of symptomatic lung disease in PiZZ persons. PiZZ individuals who smoke increase their risk for early onset of symptomatic chronic obstructive lung disease and for a shortened lifespan, compared with nonsmoking PiZZ individuals. However, pulmonary function data have shown only limited differences in diffusing capacity and elastic recoil between the smokers and the nonsmokers (Black and Kueppers 1978). 132 He terozygous De ficien t-Pi117 The PiMZ phenotype of a,-antiproteinase inhibitor occurs in approximately 3 percent of the population. Because of the high frequency of emphysema in PiZZ persons, it is important to establish whether PiMZ individuals also have an increased risk of emphysema and chronic obstructive lung disease. From the unpredictability of obstructive lung disease even among those with the PiZZ phenotype, however, one might expect difficulty in discerning the effect of the PiMZ phenotype. Among adults with symptomatic chronic obstructive lung disease, the PiMZ phenotype is more prevalent than expected (Mittman 1978). It is uncertain whether this means of subject identification is appropriate, as was noted concerning index and nonindex PiZZ individuals. Madison et al. (1981) emphasized the complexity of this issue by noting that the PiMZ phenotype was only one of several factors that appeared to be related to the risk of obstructive lung disease. Other factors identified as relevant included smoking, a family history of lung diseases, and being male. From studies of children and young adults it is evident that the PiMZ phenotype does not strongly predispose to chronic pulmonary disease. Thus, PiMZ children (Buist et al. 1980) failed to show any early changes of lung dysfunction analogous to what has been observed in some young PiZZ individuals; PiMZ adults below the age of 40 had the same results by spirometry and the single breath N2 test as PiMM individuals matched for smoking history (Buist et al. 1979b). Numerous studies involving older subjects indicate that PiMZ individuals preserve their lung function, as measured by spirometry, compared with controls matched for smoking (Tattersall et al. 1979, de Hamel and Carrel1 1981). The elastic properties of the lungs may be different in PiMZ persons, but if there are differences, they are small. Larsson et al. (1977) reported that 50-yearold PiMZ men who smoked had reduced elastic recoil at total lung capacity compared with PiMZ nonsmokers, even though they had no evidence of impaired air flow. The PiMZ nonsmokers were indistinguishable from PiMM nonsmokers. Tattersall et al. (1979) also found no effect upon airflow in PiMZ middle-aged men, and a statistically nonsignif- icant decrease in elastic recoil. Using an index of the slope of the pressur+volume curve, Knudson and Kaltenborn (1981) found no significant reduction in elastic recoil of PiMZ subjects compared with matched PiM controls. There is little direct information about the occurrence of emphyse- ma among PiMZ individuals. In an autopsy study, Eriksson et al. (1975) found emphysema among 13 of 26 subjects with diastase- resistant PASpositive inclusions in the liver, compared with an incidence of emphysema of only 18 percent in the controls. Although 133 these findings suggest an increased occurrence of emphysema with the PiMZ phenotype, this study should be interpreted cautiously because the smoking histories of the subjects and the quantification of the emphysema were not included. Moreover, the significance of the PAS-positive inclusions is not certain, because one recent study found that such inclusions represented immunoreactive al-protein- ase inhibitor in only half of the tissue studied (Qizilbash and Young- Pong 1983). It may be concluded from the studies involving a,-proteinase- inhibitor-deficient people that for those with the PiMZ phenotype, smoking has not been shown to promote a greater risk of emphysema than it does in PiMM persons. In the rare individual with PiZZ, the risk of emphysema is extremely high in both smokers and nonsmok- ers, but PiZZ smokers experience an earlier onset and more severe chronic obstructive lung disease than PiZZ nonsmokers. Observations in Experimental Animals Experimental animals have been subjected to cigarette smoke to examine whether changes typical of emphysema result. As noted below, it appears that cigarette smoke exposure can produce emphysematous-like changes in the lungs under experimental conditions, but the exposure must be quite prolonged and intense, or additional factors must be employed to "sensitize" the lungs to the effects of cigarette smoke. Pioneering studies in dogs exposed to cigarette smoke, by Hernan- dez et al. (1966) and by Auerbach et al. (19671, indicated effects consistent with emphysema, but these reports did not include quantitative morphology or data about the mechanical properties of the lungs. Moreoever, the exposures may have created problems of hypoxemia and infection that may have influenced the responses to cigarette smoke. Contrary to these findings, in later studies, beagles that inhaled cigarettes by face mask in four sessions per day for up to 1 year-an inhalation sufficient to raise the blood carboxyhemoglo- bin saturation to 5.4 + 0.9 percent-had no statistically significant changes in mean linear intercept or internal surface area, although their large airways showed epithelial cell hyperplasia, proliferation of goblet cells, and peribronchial inflammation (Park et al. 1977). Recently, Hoidal and Niewoehner (1983) presented data suggesting that cigarette smoke may be an important cofactor in the develop ment of elastase-induced emphysema. They found that inhalation of cigarette smoke led to severe emphysema in hamsters if used in conjunction with doses of elastase that did not produce emphysema when used alone. In this study, hamsters were exposed to cigarette smoke for 15 minute periods, six times per day, 6 days per week for 7 weeks in standardized chambers. The animals were challenged with small doses of elastase given intratracheally; controls consisted of 134 animals given either elastase or smoke exposure or neither. Animals receiving only smoke or only elastase showed no changes of mean linear intercept or volume-pressure relationship of the excised lungs, compared with animals given neither elastase nor smoke exposure. The combinations of smoking followed by elastase or smoking both before and after elastase produced statistically signifi- cant increases of mean linear intercept, displacement upward and to the left of the volume-pressure curves (Figure 29), and marked emphysema by light microscopy of inflation-fixed lungs. The mecha- nism of the synergism between elastase and smoking was not elucidated. One possibility considered was that cigarette smoke impaired the repair mechanism normally triggered by elastase exposure, a possibility supported by Osman et al. (19821, who found that hamsters exposed to cigarette smoke after intratracheal elas- tase did not show the heightened lung elastin synthesis typically seen after lung injury produced by elastase. summary Clinically significant degrees of emphysematous lung destruction are commonly present in individuals with COLD. Severe emphysema occurs almost exclusively in cigarette smokers and those with homozygous a,-antitrypsin deficiency. The extent of emphysematous change increases with increasing numbers of cigarettes smoked per day and with the duration of the smoking habit. While clinically significant emphysema is limited to a minority of those who smoke, most heavy smokers have some degree of emphysematous change by the sixth decade of life. Individuals with homozygous a,-antitrypsin deficiency have an exceptionally high risk of developing emphysema. This risk is present for both smokers and nonsmokers, but smokers with a,- antiprotease deficiency develop clinical symptoms earlier in life. It is unclear whether individuals with heterozygous antiprotease pheno- types are at increased risk of developing COLD. Summary and Conclusions 1. Cigarette smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. 2. In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. 3. In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- 135 o NO smoke, no elastase ? ~ontmuous smoke, no elastase * No smoke, elastase 0 Posf-elastase smoke A Pre-elastase smoke A ~ontmuous smoke. elastase p. ,05 compared wlh * No smoke. no elastase I I I I I I 5 10 15 20 25 30 Pressure (cmHtO) FIGURE 29.-The effects of combining cigarette smoking and elastase upon the pressure-volume characteristics of the lungs of experimental animals N(rTE. The m vttro measurements of lung volume are shown as percentage of predicted total lung capacity cTLCr relative to transpulmonary pressure of hamster lungs following m vwo exposure to venous combmatlons of agarette smoke and mtratracheally admlnlstered pancreatic elastase Values are the mean t SEM of messurement~ made dunng deflation Tbe animals that smoked and then recewed elastase tPre-Elastase Smoke) and those that smoked both kfore and after elastase lContmous Smoke. E1asta.wI had slgmficant changes m the elastx properties of the lungs There were no changes from control if elastase or smoking were used separately or when smoking occurred onI?. after elastase SOURCE Holdal and N,ewcehner / 19831 ic defect) are established causes of clinically significant COLD in the absence of other agents. 4. Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the 136 smoking habit, and is greater in heavy smokers than in light smokers. These abnormalities in function reflect inflammatory changes in the small airways and often reverse with the cessation of smoking. 5. Both male and female smokers develop abnormalities in the small airways, but the data are not sufficient to define possible sex-related differences in this response. It seems likely, how- ever, that the contribution of sex differences is small when age and smoking exposure are taken into account. 6. There is, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who will progress to clinical airflow obstruction. 7, Smokers of both sexes have a higher prevalence of cough and phlegm production than nonsmokers. This prevalence in- creases with an increasing number of cigarettes smoked per day and decreases with the cessation of smoking. 8. Differences between smokers and nonsmokers in measures of expiratory airflow are demonstrable by young adulthood and increase with number of cigarettes smoked per day. 9. The rate of decline in measures of expiratory airflow with increasing age is steeper for smokers than for nonsmokers; it is also steeper for heavy smokers than for light smokers. After the cessation of smoking, the rate of decline of lung function with increasing age appears to slow to approximately that seen in nonsmokers of the same age. Only a minority of smokers will develop clinically significant COLD, and this group will have demonstrated a more extensive decline in lung function than the average smoker. The data are not yet available to determine whether a rapid decline in lung function early in life defines the subgroup of smokers who are susceptible to developing COLD. 10. Clinically significant degrees of emphysema occur almost exclusively in cigarette smokers or individuals with genetic homozygous al-antiprotease deficiency. The severity of em- physema among smokers increases with the number of ciga- rettes smoked per day and the duration of the smoking habit. 137 Appendix Tables Ar.YYY a. --I'u v 1 IN wn~te adults, by smoking status, sex, and age, United States, 1971-1975 Both eexea Men Women Cigarette smoking etatua by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Never smokers L&74 3140' 21' 3669' 39' 2664' 191 25-34 6733 394 3607 791 51 2633 130 44.04 xi4 63 4099 264 3095 312 26 3.544 5278 291 3171 607 49 1669 61 3742 591 73 3609 210 2907 397 40 4.544 4642 353284a 594 35 1206 85 3487 626 72 3736 268 2631 401 29 55-64 3660 251 2511 589 31 &lo 59 3215 531 61 2781 192 2289 401 29 65-74 2875 235 2148 549 36 461 43 2856 627 96 2394 192 2oG6 402 36 Exsmokers 25-14 3112 24 3623 37 2651 28 25-34 2811 160 3677 810 60 1359 66 4303 627 92 1452 94 3091 441 55 35-44 3oF% 171 3566 767 69 1828 94 4013 643 70 1256 77 2916 361 44 45-54 3323 213 3155 742 65 2345 143 3414 663 69 978 70 2535 454 65 55-64 2669 181 2845 693 63 1826 130 3067 649 63 843 51 2319 456 90 6&7.! 1769 157 2366 6% 66 1270 121 2533 699 78 491) 36 2020 487 92 Smokers 25-74 2378 20 3281 32 2514 n ,I 2fAu 6665 487 3567 752 44 4792 239 4037 639 51 4093 248 3018 433 41 34-Mb 5849 320 3166 655 47 3027 156 3507 639 71 '2822 162 2800 439 43 4554 5606 374 2761 623 37 n43 182 3126 579 49 2863 192 2411 437 40 55-64 3251 192 2416 631 50 1700 106 2736 632 63 1551 84 2w4 m 50 65-74 933 84 2071 653 66 534 56 2222 556 79 400 28 1669 714 155 g TABLE A.--Continued Both eexea Men Women Qarette smoking ___ status (by age) N n Mean SD SE N n Mean SD SE N " Mean SD SE Light smokers 2s74 2534 3&44 454 55-64 65-74 Moderate smoker8 25-74 25-34 35-44 4.544 55-64 65-74 Heavy smokers 25-74 ?A-34 35-44 45-54 5544 &74 2951 38 3311 3425 650 97 879 43 3914 3106 618 93 308 17 37751 2683 490 73 383 24 3009 24@3 573 83 313 18 2919' 2150 737 165 131 11 222P 508 515 404 660 426 57 102 139 95 150 130 1283 70 a59 55 707 52 730 39 172 10 2626 52 3m WY 88 2891 479 83 2507 437 76 2190 350 62 2095' 901 3% 25 51 47 51 70 124 38 80 64 92 121 150 2162 113 1267 72 1090 76 1043 57 304 21 2678 23 3335 3671 810 60 2534 123 4136 3217 646 68 1214 66 3593 2679 634 53 1145 75 3106 2406 589 63 690 45 2776 2023 609 105 261 28 22.79 40 69 99 79 60 126 2466 2991 393 2836 395 2368 429 1977 408 1693' 4.84 684 624 622 455 572 1735 112 1199 64 1570 104 597 37 203 16 4269 235 2413 130 2715 179 1287 82 464 44 2785 32 3202 3514 699 70 1363 72 3927 3143 684 71 1505 75 3382 2930 649 70 1193 62 3164 2440 741 118 697 45 2619 2038' 606 151 130 16 2096' 52 82 89 75 133 172 2409 2979 393 2562 373 2411 440 lF&' 396 17&Y* 215 2417 136 2148 116 1779 118 922 53 154 18 597 646 579 737 638 1051 64 643 41 586 36 224 8 24 2 NOTE: N = weighted population estimate in thousands; n = number of people in sample; SD = standard deviatmn. SE = standard error. I Adjusted by the direct method to reflect the age distribution of the U.S. populatmn at the midpoint of the survey. ' Doe8 not meet ntanti of reliability. SOURtX National Center for Health Statiirca. Unpublished data fmm the first National Health Nutrition and Examination Survey (NHANFS 1). TABLE B.-Flow at 25 percent of FVC for white adults, by smoking status, sex, and age, United states, 1971-1975 Both sex.88 Men Women Cigarette smoking - statue by age) N n Mean SD SE N n Mean SD SE N " Mean SD SE Never smokers 25-74 2544 35-44 4554 5.544 65-74 Exsmokers w74 2534 3b4.4 4.544 5544 6s74 Smokers 25-74 2534 35-44 4554 55-64 65-74 6733 394 5278 291 4942 353 3660 251 2675 235 2811 160 3086 171 3323 213 2669 181 1769 157 487 320 374 192 84 6253' 6639 6377 5742 5368 46% 6093 6835 7020 6270 5763 4918 5647 6760 6157 5471 5123 3954 1591 1464 1566 1397 1576 1855 `2041 1896 1764 1946 1694 1740 1658 1815 1566 47' 7261' 98 2633 130 7871 114 1669 81 7715 90 1206 85 7262 101 880 59 6543 102 481 43 6097 62 7095 203 1359 66 6042 176 1828 94 7956 164 2345 143 6765 144 1826 130 6261 WI 1270 121 5194 47 6362 102 4792 239 7606 123 3027 158 6848 92 2743 182 6130 132 1700 108 5567 181 534 56 4199 1513 1545 1796 1593 1951 1715 !2059 1919 1820 2091 1663 1675 1763 2061 1745 91' 5343' 36' 157 4099 264 5847 1042 89 176 3609 210 5758 952 80 213 3736 268 5252 1141 70 265 2781 192 4996 1091 83 298 2394 192 4331 1303 108 107 5188 67 285 1452 94 5705 1126 165 232 1258 77 5659 965 116 185 978 70 5Q34 1176 151 160 I343 51 4749 1058 197 265 499 36 4213 1278 197 88 5002 52 126 4093 248 5769 1061 83 160 2822 162 5415 1200 102 137 2863 192 4840 1233 106 223 1551 84 4636 1372 169 238 400 28 3627 1274 255 c 4 TABLE B.--Continued L.. Both sexm Men Women Cigarette smokmg - data8 (by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Light smokers 2574 2.534 3544 45-54 !i5-64 65-74 Moderate smokers a-74 25-34 3.5-M 45-54 55-64 G-74 Heavy smokers 2.5-74 75-34 3!i44 4544 5.544 6574 2162 113 1267 72 1090 76 1043 57 304 21 4269 2413 2715 1287 464 2417 2146 1779 922 154 23.5 130 179 82 44 136 116 118 53 18 5834 6549 KM 5545 5222 3779 5661 6909 6384 5269 5065 3950 5485 6691 5964 5712 5090 415!'2 1652 1461 1476 1534 1272 1719 1786 1490 1787 1717 1659 1815 1940 2117 1653 91 6569 209 879 43 1688 211 308 17 7250' 217 383 24 6373 238 313 18 6096' 345 131 11 37421 66 6430 136 2534 123 7647 194 1214 66 7348 111 1145 75 5821 202 690 45 5576 304 261 28 4356 85 6219 l&i 1363 72 7468 198 1506 75 6363 207 1193 82 6326 321 697 45 5322 401 130 16 4180' 1690 1634 1572 1616 1279 1667 1736 1661 1897 1692 1640 1902 1920 2288 1758 142 5171 293 1283 70 5769 369 959 55 5653 311 707 52 5096 399 730 39 4849 462 172 10 3807' 118 164 1735 112 236 1199 64 183 1570 104 334 597 37 404 203 16 151 225 1054 64 261 643 41 251 586 36 434 224 8 463 24 2 4967 5831 5408 4867 4475 3427' 4822 5685 5031 4458 437P2 4023 2 1071 1193 1203 1333 1266 1120 1212 1202 1439 1285 1018 1084 1257 1202 904 112 140 188 193 249 489 76 132 170 137 265 319 111 176 18f 26f 3.x 62! NOTE: N = Weighted population estimate. in thousanda; n = number of people in sample; SD = standard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doea not meet Btandards of reliability ~UWE National Center for Health Statistics. Unpublished data from the first Natmnal Health Nutrition and Examination Survey (NHANES 1). TABLE C.-Flow at 50 percent of J?VC for white adults, by smoking status, sex, and age, United states, 1971-1975 Both eexee Men Women Cigarette smoking status (by age) N " Mean SD SE N " Mean SD SE N " Mean SD SE Never smokers 25-74 25-34 3544 4544 55-64 65-74 3743 ' 38' 40831 6733 394 4361 1194 69 2633 130 4998 5278 291 3904 1164 84 1669 81 4315 4942 353 3366 1212 84 1206 85 3972 3660 251 3090 1087 74 880 59 3736 2875 235 2535 1045 73 461 43 3157 86' 128 152 150 l&l 174 3342' 3964 3713 3170 2886 2410 34' 78 91 90 72 84 1255 1221 1287 1220 1060 4099 264 3609 210 3736 x33 2781 192 2.394 192 963 989 1119 955 996 Ex-smokers 25-74 25-34 35-44 45-54 s-64 65-74 Smokers 25-74 25-34 3!i-44 45-54 55-64 65-74 3579 59 4188 67 3123 81 2811 160 4329 1292 120 1359 66 5029 1243 3086 171 4249 1364 129 18'28 94 4702 1410 332.3 213 3474 1404 114 2345 143 3749 1426 2669 181 3110 1411 118 1826 130 3294 1362 1769 157 2524 1296 121 1270 121 2578 1364 195 1452 94 3674 949 114 180 1258 77 3590 1037 160 143 978 70 2816 1091 147 127 843 51 nil 1432 293 153 499 36 2384 1092 167 3475 4546 3764 3257 2193 1889 59 103 140 92 146 175 z 3325 2604 2361 1965 54 90 98 94 144 252 3169 39 4126 1268 74 3552 1296 87 2924 1208 76 2567 1248 107 1922 1220 159 s&35 487 5849 320 5606 374 3251 192 933 84 4792 239 3027 158 2743 182 1700 108 534 56 1296 1399 1278 1364 1174 4093 248 2822 162 2863 192 1551 84 400 28 1037 1137 1040 1062 1279 ;: TABLE C.-Continued Both eexen Men Women Cigarette smoking -___- status by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 2534 35-44 4544 5s64 t&74 Mcderate smokera &I4 25-34 35-44 45-a !s-& 65-74 Heavy smokers 25-74 25-34 3544 45-54 55-64 66-74 102 2162 113 1230 1248 994 162 1267 72 1076 943 1054 166 1090 76 864 969 771 103 1043 57 1375 1643 1080 200 304 21 1252 883 1415 425 3313 3964 3630 2911 2756 2056 74 169 879 43 151 308 17 107 383 24 205 313 18 292 131 11 3676 4617 4190' 3150 3542' 1706' 110 222 1263 70 226 959 55 197 707 52 395 730 39 366 172 10 2984 3516 3450 2781 2420 2321' 57 71 4269 235 1239 96 2534 123 1297 872 47 2413 130 1182 124 1214 66 1198 llcfl 142 2715 179 1205 111 1145 75 1243 1125 140 1287 82 1186 167 690 45 1191 1134 245 464 44 1239 218 261 28 1316 1047 266 3207 4246 3781 n75 2665 1881 3561 4640 4039 3079 2873 2131 79 126 1735 112 171 1199 64 124 1570 104 207 597 37 n9 203 16 2888 3671 3520 2553 2425 1558' 68 110 2417 136 1333 153 1363 72 1306 1295 247 2148 116 1469 166 1505 75 1103 185 1779 118 1355 147 1193 82 1377 1062 222 922 53 1123 173 697 45 1222 651 232 154 18 1113 285 130 16 1059 703 490 3043 4067 3239 3152 2284 1760' 3287 4326 3456 3458 2379 1559' 92 197 1054 64 m 64.3 41 168 5% 36 221 224 8 274 24 2 2828 3733 n3i 2526 1997' 28.34' NOTE N = weight& population eetunata. in thousanda; n = number of people io sample; SD = ntandard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population st the midpoint of the .wrvey. * Doea not meet standards of reliiiity. SOURCF.. National Center for Health Statistics. Unpublished data from the funt National Health Nutrition and Examination Survey (NHANFS 1). TABLE D.-Flow at 75 percent of FVC for white adults, by smoking status, sex, and age, United states, 1971-197s Both eexe8 Men Women Cigarette smokii &ha (by age) N II Mean SD SE N n Mean SD SE N n MWII SD SE Never smokers 25-74 1230' 28' 1329' 42' 1073 ' 24' 25-34 6733 394 1776 714 52 Xi33 130 2065 649 72 4099 264 1690 691 62 36-44 5278 291 1277 621 49 1669 81 1478 8.43 129 3609 210 1184 456 32 `a-54 4942 353 1044 636 44 1206 85 1184 664 14 3736 268 999 620 53 55-64 3660 251 737 611 36 880 59 978 612 83 2781 192 661 449 34 65-74 2675 235 609 463 32 481 43 795 4x3 64 2394 192 572 465 38 Exsmokers 25-74 1152 29 1403 41 992 37 25-34 2811 160 1696 678 61 1359 66 1925 664 109 1452 94 1480 616 72 354 3086 171 1460 664 62 1828 94 1623 693 92 1258 77 1224 538 59 45-54 3323 213 10% 625 48 2346 143 1148 666 59 978 70 734 376 53 5544 2669 181 734 541 54 1826 130 178 446 41 843 51 638 694 156 65-74 1769 157 588 506 43 1270 121 592 516 47 499 36 578 481 87 Smokers 2574 967 22 1053 29 889 34 25-34 8885 487 1530 688 41 4792 239 1665 665 60 4093 248 1373 692 65 3M.4 5849 320 1062 552 34 3027 158 1134 599 57 2822 162 985 4% 35 45-54 5606 374 778 511 31 2743 182 866 530 41 2x63 192 693 478 43 c5.564 3251 192 631 536 42 1700 108 713 580 63 1551 84 541 468 56 6.5-14 933 84 452 689 loo 534 56 350 445 17 400 28 558 901 199 r ts TABLE D.-Continued Both @exe8 Men Women Cigarette smoking - statue (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 35-44 45-54 55-64 65-74 Moderate smokers 25-74 25-34 35-44 4x4 55-64 65-74 Heavy smokers 25-74 25-34 35-44 45-54 55-6-t 65-74 2162 113 1261 72 1090 76 1043 57 304 21 4269 235 2413 130 2715 179 1281 82 464 44 2417 136 2146 116 1719 118 922 53 154 18 1049 1460 1122 837 706 660 970 1603 1134 711 643 373 882 1447 940 836 529 297' 679 534 4.31 540 1040 685 499 480 598 366 689 595 589 410 453 44 94 879 43 63 309 17 57 383 24 85 313 18 264 131 11 28 57 2534 123 52 1214 66 49 1145 15 12 690 45 68 261 ?a 47 956 95 1363 72 1503 63 1505 15 995 57 1193 82 941 57 697 45 545 112 130 16 258' 1120 1641 1294' 840 931' 393' 1107 1755 1265 801 784 381 587 686 517 416 637 375 593 647 416 64 985 113 1283 IO 1366 101 959 55 1067 131 707 52 836 182 730 39 609 231 172 10 864' 41 846 82 1735 112 1362 78 1199 64 lOCKI 41 1570 104 656 119 597 37 481 85 203 16 363' 38 815 101 1054 64 1374 85 643 41 811 73 586 36 620 62 224 8 479' 98 24 2 505' 703 531 388 450 1244 620 443 514 503 353 790 422 438 388 603 67 127 73 42 88 414 32 76 58 67 69 103 82 172 69 79 160 420 NOTJC N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. `Does not meet standards of reliability. SoUfKT National Center for Health Statisticsa. Unpublished data from the first National Health Nutrition and Examination Survey (NHANFS 1). TABLE E.-FEVI/FVC ratio for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking etatua Car age) N " Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers 25-74 25-34 3.544 45-54 55-64 65-74 Ersmokem 25-74 25-34 35-u 45-54 55-64 65-14 Smokers 25-74 25-34 35-M 45-54 55-64 674 79.1' 0.21' 82.5 6.06 0.34 60.3 5.67 0.37 78.7 5.84 0.38 11.6 5.03 0.35 76.5 6.41 0.52 11.9 ' 0.34 ' 80.1 5.91 0.69 18.8 5.25 0.64 71.5 5.95 0.17 15.8 5.13 0.81 13.5 7.59 1.14 80.2 ' 0.23 ' 83.6 5.93 0.44 80.9 5.73 0.45 79.0 5.75 0.41 78.2 4.85 0.39 71.0 5.97 0.55 18.1 0.41 82.4 5.81 0.18 80.4 5.26 0.69 77.0 5.04 0.69 76.0 6.60 1.36 15.3 6.58 1.05 17 5 0.39 81.1 6.85 0.61 78.2 6 16 0.41 15.4 6.32 0.52 16.0 6.61 0.15 73.6 8.67 2.09 6733 394 5278 291 4942 353 3660 251 2875 235 24233 130 1669 81 1206 85 880 59 481 43 4039 264 3609 210 3736 268 2781 192 2394 152 77.1 0.30 81.7 5.92 0.53 79.5 6.26 0.56 76.2 6.58 0.50 73.7 7.79 0.70 11.5 9.34 1.05 76.6 0.44 80.9 5.94 0.94 78.8 6.78 0.83 75.9 1.10 0.66 12.1 8.07 0.19 10.0 9.83 120 2811 160 3086 171 3323 213 2669 181 1169 157 1359 66 1828 94 2345 143 1826 130 1270 121 1452 94 1258 77 918 10 843 51 499 36 75.9 0.26 80.3 6.78 0.38 76.7 7.28 0.46 74.2 7.05 0.41 73.1 8.13 0.59 69.8 9.40 1.44 14.0 036 19.2 6.50 0.52 75.3 1.92 071 13.0 1.55 059 10.6 9.59 1.03 67.0 8.94 1.54 8885 5849 5606 3251 933 487 320 374 192 84 4792 3027 2743 1700 534 239 4093 248 2822 162 2863 192 1551 84 400 28 156 182 108 56 z TABLE E.-Continued al Both wxea Men Women Cigarette smoking statue (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 36-44 45-S 55-64 65-74 Moderate smoker8 25-74 25-34 3544 45.54 55-64 65-74 Heavy smokers 25-74 2x34 3544 45-54 5564 65-74 2162 1267 1090 1043 304 424% 2413 2715 1287 464 2417 2148 1779 922 154 77.3 0.47 113 80.9 7.43 0.84 72 78.4 6.18 0.79 76 76.5 4.94 0.66 57 76.9 7.06 0.97 21 71.4 10.59 2.65 75.8 0.36 235 80.4 6.36 0.53 130 77.9 6.18 0.65 179 73.6 7.48 0.69 82 73.2 7.46 0.81 44 69.3 8.30 1.46 75.1 0.58 136 79.1 6.65 0.73 116 14.2 8.24 0.92 118 73.7 7.21 0.74 53 68.9 10.08 1.42 18 68.0' 9.18 2.66 879 308 383 313 131 2534 1214 1145 690 %I 15.7 43 80.3 11 17.1' 24 75.1 18 74.8' 11 64.6' 74.6 123 19.3 66 77.3 75 71.3 45 72.1 28 68.4 72.8 72 78.0 75 73.3 82 74.0 45 67.1 16 66.9' 7.10 6.14 6.05 9.cQ IO.84 6.29 6.61 7.87 8.00 7.63 6.33 8.68 7.34 10.09 8.75 0.76 1.11 1.54 1.58 2.25 4.17 0.48 0.70 0.85 0.96 1.38 1.56 0.57 0.89 1.21 0.86 1.81 2.42 1283 959 107 730 172 1735 1199 1054 643 586 224 24 78.7 0.60 70 81.4 7.62 1.30 55 78.8 6.13 1.30 52 77.3 4.01 0.54 39 77.8 5.81 0.87 IO 76.5' 6.90 2.64 76.9 0.47 112 81.9 6.16 0.13 64 18.6 5.64 0.71 104 75.3 6.67 0.80 37 14.3 6.58 1.07 16 70.4' 893 2.42 77.2 1.06 64 81.9 6.90 1.16 41 76.2 6.64 1.15 36 73.2 6.91 1.30 8 74.6' 7.63 2.40 2 79.4' 6.66 4.63 NtX'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. `Adjusted by the direa method to reflect the age distribution of the U.S. population at the midpoit of the survey. ' Lhm not meet .stan&rds of reli.tbility. SOURCE Natuxsd Center for Health St&tics. Unpublished data from the fii Natiaxal Health Nutrition and Examination Survey WGNES 1). TABLE F.-MMEF for white adults, by smoking status, sex, and age, United States, 1971-1975 Both wxw Men Women cigarette 8mokiLtg atah (by age) N " Mean SD SE N " Mean SD SE N n Mean SD SE Never emokera 2s74 25-34 35-44 4564 5M4 65-74 Exsmokers 25-74 2.5-34 35-44 4554 5544 65-14 Smokem 25-74 25-34 35-M 4.554 55-64 65-14 3020' 3748 3140 2724 2301 1891 29' 64 58 50 43 51 3392' 4357 3501 3198 2734 2314 52' 106 106 113 104 130 2664' 3357 2973 2512 2164 1806 26' 58 58 48 51 56 51 103 104 102 180 115 41 77 63 66 18 220 1023 821 837 6733 394 5278 291 4942 353 3660 251 2815 236 2633 130 1669 81 1206 85 880 59 481 43 lCJJ3 911 1021 163 827 4199 3609 3736 n81 234 264 210 268 192 192 820 in 703 663 611 730 619 2910 3753 3500 2800 2318 1826 41 102 106 91 75 82 3324 4321 3882 3021 2463 1865 66 162 157 114 81 99 2537 3222 2944 2270 2005 1128 1066 1165 1111 948 873 2811 160 3086 171 3323 213 2669 181 1769 157 1359 66 1828 94 2345 143 18% 130 u-70 121 1014 1237 1171 953 922 1452 54 1258 77 978 70 843 51 499 36 809 165 714 857 123 2553 3512 2850 2283 1955 1474 31 66 65 54 67 118 2786 3857 3033 2511 49 93 107 18 106 104 2343 3109 2654 2065 1813 l&i5 4792 3027 2743 4093 248 2822 162 2863 192 1551 84 403 28 872 8lm 109 654 995 8835 5849 5636 3251 933 437 320 374 192 84 1069 970 8-96 854 831 239 158 182 109 56 1101 1073 1007 1700 534 985 677 TABLE F.--Continued Both eerxa Men Women cigarette smoking 8tatf.M (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 35-44 45-54 55-64 65-74 Moderate smokers 2b-74 25-34 3544 45-64 5E-64 65-14 Heavy smokers 25-14 25-34 35-44 4544 55-64 65-74 2162 113 1267 72 1090 76 1043 57 304 21 424% 235 2413 130 2715 179 1287 82 464 44 2417 136 2146 116 1779 118 922 53 154 18 2736 3457 2936 2334 2252 1667 2542 3605 2993 2169 1894 1395 2404 3389 26243 2421 1706 1313' 1034 839 641 894 102-3 1106 907 82.3 811 738 1018 1663 1087 764 591 57 2985 144 819 43 3923 110 308 17 3`uma 84 383 24 2521 124 313 18 2694' 257 131 11 1339' 41 2848 93 2534 123 3S60 99 1214 66 3257 14 1145 75 2245 103 690 45 2144 12.6 261 28 1535 53 2620 120 1363 72 3614 119 1505 75 n77 125 1193 82 2663 166 697 45 1754 151 130 16 12471 1044 760 806 1239 563 1132 968 891 848 746 1045 1144 1145 828 601 93 2510 196 1283 70 3137 184 959 55 2787 173 707 52 2232 321 730 39 2063 238 172 10 1917' 64 2266 123 1735 112 3087 145 1199 64 2725 92 1570 104 2041 162 597 87 1604 159 203 16 1214* 72 2210 167 1054 64 3122 157 643 41 2280 150 536 36 1926 136 224 8 1557' 160 24 2 1665' 807 808 502 605 1206 828 752 744 655 687 911 135 766 439 369 17 153 124 68 87 404 40 98 92 95 106 157 87 187 123 185 169 NOTI? N = weighted population estimate. in thouann&; n = number of people in sample; SD = standard deviation: SE = standard ermr. ' Adjuted by the direct method to reflect theage distribution of the U.S. population at the midpoint of thesurvey. *Does not meet standa& of reliability. SOURCE: Natmnal Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANlB 1). TABLE G.-MEFR for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexen Men Women Cigarett.e smoking statue by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Never smokers 25-74 2544 36-44 45-54 lk5-64 65-74 Extlmokers s-14 2544 35-44 45-54 5!%4 65-74 Smokers %I4 25-34 35-44 45-54 66-64 65-74 6545' 7103 6144 5887 5260 4317 62' 123 144 110 98 112 7894' 8833 8519 7805 6722 6526 7809 9164 8789 7451 6532 5425 114' 167 223 268 226 269 5321' 5991 5923 5268 4824 3832 41' 94 103 86 98 118 83 167 131 191 245 220 55 101 94 113 171 263 5733 394 5278 291 4942 353 3660 251 2855 234 1895 1774 1625 1559 1776 2633 130 1669 81 1206 85 880 59 412 42 1551 1710 2106 1527 1863 4099 264 3609 210 3736 268 2781 192 2394 192 1081 1058 11% 1264 1394 5229 6453 7521 7664 6713 5644 4986 5914 7393 6712 5762 to30 3753 12 232 212 202 194 221 120 295 239 213 220 280 96 133 211 137 211 260 2311 160 171 213 181 157 2246 2241 2056 2002 2187 1359 66 1826 94 2345 143 1826 130 1270 121 1911 2006 1901 1997 2267 1452 94 5964 1153 1258 71 5759 1017 978 70 5146 1396 843 51 4671 1297 499 36 3867 1463 3086 3323 2669 1769 52 122 152 104 147 216 7041 8629 7780 5758 6834 4341 4691 5847 5566 4607 4149 2969 8885 5849 5606 3251 933 487 320 374 192 84 2019 1974 1864 1962 1662 4192 239 30!27 158 2743 182 1700 108 534 56 1728 1922 1819 2022 1961 4093 24.8 2.822 162 2863 192 1551 84 400 28 1216 1256 1332 1421 1373 z TABLE G.-Continued I- Both aexea MelI Women Cigarette smoking 8k3tu8 (by age) N " Mean SD SE N n Mm SD SE N n Mean SD SE Light smokers 25-74 2534 3544 45-54 5s64 65-74 Moderate smokers 25-74 25-34 35-44 4.5-54 55-64 65-74 Heavy smokers 25-14 2534 35-44 45.54 55-64 65-74 2162 113 1267 12 1090 76 1043 57 304 21 4269 235 2413 130 2715 179 1267 82 464 44 2417 136 2146 116 1119 118 922 53 154 18 6068 104 7085 7006 1792 233 879 43 8347 6450 1784 275 308 17 8275' %56 1632 232 383 24 6718 4979 1611 240 313 18 6142' 3535 1296 350 131 11 4054' 5921 76 7165 7616 2146 154 2534 123 8755 6819 1992 230 1214 66 8112 5513 1755 137 1145 75 6633 5100 1996 243 690 45 6122 3701 m4 373 261 28 4495 5755 98 6902 7356 1925 204 1363 12 8573 6751 x63 223 1505 75 7412 6167 2034 214 1193 82 6945 4989 2221 366 697 45 5410 41368 2060 496 130 16 4249' 1559 1918 1445 1903 1318 1864 1734 1799 1687 2122 1544 1996 1909 2187 177 5150 2.46 1283 70 6088 530 959 55 5864 269 767 52 xl80 478 730 39 4462 451 172 10 3228' 120 4798 176 1735 112 5952 264 1199 64 5511 181 1570 104 4769 261 591 37 3917 466 203 16 2681' 155 4120 192 1054 64 5781 289 643 41 5205 239 586 36 4561 433 224 8 3679 2 571 24 2 3535' 1294 1270 1425 1154 1157 1263 1241 1286 1640 1512 1010 1164 1280 1327 964 114 193 192 249 m8 388 376 671 N(JITI: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviatmn; SE = @amlard ermr ' Adjusted by the direct method to reflect the age distribution of the U.S. population et the midpoint of the survey. ' Ihe not meet standard9 of reliability. SOURCE: Natmnal Center for Health Statistic-a Unpublished data from the first Natuxml Health Nutrition and Exammatlon Survey (NHANIB 1) TABLE H.-Forced vital capacity for white adults, by smoking status, sex, and age, United States, 1971-1975 Both aexea Men Women Cigarette smoking ~- Stahl8 (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers %I4 25-34 35-44 4544 55-54 65-74 Fzsmokere 25-14 25-34 3!%44 45-54 55-64 66-74 Smokers 2s74 25-34 35-44 45-54 55-64 65-74 3978' 4403 3972 3624 3252 2615 29' 67 65 45 47 46 52' 759 89 159 98 795 92 758 123 774 127 24' 32 54 39 38 43 32 68 49 79 79 99 35 50 55 4.5 59 185 130 5480 81 4761 85 4506 59 4265 43 3867 3712 3607 3340 6733 5278 4942 394 291 353 251 235 1052 814 182 820 719 4099 3609 3736 2780 2394 264 210 268 192 192 464 so 522 526 462 30 101 91 78 94 86 4703 5335 5096 4499 46 816 118 753 86 796 76 186 95 821 92 3357 3760 3633 3291 3044 2615 150 171 213 181 157 1043 972 915 898 864 1359 66 1826 94 2345 143 1826 130 1270 121 94 71 70 51 36 1256 978 843 499 1769 3793 4464 4146 3731 3316 2985 2% 55 59 49 66 118 4405 5111 4665 4264 38 784 59 750 81 678 65 730 71 141 117 461 320 374 192 84 248 3707 539 162 3588 546 1% 3202 532 84 2712 467 28 7533 815 977 851 814 84.5 870 4792 239 3027 158 2743 182 1700 108 534 56 5 TABLE H.-Continued Both aexea Men Women cigarette smoking statue by ege) N " Mean SD SE N n Mean SD SE N 0 Mean SD SE Light smokers 25-14 2x34 35-44 45-54 5564 65-74 Moderate smokers 25-74 25-34 35-44 4544 55-64 65-74 Heavy smoken, 25-14 25-34 35-44 4&54 554% 65-74 2162 1267 2417 136 2148 116 1779 118 922 53 154 18 113 72 76 57 21 235 130 179 82 44 3824 4260 3986 3521 3135 3042 3789 4584 4145 3658 3312 2928 3710 4244 3971 3524 3036' 857 875 680 704 917 1020 a46 852 854 820 988 a32 75-a 928 938 54 116 879 43 135 308 17 103 383 24 108 313 18 237 131 11 30 4454 14 2534 123 5217 90 1214 66 4671 73 1145 75 4351 99 690 45 3881 149 261 28 3327 43 91 a2 81 151 240 1363 12 1505 75 1193 82 697 45 130 16 3866' 3470 q 4364 5055 4609 4304 3851 3189' 641 768 555 636 555 793 812 131 696 734 ala 679 638 798 925 ai 118 235 155 141 159 1283 70 959 55 707 52 730 39 172 10 50 a0 1735 112 125 1199 64 111 1570 104 a9 591 31 172 203 16 61 102 1054 64 94 643 41 a4 586 36 142 22-i a 252 24 2 3342 3828 3686 3249 2822 2ll7 * 3190 3660 3612 3147 2651 2414' 3120 3644 3392 2%3' 2223' 64 705 118 671 119 580 107 451 87 1001 347 38 447 55 457 66 521 57 453 80 614 173 54 404 69 440 73 480 95 438 143 472 328 No'I'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standani deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doee not meet standa& of reliability. SOURCE: National Center for Health St&i&ice.. Unpublished data from the first National Health Nutrition and Examination Survey (NHANEZ 1). TABLE I.-Recurring persistent cough attacks for adults, by sex, age, and smoking status, United states, 1971-1975 Never Former Men Smoking statue Current Light Moderate Never Former Women Smoking status Current Light Moderate 2544 P SE ii 3.2 4.4 6.7 7.6 5.7 1.1 4.4 6.0 8.4 5.1 7.1 15.2 1.85 2.23 1.57 4.01 1.98 2.79 1.21 2.46 1.63 1.92 2.n 4.93 3319 168 1593 78 6608 321 1383 72 3335 160 1875 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 81 3.544 P 4.9 8.0 13.8 9.0 5.9 22.1 5.4 5.0 8.9 2.3 8.0 25.8 SE 2.59 3.47 3.17 6.39 2.69 6.40 1.60 2.46 1.89 1.21 2.85 7.37 ii 2114 101 2384 117 4412 226 614 33 1769 93 2029 100 5197 310 1771 107 4563 no 1776 103 1968 114 799 51 4554 P " 4.3 9.2 10.3 6.4 12.0 10.6 4.9 3.0 11.5 7.8 9.9 21.8 SE 1.61 2.28 2.07 2.13 3.65 3.53 1.55 1.97 2.16 2.61 2.99 4.04 i 1568 114 3290 204 4282 296 810 61 1705 122 1745 112 5989 435 1458 101 4&m 329 1497 18 2413 163 890 57 55-64 P 1.1 14.6 20.5 2.4 14.4 25.9 6.8 9.9 15.7 6.4 14.8 50.1 SE 1.06 3.21 3.27 8.88 4.33 5.87 1.65 3.35 3.46 3.17 3.93 15.8 F4 1320 94 2791 192 2990 205 708 50 1305 91 976 64 5599 394 1501 86 3014 178 1263 76 1369 a2 378 20 G cn ii TABLE I.-Continued Men Women Smoking status Smoking statue Never Former current Light Moderate Heavy Never Former Current Light Moderate H-W 65-74 P 7.5 17.5 23.7 3.6 34.4 25.4 8.1 5.4 `2.31 17.2 24.8 59.9' SE 3.16 3.44 4.55 2.31 6.96 10.1 1.52 2.85 4.93 6.06 8.02 22.31 E; 864 98 2232 232 1199 135 318 39 574 60 295 35 5467 461 958 61 952 a3 523 46 362 32 66 5 25-74 P' 3.9 9.6 13.4 10.2 12.0 16.7 5.7 5.8 12.4 7.1 11.6 31.1 SE' 0.92 1.51 1.30 2.22 1.66 2.31 0.66 1.25 1.19 1.32 1.84 5.63 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousands. ' Adjwted by direct method to reflect the age dintribution of the U.S. population at the midpoint of the survey. * Dew not meet standards of reliability. SOURCE NatIonal Center for Health Statistics. Unpublished data from the fust National Health Nutrition and Examiition Survey (NHANFS 1). TABLE J.-Three-week periods of increased cough or phlegm for adults, by sex, age, and smoking status, united states, 1971-1975 Never Former Men Smoking et&u8 curre"t Light Moderate Never Former Women Smoking statue current Light Moderate 25-34 P 6.9 2.9 1.2 6.9 7.9 6.5 SE 2.39 1.67 1.83 4.04 2.63 2.33 ii 3319 168 1593 78 6608 321 1383 72 3335 160 1875 94 3.544 P 6.0 3.3 5.2 1.2 3.9 7.6 SE 2.43 1.98 1.68 1.20 2.06 2.86 ii 2114 101 2384 117 4412 226 614 33 1769 93 2229 100 4.544 P 1.7 3.9 6.3 0.3 5.5 9.8 SE 1.24 1.82 1.72 0.32 2.10 366 l 1568 114 3290 204 4282 298 810 61 1706 122 !745 112 5.5-64 P 1.2 2.9 11.4 6.8 10.2 16.2 SE 0.91 1.33 2.61 4.00 4.07 5.39 i 1320 94 2191 192 2990 205 708 50 1305 91 976 64 4.2 5.6 10.7 5.4 11.1 18.0 1.07 2.39 1.91 2.06 2.97 5.18 399 121 367 119 164 81 6416 1873 6304 2239 2642 1393 3.8 1.9 8.1 5.1 10.9 8.3 1.54 1.37 2.01 1.89 3.67 4.20 310 107 270 103 114 51 5197 1771 4563 1776 1968 799 3.5 6.1 10.8 8.4 a.4 21.6 1.00 2.39 2.14 2.93 2.12 6.49 435 101 329 109 163 57 5989 1458 4800 1497 2413 890 6.6 13.7 14.7 7.0 13.1 46.2 1.63 4.88 3.57 3.44 3.96 16.61 394 86 178 76 82 20 5599 1501 3014 1268 1369 378 TABLE J.--Continued Men Women Smoking statue Smoking status 65-14 P SE l Never Former Current Light Moderate Heavy Never Former Current Light Mcderab HMV 15 4.5 12.0 3.3 14.2 17 5 5.1 9.1 11.5 2.6 26.4 0.0 = 3.10 1.38 4.11 2.55 6.01 10.31 1.25 3.47 4.24 2.55 9.80 0.0 864 98 2232 232 1199 135 318 39 514 60 295 35 5487 461 958 81 952 a3 523 46 362 32 66 5 25-74 P' 4.6 3.4 79 3.8 7.6 10.5 4.5 6.9 11.0 SE' 1.04 0.93 102 1.43 1.31 2.04 0.63 1.34 1.26 NDl'E. P = proportion; SE _ standard rrror: n = number of people in sample. N = weighted population estimate. in thousands. I Adjusted by direct method LO reflect the age dkibutmn of the U S population at the midpoint of the 8urvey. * Ikea not meet standards of reliability SOURC'E Natr.mnl Center for Health Statistca. Unpublished data fmm the timt National Health Nutrition and Examination Survey (NHANE 1). 5.9 12.9 19.5 1.18 1.84 3.86 TABLE K.Qhortness of breath for adults, by sex, age, and smoking status, United States, 1971-1975 Never Former Men smoking atatua cumnt Light Women Smoking status Moderate H-V Never F0ITller Current Light Moderate H=V 25-34 P SE : 35-44 P SE i `S-54 P SE ii 554 P SE it 5.6 15.2 23.3 10.0 23.1 33.6 14.4 17.9 31.0 30.9 1.99 4.97 3.20 3.61 4.01 7.21 1.92 4.94 3.17 5.65 168 78 321 72 160 94 399 121 367 119 3319 1593 6eQ8 1383 3336 1875 6416 1873 6304 223s 20.1 3.56 164 2642 51.5 1.43 61 1393 17.1 19.9 22.9 15.6 15.9 31.2 22.5 26.5 39.0 36.4 45.3 30.3 4.62 4.89 3.26 7.08 4.71 5.46 2.42 5.32 4.62 5.48 7.07 7.08 101 117 226 33 93 100 310 107 no 103 114 51 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1966 799 19.3 21.2 35.5 25.4 34.9 41.3 28.1 32.5 42.5 30.3 46.1 47.9 4.07 3.56 2.99 6.35 4.64 5.40 2.85 6.05 3.93 5.01 4.95 7.57 114 204 296 61 122 112 4.35 101 329 109 163 57 1568 3290 4232 610 1706 1745 5989 1456 4m 1497 2413 690 25.6 31.3 42.2 37.7 42.4 45.2 38.0 56.8 39.0 29.8 43.1 54.6 5.79 3.94 4.37 9.57 6.14 6.39 2.94 6.24 4.60 6.65 6.06 16.51 94 192 205 50 91 64 394 86 178 76 82 20 1320 2791 2sso 708 1305 9761 5599 1501 3014 1266 1369 370 E TABLE K.-Continued Men Women Smoking at&us Smoking status Never Former Current Light Moderate H@W Never Former Current Light Moderate H@W 65-74 P 27.0 45.8 41.7 26.7 42.4 54.4 41.6 32.3 43.2 48.6 40.0 17.4' SE 5.46 4.06 4.59 7.87 6.86 9.12 2.92 5.63 6.70 9.64 10.66 16.12 i 664 98 2232 232 1199 136 318 39 574 60 296 35 5487 461 958 61 952 83 523 46 362 32 66 5 25-74 P' 17.1 25.2 31.4 21.5 29.9 39.2 27.0 31.8 38.2 34.1 38.2 42.4 SE' 1.69 2.38 1.75 2.64 2.31 2.74 1.27 2.82 2.03 2.59 2.88 5.07 NVl% P = prow'tion; SE = miandard error; n = number of people in sample: N = weighted population e&mate, in thouan&. ' Adjured by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey `Do% not meet standards of reliability. XXIRCE National Center for Health Statistics. Unpublished dats from the first National Health Nutrition and Examicmtioo Survey (NHANE3 1). TABLE L.-Wheezy chest sounds of adults, by sex, age, and smoking status, United States, 1971-1975 Men Women Smoking atatna Smoking status Never Former Current Light Moderate Hf=Y Never Former Current Light Mcderate HeaT 25.34 P 2.7 13.0 15.0 11.5 12.6 22.0 7.6 11.6 175 12.9 148 29.5 SE 1.17 4.67 2.42 4.43 2.72 6.14 1.46 3.54 2.33 3.13 2.94 6 13 : 3319 166 1593 70 6608 327 1363 72 3335 160 1876 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 RI 3iM-4 P 14.0 5.1 18.4 13.6 12.3 25.2 7.9 77 16.4 9.9 21.9 179 SE 4.72 2.12 3.28 6.14 4.03 5.61 1.83 2.98 2.56 3.77 4.53 4.89 it 2114 101 2384 117 4412 226 614 33 1769 93 2029 100 5197 310 1771 107 4563 no 1776 103 1968 114 799 51 45-54 P 4.3 12.3 18.8 10.2 23.2 18.7 8.5 5.3 22.7 12.9 24.1 35.7 SE 1.97 2.60 2.60 3.99 4.05 4.13 1.39 1 .a2 2.96 3.59 4.37 6.24 ii 1568 114 3290 204 4282 296 810 61 1706 122 1745 112 5969 435 1458 101 4800 329 1497 109 2413 163 890 57 6.544 P 12.0 13.6 26.9 29.9 26.6 22.1 12.7 22.0 27.3 19.5 31.0 40.0 SE 4.24 2.50 4.46 9.22 5.87 6.10 2.09 5.93 3.64 4.98 5.21 14.00 ii 1320 94 2791 192 2sso 205 708 50 1305 91 976 64 5599 394 1501 86 3014 178 1268 76 1369 A2 378 20 TABLE L..-Continued Men Women Smoking statue Smoking status Never Former Current Light Moderate Never Former current Light Moderate 65-74 P 5.0 20.7 33.1 34.7 31.6 35.6 15.1 21.5 28.6 34.6 18.1 39.02 SE 2.04 3.00 5.25 10.10 7.47 9.91 2.16 4.78 5.60 8.99 6.69 21.96 ii 864 98 2232 232 1199 135 316 39 574 60 295 35 461 81 03 46 32 5 5487 968 952 523 362 66 w74 P' 7.4 12.1 20.6 17.6 19.6 23.5 SE' 1.33 1.63 1.42 2.69 1.96 2.69 9.8 12.6 21.7 16.4 21.7 31.6 0.62 1.66 1.49 2.01 1.66 4.60 NOTE P : proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousandn. ' Adjusted by direct method to reflect the age distribution of the U.S. `Doe not meet standards of reliability population at the midpoint of the survey. SOURCE National Gnter for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). TABLE M.-Diminis hed or absent breath sounds of adults, by sex, age, and smoking status, United stat43, 1971-1975 Never Former Men Smoking etatus Current Light Moderate Never Former Women Smoking status Current Light Moderate 25-34 P 1.8 0.0 0.3 0.4 0.0 0.7 0.1 0.0 0.6 0.3 0.0 2.2 SE 1.76 0.0 0.21 0.36 0.0 0.71 0.07 0.0 0.51 0.31 0.0 2.21 ii 3319 168 1593 78 6608 321 1383 72 3336 160 1875 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 61 3544 P 0.6 0.5 0.6 0.0 0.7 0.6 0.3 0.2 2.3 0.4 3.4 3.5 SE 0.61 0.47 0.55 0.0 0.73 0.57 0.26 0.22 1.56 0.44 3.33 3.39 Li 2114 101 2384 117 4412 2% 614 33 1769 93 2029 100 5197 310 1771 107 4563 270 1776 103 1968 114 799 51 45-54 P 0.7 1.0 5.9 0.4 9.8 4.7 0.8 2.4 14 1.0 1.6 1.5 SE 0.55 0.53 1.71 0.41 3.33 2.64 0.64 187 0.56 0.36 0.82 1.24 ; 1568 114 3290 xl4 42.82 2% 810 61 1706 122 1745 112 5989 435 1458 101 4t?.w 329 1497 109 2413 163 890 57 5.544 P 2.5 5.7 12.4 8.4 13.0 14.4 0.8 4.1 3.36 2.7 3.9 3.5 SE 2.12 1.66 3.15 4.75 4.57 4.99 0.53 2.51 1.44 1.82 2.40 3.55 ii 1320 94 n9i 192 2sw 205 708 50 1305 91 976 64 5.599 394 1501 86 3014 176 1268 76 1369 82 376 20 E w z TABLE M.-Continued Never Former Men Smoking status Current Light Moderate Never Former Women Smoking status Current Light Moderate 65-74 P 8.8 9.1 17.9 13.9 25.2 8.8 2.4 4.5 2.7 3.3 2.3 0.0' SE 3.53 2.57 3.76 8.10 5.86 4.5 0.81 2.63 1.58 2.34 2.27 0.0 i 664 98 2232 232 1199 135 318 39 574 60 295 35 5487 461 958 81 952 83 523 46 362 32 66 5 s-74 P' 2.2 2.44 5.8 3.3 7.5 5.0 0.7 1.9 1.9 1.32 2.1 2.3 SE' 0.72 0.46 0.96 1.33 1.47 1.08 0.20 0.71 0.46 0.49 0.88 1.16 NW: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thouwand.% ' Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doea not meet n&anti of reliabiiity. SOURCE Natronal Center for Health Sk&&a. Unpublished data from the fti National Health Nutrition and Examination Survey (NW 1). TABLE N.-Wheeze of adults, by sex, age, and smoking status, United States, 1971-1975 Never Former Men Smoking Btatua Current Light Moderate Never Former Women Smoking etatua Current Liiht Moderate 2L3.4 P SE i 35-44 P SE i 4544 P SE ii &64 P SE ii 0.0 1.2 1.7 1.1 1.6 2.2 0.4 0.0 0.7 0.0 13 0.0 0.0 1.24 0.77 1.06 1.25 1.28 0.29 00 0.37 0.0 0.79 0.0 166 78 327 72 160 94 399 121 367 119 164 81 3319 1593 8809 1363 3336 1875 6416 1873 6304 2239 2642 1393 0.0 1.0 1.3 0.0 0.9 2.1 0.3 0.0 3.2 0.0 3.6 9.6 0.0 0.75 0.67 0.0 0.89 1.22 0.26 0.0 126 0.0 1.50 4.97 101 117 226 33 93 100 310 107 no 103 114 51 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 0.0 1.2 2.5 0.0 4.5 1.8 0.3 0.0 2.4 0.8 3.3 2.5 0.0 1.02 0.93 0.0 2.13 1.27 0.33 0.0 0.94 0.76 1.40 1.76 114 204 296 61 122 112 435 101 329 109 163 57 1568 3290 4262 810 1706 1745 5989 1456 48al 1497 2413 890 0.0 0.4 5.6 2.3 3.3 10.9 0.1 0.0 1.7 0.8 1.4 5.8 0.0 0.37 1.76 1.95 1.69 4.48 0.05 0.0 0.95 0.77 1.18 5.76 94 192 m5 50 91 64 394 86 178 76 82 `20 1320 nsi 2990 708 1305 976 5599 1501 3014 1266 1369 378 z TABLE N.-Continued Men Women Smoking status Smoking status Never Former Current Light Moderate H=V NWW Former CutTent Jight Moderate H=-Y 65-74 P 0.0 2.5 10.0 0.0 11.4 18.4 1.0 1.9 3.6 2.1 1.6 20.92 SE 0.0 1.11 3.75 0.0 5.27 10.98 0.56 1.85 2.14 2.66 1.64 18.53 i 864 96 2232 232 1199 135 318 39 574 60 295 35 5467 461 956 81 952 83 523 46 362 32 66 5 2%14 P' 0.0 1.2 3.4 0.7 3.5 5.5 0.4 0.2 2.1 0.7 2.3 6.3 SE' 0.0 0.46 0.71 0.46 0.92 1.65 0.14 0.25 0.45 0.41 0.46 2.79 NOTE P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, m thousands. 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MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE DUE TO CIGARETTE SMOKING 185 CONTENTS Introduction COLD Mortality Patterns in the United States Prospective Studies The British Doctors Study The American Cancer Society 25-&&e Study The U.S. Veterans Study The Canadian Veterans Study The American Cancer Society g-State Study California Men in Various Occupations The Swedish Study The Japanese Study of 29 Health Districts Cigarette Smoking and Overall COLD Mortality Retrospective Studies Male and Female Differences in COLD Mortality Amount Smoked and Mortality From COLD Inhalational Practice and Mortality From COLD Age of Initiation and COLD Mortality Smoking Cessation and COLD Mortality Pipe and Cigar Smoking Mortality From COLD International Comparison of COLD Death Rates a Smoking Habits: The Emigrant Studies COLD Mortality Among Populations With Low SI Rates Summary and Conclusions References Introduction The chronic obstructive lung diseases (COLD) that are causally related to cigarette smoking are chronic bronchitis, emphysema, and chronic obstructive pulmonary disease and allied conditions without mention of asthma, bronchitis, or emphysema. The last classification was introduced by the National Center for Health Statistics in response to the changes that occurred in the late 1960s in patterns of reporting causes of death on death certificates. During this period, physicians increasingly recorded deaths as due to "chronic obstruc- tive lung disease" rather than the more specific categories of "emphysema" or "chronic bronchitis" (NCHS 1982). Because of this shift in patterns of reporting, and in recognition of the difficulty of clinically separating these categories from one another as a cause of death, the discussion in this chapter combines all of these categories for analysis, where possible, which should result in a more complete description of death rates from COLD. COLD Mortality Patterns in the United States The three chronic obstructive lung diseases related to smoking may account for almost 62,000 deaths in 1983, compared with 56,920 deaths in 1982, according to provisional mortality data recently published by the National Center for Health Statistics. This data is based on a 10 percent sample of all deat.h certificates for the 12- month period ending in November (NCHS 1984). This is a dramatic increase from 1970, when slightly over 33,000 deaths were attributed to COLD. Complete mortality data are available through 1980, and Table 1 presents the numbers of male and female deaths from COLD for 1970,1975, and 1980. In addition to the relatively rapid rise in COLD deaths during these years, there was also a shift in the male to female ratio of these deaths. In 1970 male deaths outnumbered female deaths by a ratio of 4.3 to 1. By 1980 this ratio had declined to 2.36. The ageadjusted death rates for COLD during the years 1960 through 1980 are presented in Figure 1 for white men, white women, and men and women of other races. As described in the previous chapter, however, COLD is a slowly progressive disease, and death from COLD usually occurs only after extensive damage has devel- oped in the diseased lungs. Many individuals with COLD will die with their disease rather than because of it, and even those who do die of COLD are usually symptomatic for an extended period of time prior to death. Therefore, death rate data may not accurately reflect the true prevalence or incidence of COLD in the U.S. population. In addition, COLD is often not recorded as a cause of death in hospital records 189 TABLE l.-Number of and ratio of male to female chronic obstructive lung disease (COLD) deaths for three time periods, United States Cause of death 1970 1975 1980 Men Women Men Women Men Women Chronic bronchitis Emphysema COLD and allied conditions 4,262 1,564 3,260 1,452 2,380 1,348 18,901 3,820 14,649 3,946 10,133 3,744 3,601 848 13,411 4,182 24,820 10,734 Total COLD deaths 26,764 6,227 31,520 9,580 37,333 15,826 M:F ratio 4.30 3.29 2.36 SOURCE: National Center for Health Statistics (1982, and unpublished mortality data) OTHERd 15 10 WHITE? 5 OTHER? 1960 1965 1970 1975 1980 YEAR FIGURE l.-Age-adjusted COLD mortality rates for whites and nonwhites in the United States, 1960-1980 SOURCE National Center for Health Statistics (1962, and unpublisheddata). (Moriyama et al. 1966) or on death certificates (Mitchell et al. 1968), even though it may have played an important role in a person's death. In a recent prospective study, nearly half of the excess mortality associated with significantly lowered FEV, was attributed to other causes (Pete et al. 1983). Relatively advanced lung disease (as judged by pathologic examination) may also exist without clinical 190 recognition because of the lung's large ventilatory reserve (Mitchell et al. 1968; Hepper et al. 1969). A joint committee of the American College of Chest Physicians and the American Thoracic Society (ACCP-ATS 1975) has developed standardized definitions of these conditions that may improve the accuracy of mortality reporting in the future. As discussed in the chapter on morbidity in this Report, COLD in an individual is usually a combination of mucus hypersecretion, airway narrowing, and emphysema. The extent of damage represent- ed by each of these three processes can vary substantially from individual to individual, both in the absolute magnitude of the damage and in the proportional contribution of each of these three components. The majority of those with smoking-induced lung damage do not have enough damage to result in clinically significant disease, and only some of those with clinically significant disease have damage to the lung that results in death from COLD. The progressive loss of FEV, in smokers described in the preceding chapter is one measure of the extent and progression of lung damage, and individuals with a markedly reduced FEV, are far more likely to die of COLD (Peto et al. 1983). These deaths commonly occur secondary to the failure of these severely damaged lungs to carry out the gas exchange required for survival. Because death from COLD is the end result of lung damage accumulated over many years, these deaths would be expected to occur disproportionately in the older age groups; therefore, the presentation of a single age-adjusted death rate might not reflect a true picture of the changes in this disease with time. Figure 2 presents the age-specific death rates in 1977 for COLD in the different sexes and racial groups. Death rates increase rapidly over the age of 45, and this increase is particularly dramatic over the age of 65. In addition, the bulk of the difference between white men and men of other races, evident in Figure 2, occurs in those over age 65. Indeed, the COLD death rates for nonwhite men are actually higher than that for white men under age 55. The examination of age-specific death rates over time also presents a somewhat different picture from that presented by the age- adjusted numbers in Figure 1. The age-adjusted rates for white men in Figure 1 seem to have changed only slightly between 1968 and 1980. However, when the age-specific rates for the years 1968 and 1977 are examined (Figure 31, this apparent stability can be seen to be a product of counterbalancing trends in those under and over 65 years of age. The death rates from COLD declined in white men under age 65 between 1968 and 1977, but COLD death rates increased in white men over age 65 during the same years; this increase was particularly dramatic in those over age 75. 191 I 25-34 AGE FIGURE 2.-Age-specific COLD mortality rates for whites and nonwhites in the United States, 1977 SOURCE: National Center for Health Statida, (1982). Figure 4 presents the age-specific COLD mortality rates for white women in 1960, 1968, and 1977. As with the male rates, the female COLD death rates rise rapidly with age, but they are substantially lower than the male rates. In contrast with the male rates, however, the white female death rates increased steadily with time from 1960 through 1977 both above and below age 65. In each of the age groups over the age of 45, where significant numbers of COLD deaths would be expected, there was a steady increase in rates from 1960 to 1968 and from 1966 to 1977. As is discussed later in this chapter, these differences between men and women over time are consistent with their differences in smoking behavior. The effect of the normal aging process on the lung is small, rarely limits maximal exercise, and never results in ventilator-y failure. Therefore, death from chronic obstructive lung disease is never a natural part of the aging process; it is the result of an infectious or other disease process or of the cumulative damage of environmental respiratory toxins. The most important of these toxins in the United States is cigarette smoke. 192 25-34 35-44 45-54 55-64 65-74 75-84 85+ FIGURE 3.-Age-specific COLD mortality rates for white men in the United States, 1960, 1968, and 1977 SOURCE: National Center for Health Statistics (1982). In spite of the large ventilator-y reserve possessed by the lung, death from COLD is a major cause of U.S. mortality. This mortality is closely linked to cigarette smoking and has been examined extensively. Figure 5 shows the differences in COLD death rates for smokers and nonsmokers at different ages. From the rarity of COLD death in nonsmokers and the magnitude of the increased risk associated with smoking, it is clear that the overwhelming impor- tance of cigarette smoking as a determinant of abnormal lung function demonstrated in the previous chapter is matched by the importance of cigarette smoking as a determinant of death from COLD. Examination of the death rates from COLD in smokers and nonsmokers suggests that from 85 to 90 percent of the COLD deaths in the United States can be attributed to cigarette smoking. Prospective Studies The relationship between smoking and death from COLD has been evaluated in a large number of prospective mortality studies. There are eight major prospective studies of the disease consequences of smoking. They involve large numbers of smokers and nonsmokers 193 AGE FIGURE 4.-Age-specific COLD mortality rates for white women in the United States, 1960, 1968, and 1977 SOURCE Natmnal Center for Health Statmtics / 19H2 I and have examined the death rates from COLD in both groups. These studies cumulatively represent more than 17 million person- years of observation and over 330,000 deaths. The size of the populations studied allows a detailed examination of the relationship between smoking and death rates. The characteristics of the populations studied are summarized in Table 2 and are briefly reviewed here. The British Doctors Study The British doctors study (Doll and Hill 1954, 1956, 1964a, 1964b, 1966; Doll and Peto 1976, 1977; Doll and Pike 1972; Doll et al. 1980) of 40,000 male and female physicians in Britain was the first prospective study and is the longest running. Deaths from chronic bronchitis and emphysema were combined. Deaths from car pulmo- nale (i.e., heart failure secondary to lung disease) were separately analyzed by smoking category and probably include some deaths from chronic bronchitis and emphysema. 194 450 400 100 FIGURE - -1 ! I , ._ I ! I Z-Death rate for bronchitis, emphysema, or both, per 100,000 population, by age and smoking status I, U.S. veterans study, 16-year followup `Smoker LS defined as all people who smoke agarettes and those who have ever smoked other tohocco products SOURCE- Adapted fmm Fbgot and Murray / 19801 The American Cancer Society 25State Study The American Cancer Society 25-State study (Hammond 1965, 1966; Hammond and Garfinkel 1969; Hammond et al. 1976; Lee and Garfinkel 1981) represents the largest investigation. Deaths from emphysema were separately analyzed by smoking habit; deaths from car pulmonale were also separately recorded. The U.S. Veterans Study The mortality experience of approximately 294,000 U.S. veterans who held U.S. Government life insurance policies in December 1953 was examined in the U.S. veterans study (Darn 1959; Kahn 1966; Rogot 1974a, b; Rogot and Murray 1980). Deaths from COLD were recorded as "bronchitis and/or emphysema"; "bronchitis, underlying or contributory"; and "emphysema without bronchitis." The Canadian Veterans Study Initiated in 1955 by the Canadian Department of National Health and Welfare, the Canadian veterans study (Best 1966; Best et al. 1961) included 78,000 men and 14,000 women. Over the next 6 years of followup, there were 9,491 male and 1,794 female deaths. The cause of death in most of these cases was confirmed by autopsy. 195 z - TABLE 2 .-Outline of eight major prospective studies Doll Darn kat Weir GxiwkJf Aulhon Hill Hammond Krhn H~nyama JOUC ltammmd Dunn fibsy Pet0 Roaol Walker HW!l laden HNbc Rke BraloW Lonch Melee and Total population Ghfomu ProtaMity Bntinh femalea US of Gnadlan while m&a rmple of Sub@a I" 29hdth nuke I" do2lon I" votorura the 25 dmtncLs I" "UWU peMlolW" nme stata SW&h SlAkB JW mupllom pophtion Population aize wm l.~.~ mw 266.ooo ' 9zoal 187,oal wax) mm FellUka WQ 562.671 (1% lw?57 14,ma n.700 AIF nn% B435+ 3M.4 3544 40 3cao d up 504 D-64 18.4 Year of 1961 1960 1W 1966 1966 cnrdlment 1967 1962 1954 1969 Yeem of fdlowup 20-22 UY- 16 YAM 13 y- 6y- 4 Y- 54 Y- 10 yean Y- Number Of ll.166 150,ooO ICnJoo 39.100 11,oal I2m 4.700 4aO death Person y- of woo0 J%~.~ 35Qo.w 3.W~ WoaJ 670,ooO @A~ We cxpricmx The American Cancer Society S-State Study In the American Cancer Society g-State study (Hammond and Horn 1958a, b), 187,783 white men were followed for an average of 44 months by 22,000 American Cancer Society volunteers. All deaths from pulmonary disease (except pulmonary neoplasms) were consid- ered as one group and included deaths from pneumonia, asthma, tuberculosis, lung abscess, pneumoconiosis, bronchiectasis, and em- physema. California Men in Various Occupations The study of California men in various occupations (Dunn et al 1960; Weir and Dunn 1970) examined the mortality experience of 68,153 men, aged 35 to 64, drawn from labor union rolls in specified occupations. Deaths from emphysema were separately categorized. The Swedish Study The study of a probability sample of 55,000 Swedish men and women (Cederlof et al. 19751, aged 18 to 69, represents a detailed analysis of mortality by smoking status over a period of 10 years. The cause of death was ascertained by death certificates collected by the Central Bureau of Statistics for all of Sweden. The Japanese Study of 29 Health Districts In the fall of 1965, a total of 265,118 men and women in 29 health districts in Japan were enrolled in a prospective study (Hirayama 1967,1970,1972,1975a, 1975b, 1977, 1981). Mortality data regarding deaths from asthma and emphysema have recently been reported. Cigarette Smoking and Overall COLD Mortality The data from the major prospective studies relating smoking to mortality from COLD in men and women are presented in Table 3. These data demonstrate a uniform increase in death rates from COLD among male and female smokers when compared with nonsmokers of either sex. The mortality ratios for smokers compared with nonsmokers vary markedly, however, from 2.2 in the Japanese study to 24.7 in the study of British doctors. Some of this variability can be attributed to different patterns of certification of cause of death in different countries, but a number of other factors are also important. Perhaps the most important other factor is the age range of the population studied. As described earlier in this chapter, death rates from COLD rise steeply with age, particularly over the age of 65. Studies of populations under age 65 may significantly underesti- mate the impact of cigarette smoking on COLD because of the long duration of smoking required to damage enough lung to result in 197 death from COLD. The population under 65 contains large numbers of individuals who have significant airflow obstruction and who will die of COLD, but who have not done so prior to age 65. This effect is demonstrated in the American Cancer Society 25-State study, in which the COLD mortality ratio for male smokers aged 45 to 64 was 6.55, but increased to 11.41 in male smokers aged 65 to 79. A second reason for differences in mortality ratios is the selection of study populations who are currently employed, particularly if the duration of followup is relatively short. The incremental nature of the lung injury in COLD often results in a prolonged period of disability prior to resulting in death. This disability is usually incompatible with full-time work, particularly in those occupations requiring substantial exertion. Therefore, the study of a working population excludes those with significant existing disability from COLD and underestimates the COLD death rates in the general population. Unless the followup period is long enough to observe the progression of COLD from its asymptomatic stages through the development of disability and finally death, the impact of cigarette smoking on COLD death rates will be underestimated. This effect is particularly important because cigarette smoking is overwhelmingly the major determinant of COLD risk, and therefore an underestima- tion of the true COLD prevalence leads to an underestimation of the relative risk of smoking. As the followup period is extended for a duration sufficient to allow the full time course of COLD to be observed, the impact of cigarette smoking on COLD death rates also emerges from the small background rate of COLD death certification in nonsmokers (which includes those classified in error and those with disease induced by agents that results in a more rapid progression to death). This "healthy worker" effect is present to varying extents in all of the prospective studies and is one of the reasons the studies with the longest followup periods also tend to have the largest COLD mortality ratios. This is particularly evident in the study with the longest followup. The British doctors study, with a followup of 20 years, revealed a mortality ratio for male smokers of 24.7. A final reason for the differences in mortality ratios is the differences in the smoking habits of the various populations. As was discussed in the previous chapter, the extent of lung injury is influenced by both the number of cigarettes smoked per day and the duration of the smoking habit. As is shown in Table 4, some of the variability in mortality ratios among the studies disappears when the mortality ratios are reported by number of cigarettes smoked per day. However, there are also substantial differences in the pattern of cigarette use in different countries, particularly in the use of the milder types of tobacco cigarettes that are more likely to be inhaled and are smoked in the United States. For example, these cigarettes 198 TABLE 3.-COLD mortality ratios by disease category, eight prospective studies Study size of population Nonsmoker Emphysema Bronchitis Both Other Cfimments Brltlsh physicians Men Women 34.ooo 1.00 6.195 loo 24 7 Ratio for women by amount smoked only. see Table 4 Cahforma men m Yar\ous occupations Canadian veterans Men American Cancer Society 25-state Men Women US veterans Men Amcrlran Cancer Society 9.Stale Men 66.00(1 78.ooo 440.500 562.7llu 290K1.000 100 100 1.00 1.00 100 100 12 33 5 85 11.42 45-64' 6S79 ' 6 55 11.41 4 89 750 1482 5 II `Age range 1207 2.85 All pulmonary &eases uLher than cancer ipneumoma. mfluen~~. TB. asthma, bronchitis. lung abscess. etc.1 8 TABLE 3.-Continued SW.. of Study population Nonsmoker Emphysema Bronchltls Both Other Comments Swedish Men Women 27,0(x) 28.ooo 100 100 . 2.20 ' Number of deaths too small for statistical analysw Includes deaths due to asthma Japanese Men Women 12w.M 143,GGo loo 1.00 Data by amount smoked only; see Table 4 were not introduced into Japan in large numbers until after the Second World War. The chronicity of tobacco use, particularly of those forms of tobacco that are commonly inhaled, is probably more important than age per se in producing COLD death. The chronicity of tobacco use differs in different countries and between men and women in the same country; these differences would be expected to result in different COLD mortality ratios. In several of these prospective mortality studies, the mortality ratio for COLD deaths in smokers compared with nonsmokers was even larger than that found for lung cancer. This is consistent with the data in the previous chapter showing that cigarette smoking is the major predictor of decline in lung function and is also consistent with the clinical observation that clinically significant airflow obstruction is rare in the absence of a history of smoking. Retrospective Studies The relationship between smoking and mortality from COLD was also examined in several large retrospective studies. Wicken (1966) conducted a study of 1,189 men living in Ireland who died from chronic bronchitis. Smoking habits were determined through person- al interviews with relatives of the decedents. The relative risk for mortality from COLD was increased in smokers as compared with nonsmokers. Smokers of as few as 1 to 10 cigarettes per day had a 2.95fold higher risk for mortality from COLD as compared with nonsmokers. Dean and associates conducted two retrospective studies of the relationship between changes in smoking patterns and changes in mortality from bronchitis among a sample of the population in urban areas and in rural areas of northeast England. The periods of observation in the two studies were 1952 to 1962 (Wicken and Buck 1964; Wicken 1966) and 1963 to 1972 (Dean et al. 1977, 1978), respectively. Smoking status classifications in the two studies were similar, and were based upon questions relevant to the last 2 years before death or interview. In both studies, the relative risk for mortality from chronic bronchitis was substantially increased for smokers as compared with nonsmokers. In summary, data from both the prospective and the retrospective studies consistently demonstrate an increase in mortality from COLD for smokers as compared with nonsmokers. These studies include populations of widely different ages, social and ethnic groups, geographic locations, and occupations; nevertheless, they strongly support a causal relationship between smoking and COLD. 201 480-144 0 - 85 - 8 TABLE I.-COLD mortality rates for men and women, by number of cigarettes smoked per day, prospective studies Study MelI Women Cigarettes Mortality Cigarettes Mortality COLD disease per day ratios per day ratios classification British physicians Nonsmoker 1-14 1524 25+ U.S. veterans Nonsmoker 1-9 10-20 2139 40+ 1.03 17.00 26.00 36.00 1.00 3.63 4.51 4.57 8.31 Nonsmoker 1.00 1-14 10.50 l&224 28.50 25+ 32.00 Nonsmoker 1.M) l-9 5.33 l&19 14.04 2139 17.04 40+ 25.34 Emphysema Nonsmoker 1-9 l&19 2139 40+ 1.00 4.84 11.23 17.45 21.98 Chronic bronchitir and emphysema Canadian veterans Nonsmoker l.cMl l-9 7.02 10-20 13.65 2lf 14.63 Chronic bronchitis Nonsmoker Loo l-9 4.81 l&20 6.12 21-t 6.93 Emphysema Japanese Nonsmoker 1.00 Nonsmoker 1.00 < 100,m' 0.51 < 100,ooo 2.28 < 200,oGfl 2.57 <2CQOOO 3.14 > 3oo.ooo 1.93 > 300,oca 10.93 California men Nonsmoker2 1.00 in various About `12 pk 8.18 occupations About 1 pk 11.80 About 1'1, pk 20.66 Emphysema American Cancer Nonsmoker 1.00 Society l-9 1.67 sstate i&20 3.00 20- 3.64 All pulmonary diseases other than cancer3 Chronic bronchitb emphysema: or both Chronic bronchith Emphysema ' Data for the Japanese study are for lifetime exposure by > total number of crgarettea consumed `Nonsmoker m the Cabfornia occupations study aleo includes > smokers of pipes and cigars. a Pneumoma. mfluenza. TB. asthma, bronchitis, lung abscess. etc. 202 Male and Female Differences in COLD Mortality Mortality data presented by the National Center for Health Statistics indicate that in 1980 the number of deaths from COLD was 2.36 times higher among men than among women (9th ICDA nos. 490, 491, 492, and 494496). In the prospective studies reviewed above, it is also apparent that the relative risk for death from COLD was greater for male smokers than for female smokers, although both male and female smokers exhibited a greater risk than nonsmokers for death from COLD. These differences are most likely a consequence of differences in male and female smoking patterns. The women in these studies tended to smoke fewer cigarettes, inhale less deeply, and begin smoking later in life than the men. They more frequently smoked filtered and low tar and nicotine cigarettes and had less occupational exposure to pulmonary irritants than men. These differences in mortality from COLD are narrowing because of a more rapid rise in female mortality from COLD (see Table 1). Figures 6 and 7 help to explain the male-female differences in COLD mortality ratios in the prospective mortality studies and in U.S. COLD death rates. The figures are descriptions of the preva- lence of cigarette smoking in successive lO-year birth cohorts of men and women as those cohorts progressed through the years 1900-1980 (Harris 1983). Examination of these figures revealed several impor- tant findings. Relatively few women took up smoking prior to 1930. The heaviest smoking cohorts of men have a prevalence of over 70 percent compared with 45 percent of women, and the male cohorts with these peak prevalences are older than the female cohorts. However, as discussed earlier, the incremental and progressive nature of cigarette-induced lung injury results in both prevalence and duration of cigarette smoking having an impact on COLD death rates. Therefore, in examining Figures 6 and 7 it is important to consider the span of years of a given prevalence of smoking maintained by a given birth cohort as well as the peak prevalence achieved by that cohort. The COLD death rates should then be proportional to the area under the prevalence curve described by each cohort, rather than to the peak of that curve. A careful examination of Figure 6 reveals that the area under the prevalence curve for the cohort born between 1921 and 1930 is less than the area under the curve for the cohort born between 1911 and 1920, in spite of their similar peak prevalences. This difference is due to the more rapid decline in prevalence with age in the 1921 to 1930 cohort. Similarly, the cohort born between 1901 and 1910 partially compensates for a peak prevalence that is lower than the 1911 to 1920 cohort by having a somewhat a broader base. Each of the cohorts born prior to 1900 have substantially smaller areas under their curves than those born during the first three decades of this century. These differences in prevalence are reflected in the changes 203 1910 1920 1930 .R 1940 1950 1960 1970 I I 1 I Men i 1921-30 .7 .6 . .5 - .4 - 1891 1900 1910 -1920 1930 1940 1950 1960 1970 l! FIGURE &-Prevalence of cigarette smoking among successive birth cohorts of men, 1999-1999, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Harris 1983. in age-specific death rates portrayed in Figure 8 and Table 5. The oldest age group (7584) continues to show a rapid rise in COLD death rates as those birth cohorts with increasing prevalence and duration of smoking move into this age range. In the age range 65-74 the rates rose rapidly from 1960 through the mid 19708, but seem to be leveling off, consistent with the fact that this age group is now made up entirely of men born after 1900. In the age range S5-64 the rates suggest a slight downturn beginning in the mid 197Os, coincident with the entry of the 1921 to 1930 birth cohort into this age group. The numbers for the age range 45-54 are too small to 204 2 2 1 1 0 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 FIGURE 7.-Prevalence of cigarette smoking among successive birth cohorts of women, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Hmie 1983 permit firm conclusions, but also suggest that a downturn in rates occurred in this group in the late 1960s. A close examination of Figures 6 and 7 also offers an explanation of the differences in mortality ratios for men and women observed in the prospective studies. COLD is a slow, progressive disease, and death from COLD usually results only after extensive lung damage has occurred. The fact that death from COLD is unusual prior to age 45 reflects, in part, the 30 or more years required for cigarette smoke to damage enough lung to result in death. The substantial ventilato- ry reserve of the lung allows a significant amount of damage to exist in a person without symptomatic limitation or risk of death from COLD. The prospective mortality studies were conducted in the 1950s and 1960s a point in time approximately 30 years after the beginning of the rise in smoking prevalence among women demon- strated in Figure 7. Even the older cohorts, where significant mortality might be expected, had begun smoking largely after 1930, and therefore had a shorter duration of smoke exposure than the men born in the same years. This shorter duration of the smoking habit, together with the previously described tendency of women to 1960 1965 1970 1975 YEAR FIGURE 8.-Age-specific COLD mortality rates for white men in the United States, 1960-1977 NOTE ICDA Nc.s 49@492 and 519.3 SOURCE Nat,onal Center for Health Statlstux 119821. smoke fewer cigarettes per day and to inhale less deeply, would be expected to result in less cumulative lung damage at any given age. This difference in extent of lung damage could explain the difference in COLD mortality ratios between men and women observed in the prospective mortality studies. The British doctors study examined the risk of COLD death for male and female physicians who smoked similar numbers of cigarettes per day (Table 41, and the mortality ratios were similar for similar numbers of cigarettes smoked per day. In summary, data from the prospective studies indicate that the: relative risk of death from COLD is greater for male smokers than for female smokers. These differences are most likely a consequence of differences in female smoking patterns. Women tend to smoke- fewer cigarettes, inhale less deeply, and begin to smoke later in life- than men. These differences in mortality from COLD are narrowing- because of a more rapid rise in female mortality from COLD than in male COLD mortality. This reflects the narrowing in differences between male and female smoking patterns and the rising preva- lence of female smokers in successive cohorts born between 1920 and 206 TABLE 5.-Age-specific COLD death rates per 100,000 population Year 45-54 55-65 65-74 75-a 1960 8.6 361 1961 7.6 38.7 1962 9.6 44.2 1963 11.7 52.3 1964 12.1 518 1965 12.4 57 8 1966 12.4 61.9 1967 12.4 61.2 1968 13.1 67.4 1969 13.9 67.5 1970 13.6 66.1 1971 13.5 67.4 1972 13.0 67.7 1973 12.7 69.9 1974 12.8 64.8 1975 11.9 64.7 1976 12.2 64.0 1977 11.4 60.1 SOURCE: Natmnal Center for Health Statimcs (1982) 82.9 101.8 87.9 111.8 107.2 136.7 131.2 169.6 131.6 181.9 153.6 216.6 161.9 244 8 164.8 248 6 1867 266.5 189.5 294.3 196.5 311.5 105 6 327 4 204.8 351.4 210.1 378.4 2048 3804 207.6 399.7 210.7 419 7 2061 4315 1950. These data are ominous for women, portending a rising mortality from COLD over the next decades. Amount Smoked and Mortality From COLD Six of the major prospective studies evaluated the influence of different smoking levels on mortality from COLD. These studies employed a variety of measures of tobacco exposure, including number of cigarettes smoked per day, grams of tobacco smoked, and total number of cigarettes smoked in a lifetime. The data, presented in Table 4, show a gradient in risk for mortality from COLD as the number of cigarettes smoked per day increases and as the cumula- tive number of lifetime cigarettes smoked increases. In the U.S. veterans study, smokers of two packs or more per day had 22 times the risk of COLD death of nonsmokers. Furthermore, mortality ratios between the two followup periods for bronchitis and emphyse- ma actually increased overall and by the amount smoked (Figure 9). The authors noted that this was the only major disease of those associated with cigarette smoking that showed such an increase, suggesting that mortality ratios have been increasing over time at all levels of smoking. In the British and Japanese studies, women smokers at the highest levels exhibited a 32- and an 11-fold higher risk for death from COLD (respectively) than their nonsmoking counterparts. The variability in COLD mortality ratios noted in 207 20 15 9 F f fi = 10 5 0 3 0112years m 16 years 17.45 12.07 .65 1 4.84 4.14 Ia 11.23 a.73 I Nmsmdtw All cigarette l-9 lo-20 2139 smokers Clgerenessmokedpwday 21.90 02 240 FIGURE O.-Bronchitis and emphysema for male smokers number of cigarettes smoked per day, U.S. veterans study, W/,-year and H-year followup Table 3 is much less evident when the mortality ratios are presented by amount smoked. In summary, the degree of tobacco exposure strongly affects the risk for death from COLD in men and in women. This clearcut dose- response relationship enhances the strength of the causal relation- ship between smoking and COLD. Inhalational Practice and Mortality From COLD The inhalation of tobacco smoke is the major mechanism whereby- bronchial and alveolar tissues are exposed to the potentially damaging effects of tobacco smoke. In the British doctors study, subjects who acknowledged inhaling exhibited a 1.53-fold higher risk- for COLD death as compared with those who stated they did not- inhale (see Table 6). However, all smokers, regardless of their inhalational practice, exhibited higher risk for COLD mortality than did nonsmokers. In the retrospective study from northeast England (Dean et al. 1977, 19781, the risk among men for mortality from chronic bronchitis steadily declined with a decrease in the depth of inhala- tion (Table 7). Among women, the risk for mortality from chronic bronchitis was lower for all other groups than for those who stated- they "inhaled a lot." TABLE 6.-COLD mortality by inhalation practice, British doctors study, men Cause of death Number of deaths Annualized death rate per Risk in Inhalers 100,ooO men responding compared wth unity to question: do you inhale? in noninhalers Chronic bronchitis and emphysema end pulmonary heart dieease Yes No 71 89 58 1.53 Table 7.-Relative risk for mortality by depth of inhalation, 1963-1972, second retrospective mortality study in northeast England Relative risk for chronic bronchitis Depth of inhalation Men Women A lot (baee~ 1.00 1.00 A fair emount 0.98 0.54 A little 062 0.41 None 0.58 0.58 SOURCE, Dean &al. 11977.19781 Results from prospective mortality studies comparing COLD death rates by inhalation are identical to those observed in the morbidity studies, which have consistently shown that COLD is more prevalent among inhalers than noninhalers (Ferris et al. 1972; Comstock et al. 1970; Rimington 1974). These data suggest that inhalational practice affects the risk of mortality from COLD. People who inhale deeply experience a higher risk for mortality from COLD than people who do not inhale. Regardless of their inhalational practice, however, smokers still experience higher rates of death from COLD than nonsmokers. Age of Initiation and COLD Mortality Another indicator of exposure to tobacco smoke that may influ- ence risk for mortality from COLD is the age of initiation of smoking. If their smoking habits are otherwise similar, people who take up smoking at a younger age have a greater total exposure to tobacco smoke than those who take up smoking later in life, and might be expected to experience greater adverse consequences from smoking. In the Japanese prospective study (Hirayama 19811, men who began to smoke before the age of 19 exhibited slightly higher mortality ratios for emphysema than did men who began to smoke after the TABLE S.-Number of deaths from chronic bronchitis, emphysema, and pulmonary heart disease in ex- cigarette smokers, by years of cessation, versus number of deaths in lifelong nonsmokers, British doctors study Number of deaths in ex-smokers, divided by Number of deaths number expected in lifelong smokers in nonsmokers Years of cessation 0' <5 69 lo-14 >14 35.6 34.2 47.7 7.3 8.1 2 age of 20. In the retrospective study from northeast England (Dean et al. 1977, 19781, the relative risk for death from chronic bronchitis among men who began to smoke after the age of 25 was 60 percent of that of men who began to smoke between the ages of 15 and 19. Among women in the same study who began to smoke between the ages of 15 and 19, the relative risk for death from chronic bronchitis was 1.28fold higher than for women who began to smoke after age 25; however, the number of deaths was small. Smoking Cessation and COLD Mortality The effects of smoking cessation on mortality from COLD were examined in the British doctors study and the U.S. veterans study. In the British doctors study, men who quit smoking experienced no change in mortality from COLD in the first 4 years and a rise in the next 5 years; presumably, this is related to the presence of many people in this group who quit smoking for health reasons (Table 8). Thereafter, ex-smokers experienced lower death rates from COLD, although their rates were still higher than those of the nonsmokers. Female ex-smokers also experienced lower mortality rates than current smokers, but the rates in ex-smokers were still higher than those in nonsmokers. In the U.S. veterans study, ex-smokers who had quit for reasons other than ill health experienced lower mortality rates for COLD than did current smokers. However, the benefit of cessation upon risk for mortality was heavily dependent upon the prior level of smoking and the length of time of cessation. These data are presented in Table 9. Ex-smokers who had smoked less than 10 cigarettes per day had a 1.64-fold higher risk for mortality from COLD than nonsmokers; in contrast, ex-smokers who smoked more than 39 cigarettes per day had a 9.91-fold higher rate of death from COLD than nonsmokers. For any given number of cigarettes smoked 210 TABLE O.-Mortality ratios for bronchitis and emphysema in nonsmokers and in ex-smokers and current smokers by number of cigarettes smoked daily and number of years of cessation, U.S. veterans study Cigarettes/day Smoking status 0 < 10 1620 21-39 >39 Nonsmoker 1.00 - Ex-smoker 1.64 5.35 7.68 9.91 Current smoker 4.84 11.23 17.45 21.98 Years of cessation CUTC3d Nonsmoker smoker <5 5-9 l&14 15-20 >20 1.00 12.07 11.66 14.35 10 19 5.66 2.64 per day, however, ex-smokers had a lower risk than current smokers. As in the British study, mortality ratios initially increased over the first 9 years of cessation. After the first 9 years, mortality ratios for ex-smokers fell, but never reached the level of the nonsmoker. Two studies have evaluated mortality rates from COLD among physicians, a group among whom many quit smoking to protect their health. Fletcher and Horn (1970) assessed the mortality rates from bronchitis among physicians in England and Wales. Among doctors aged 35 to 64, there was a 24 percent reduction in bronchitis mortality between 1953-1957 and 1961-1965, as compared with a reduction of only 4 percent in the national bronchitis mortality rates for men of the same age in England and Wales. Enstrom (1983) assessed mortality trends from COLD in a cohort of 10,130 physi- cians in California. The standardized mortality ratio for bronchitis, emphysema, and asthma among male California physicians relative to American white men declined from 62 during the period 1950 to 1959 to 35 during the period 1970 to 1979. In summary, cessation of smoking leads to a decreased risk for mortality from COLD as compared with that of current smokers. The residual risk of death for the ex-smoker is determined by the person's prior smoking status and the number of years of cessation. However, the residual risk remains larger than that of the nonsmok- er, presumably because of the presence of irreversible lung damage acquired during prior smoking. Pipe and Cigar Smoking Mortality From COLD Several of the prospective epidemiological studies examined the relationship between pipe and cigar smoking and mortality from COLD. The data from these studies indicate that pipe smokers and 211 TABLE lO.-COLD mortality ratios in male pipe and cigar smokers, prospective studies Type of smoking Study Catwry Total NOtI- Cigar pipe pipe and Cigarette smoker only only cigar tdy Mixed American Cancer Society 9-State COLD total Emphysema Bronchitis 1.00 1.29 1.77 2.85 British doctors Canadian veterans American Cancer Society 25-State COLD total Emphysema Bronchitis COLD total Emphysema Bronchitis COLD total Emphysema Bronchitis 1.00 9.33 24.67 11.33 1.00 4.00 7.oil 6.67 1.00 3.33 .75 5.65 1.00 3.57 2.11 11.42 1.00 1.37 6.55 ' U.S. veterans COLD total (E&year Emphysema followup~ Bronchitis U.S. veterans COLD total !&year Bmnchitis, followup) emphysema 1.00 .79 2.36 39 10.08 1.00 1.24 2.13 1.31 14.17 1.00 1.17 1.28 1.17 4.49 1.00 0.84 2 1.44' 4.75 ' 1.00 2.535 13.13' ' Mortality rake for agea 55 to 64 only BIT presented. ' Pure ctgar. ' Pure pipe cigar smokers also experience higher mortality from COLD as compared with nonsmokers. However, the risk of dying from COLD is less than that of current cigarette smokers (Table 10). International Comparison of COLD Death Rates and Smoking Habits: The Emigrant Studies Reid (1971) reported that age-adjusted mortality rates from chronic nonspecific lung disease among British citizens varied with migration patterns. British men living in the United Kingdom had a- chronic, nonspecific lung disease death rate of 125 per 100,000, whereas migrants to the United States experienced a mortality rate of only 24 per 100,000, which is similar to the rate found in the U.S. population. Differences in cigarette smoking and air pollution were identified as the major factors contributing to the real excess in bronchitis morbidity experienced by the British in the United Kingdom. Rogot (1978) conducted a study of British and Norwegian emigrants to the United States. The mortality rate from chronic nonspecific lung disease (CNSLD) in Great Britain is about fivefold 212 that in the United States, whereas the mortality rate from CNSLD in Norway is slightly lower than that in the United States. In contrast, the British migrant rates were about equal to those of native-born Americans and the Norwegian migrant rates were the lowest. Mortality rates for CNSLD were higher for smokers than for nonsmokers in all groups. These data suggest that ethnic origin plays a minor role, if any, in determining COLD risk. Regardless of country of origin, these studies indicate that tobacco smokers experience higher mortality rates for COLD than do nonsmokers. COLD Mortality Among Populations With Low Smoking Rates Numerous studies have reported that certain population groups who traditionally abstain from cigarette smoking for religious or other reasons have lower mortality rates from those diseases traditionally related to tobacco use. The 1982 and 1983 Reports of the Surgeon General, The Health Consequences of Smoking (USDHHS 1982, 19831, extensively reviewed this phenomenon as it relates to cancer and cardiovascular diseases among Mormons, Seventh Day Adventists, and others. Because Amish are seen as strict and fundamentalist in outlook, it is assumed that their use of tobacco is severely restricted. While cigarettes are largely considered taboo, pipe and cigar smoking and tobacco chewing are widespread (Hostetler 1968). Hamman et al. (1981) examined the major causes of death in Old Order Amish people in three settlements in Indiana, Ohio, and Pennsylvania to determine if their lifestyle altered their mortality risk compared with neighboring non-Amish. Mortality ratios from all respiratory diseases were significantly lower by over 80 percent in Amish men 40 to 69 years old, and by 50 percent in those 70 and older. In the chronic pulmonary disease categories including emphysema, bronchitis, and asthma, only one Amish male death occurred, whereas approximately 23 were expected. The pattern of mortality "om chronic respiratory diseases was similar for Amish women. Summary and Conclusions 1. Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. 2. The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in 213 past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. 3. Differences in lifetime smoking behavior are less marked for younger age cohorts of smokers. The ratio of male to female mortality from COLD is decreasing because of a more rapid rise in mortality from COLD among women. 4. The dose of tobacco exposure as measured by number of cigarettes or duration of habit strongly affects the risk for death from COLD in both men and women. Similarly, people who inhale deeply experience an even higher risk for mortality from COLD than those who do not inhale. 5. Cessation of smoking eventually leads to a decreased risk of mortality from COLD compared with that of continuing smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overall lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. 6. Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. 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PATHOLOGY OF LUNG DISEASE RELATED TO SMOKING 219 CONTENTS Introduction Lesions Associated With Chronic Airflow Obstruction Central Airways Mucus Other Abnormalities of Central Airways Peripheral (Small) Airways General Review Smoking and Lesions of Peripheral (Small) Airways Vascular Lesions Related to Smoking Emphysema Definition Classification Proximal Acinar Emphysema Panacinar (Panlobular) Emphysema Distal (Paraseptal) Acinar Emphysema Irregular Emphysema Tobacco Smoking and Emphysema Summary and Conclusions References 221 introduction It is usual to think of chronic airflow obstruction as being caused by airway narrowing or loss of airflow driving pressure-the elastic recoil of the lung (Macklem 1971J-or both. Lesions of the airways are often divided into those of the "large airways" and those of the "small airways." The reasons for this division are both historical and conceptual. Hogg et al. (1968) showed that in patients with chronic obstructive lung disease (COLD) the major site of airway obstruction lay in airways that were peripheral to the wedged catheter that the researchers used to partition airway resistance. The catheter was wedged in airways 2 or 3 mm in diameter, and thus the airways peripheral to the catheter included the smallest bronchi (airways with cartilage in their walls) and bronchioles (conducting airways without cartilage in their walls). Since both bronchi and bronchioles were involved, Hogg and associates used the term "small airways" to describe them, which has since become a popular term. Conceptual- ly, lesions of airways may consist of an intraluminal component (mucus) or a mural component. Most of the mucus in the airways is thought to be secreted by the tracheobronchial submucosal glands (Reid 1960); these are mainly confined to airways more than 2 or 3 mm in diameter, or large airways. Because of the documented association between chronic productive cough and airflow obstruc- tion (Fletcher et al. 1959), for a long time it was thought by many that intraluminal mucus was a major source of chronic airflow obstruction. Thus, the notion developed, without proper substantia- tion, that central airways obstruction was due to intraluminal mucus and peripheral airway obstruction was due to inflammation and narrowing. It is also true that many have equated emphysema with loss of elastic recoil, but when this has been examined in vivo (Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al. 1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers et al. 1980), the association has not been close, with some notable exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980). Thurlbeck (1983) reviewed the evidence and argued that loss of recoil in emphysematous lungs may not be due to the lesions of emphyse- ma per se but to defects in apparently morphologically normal intervening lung tissue. The classical approach to considering the different sites of flow obstruction is used in this chapter to analyze the relationship between smoking and the morphologic lesions associated with chronic airflow obstruction in humans. Lesions of the large airways (bronchi) are discussed first, followed by small airways, and then by alveolated structures. It has very recently become apparent that it is important to include respiratory bronchiolitis as well as emphysema in the last category (Wright et al., in press); this issue is discussed in the paragraphs on peripheral (small) airways. Definitions and a brief 223 review of the diseases involved are provided. This chapter attempts to present the morphologic changes associated with chronic obstruc- tive lung disease. The detailed epidemiologic and experimental evidence relating cigarette smoking and COLD are presented elsewhere in this Report. Lesions Associated With Chronic Airflow Obstruction Central Airways MUCUS It is convenient to discuss intraluminal mucus and increased tracheobronchial mucus gland size together, because they are thought to be related (Reid 1960). Chronic bronchitis is defined as "the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree" (Ciba Foundation Guest Sympo- sium 1959). Because there is no way to accurately measure the amount of mucus secreted into the bronchi, the empirical approach was taken that production of any sputum was abnormal. Chronic was defined as "occurring on most days for at least 3 months of the year for at least 2 successive years" (Ciba Foundation Guest Symposium 1959). A further qualification was that such sputum production should not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. The initial step was to correlate chronic bronchitis, as defined above, with lesions in the central airways. This was first done by Reid (19601, who assessed gland size by comparing the thickness of the submucosal bronchial mucus glands in histologic sections to the thickness of the bronchial wall. The latter was defined as the distance from the basement membrane of the epithelium to the- inner periochondrium. This measurement is now known as the Reid Index. This increase has been confirmed by several observers (Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al. 1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and Yates 1968; Karpick et al. 1970). An important observation was that there was a distinct overlap in the value of the Reid Index between bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as opposed to Reid's 1960 finding that there were two completely separate groups. In practical terms, this meant that the Reid Index had limitations in predicting the presence or absence of chronic bronchitis. More important, it suggested a broad border between- health (nonbronchitis) and disease (bronchitis). For a variety of technical reasons (Jamal et al., in press), the Reid Index is a difficult measurement to use; thus, other measurements of mucus gland size- were developed. The most popular was the volume density of mucus glands, i.e., the ratio of area of mucus glands to area of the entire bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill 224 et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978). Other methods included absolute gland size (Restrepo and Heard 1963; Bedrossian et al. 1971) and a radial intercept method (Alli 1975). The size of the acini (tubules) of mucus glands, the number per unit area, and the ratio of mucus to serous tubules have also been used (Reid 1960). The Reid Index, the volume density of mucus glands, and the ratio of mucus to serous acini have been examined in smokers and nonsmokers; the results are shown in Table 1. When one considers the overwhelming association between smoking and chronic bronchi- tis in living subjects, differences in mucus gland size are insignifi- cant. For example, three laboratories (Reid 1960; Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference in Reid Index between smokers and nonsmokers; two have not (Bath and Yates 1968; Hayes 1969). The results from volume density of mucus glands are clearer-Ryder et al. (1971) found a higher volume density of mucus glands in both male and female subjects. In populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980) found a higher volume density of glands, but Sobonya and Kleiner- man (1972) and Scott (1973) did not. When observers have expressed their morphologic findings as either "normal" or "abnormal" (using different criteria), the smokers have been significantly abnormal in all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al. 1967; Vargha 1969). The balance of the evidence is that there is an increase in mucus gland size in smokers. The discrepancy between the clinical and the morphologic findings may reflect several factors: the wide variation in mucus gland size in normal subjects, the difficulties in measuring the Reid Index and volume density of mucus glands, the different ways in which the cases have been collected, and the errors inherent in assessing smoking histories- from analysis of charts; also, the fact that mucus glands can enlarge terminally (Helgason et al. 1970) might obscure true differences between the two groups. In addition, submucosal gland enlargement is a nonspecific change that can also occur in pneumoconiosis and cystic fibrosis. Mucus is also secreted by goblet cells, most of which are in the major airways. Pratt et al. (1980) showed that goblet cells constituted 10.7 percent of the cells in the central airways of nonsmoking nontextile workers and 20.4 percent in smoking nontextile workers. Interestingly, they found an 18 percent frequency of goblet cells in nonsmoking textile workers; the frequency was about the same in smokers, whether or not they were textile workers. Other Abnormalities of Central Airways A variety of other changes have been described in the central airways in patients with chronic airflow obstruction, including 225 TABLE L-Comparison of mucus gland size in smokers and nonsmokers Findings in smoking category Assessment of mucus gland enlargement Author Light and NOW moderate Heavy smokers Smokers smokers smokers Reid index Reid (1960) 0.46 0.43 Thurlbeck et al. (19631 0.43 0.50 0.45 0.53 Thurlbeck and Angus 11964) 0.44 0.49 Bath and Yates 119681 0.45 0.49 Hayes (19691 0.32 0.33 Scott (1973) 0.41 0.46 Mucus gland proportion Ryder et al. (1971) (men) 14.5% 17.8% Ryder et al. (1971) women) 14.5% 17.1% Sobonya and Kleinerman (1972) 11.2% 10.7% Scott 119731 14.1% 14.4% C&o et al. (1980) Increased Pratt et al. 11980~ 9.3% 12.6% Frequency of cases Field et al. 119661 (men) with MGH ' expressedField et al. (1966) lwomenl as a percentage of Megahed et al. (1967) cases m the group Petty et al. (19671 Vargha 11969) 12% 37% 18% 26% 14% 61% 8.8% 37% 18% 44% 1 MGH = Mucus gland hypertrophy inflammation and edema of the wall (Reid 1954), increase in bronchial smooth muscle (Hossain and Heard 1970; Takizawa and Thurlbeck 19711, and diminished cartilage, which is related more to emphysema than to chronic bronchitis (Thurlbeck et al. 1974a). Peripheral (Small) Airways General Review As indicated, it was as recent as 1968 that the obstruction in patients with chronic airflow obstruction was conclusively shown to be due mainly to lesions in airways less than 2 or 3 mm in diameter. However, abnormalities in these airways had long been recognized. Indeed, Laennec (1962) pointed out in 1826 that air remained trapped in emphysematous lungs even when the major bronchi had been opened, and he reasoned that the source of the air-trapping was obstruction in the airways peripheral to the opened ones Since then, numerous descriptions have been made of the peripheral airways in severe chronic airflow obstruction (see Table 2). Smokers were not compared with nonsmokers in any of these series. The probable reason is that for a long time it was thought that bronchiolitis was an infective complication of chronic bronchitis. Only very recently, and from studies in patients with mild chronic airflow obstruction, 226 has the link between smoking and peripheral airway lesions become established. Hogg et al. (1968) not only found that the peripheral airways were the site of airflow obstruction in patients with severe disease, but also observed that peripheral airways contributed only about 15 percent of resistance to flow in normal lungs. It followed that considerable disease could be present in these peripheral airways without airway resistance being measurably increased. It was reasoned also that standard tests of expiratory function, such as the FEVl and the FEFww, might not be abnormal in the presence of significant disease. Thus a variety of "tests of small airway function" were devised; these evolved to the single breath nitrogen washout test and to flow volume studies, in some instances comparing the effect of breathing helium mixtures with the effect of breathing room air. It soon became apparent that these tests could be abnormal when the FEVl was greater than the 80 percent predicted and that tests of small airway function could return to normal after cessation of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al. 1981). The term "small airways disease" was and is often applied to these abnormalities. It then became of interest to determine what the lesions in the airways were. Long before this, Reid (1955) had studied nine lungs resected from patients with chronic bronchitis and two lungs from chronic bronchitics obtained at autopsy. She found excess intraluminal mucus and narrowing and obliteration of airways, as assessed subjectively. Because the surgical patients also had lung cancer, most likely they were chronic smokers. Matsuba and Thurlbeck (1973) compared the airways of chronic bronchitics to those of nonbronchitics in nonemphysematous lungs. All the bron- chitics were smokers and two nonbronchitics were smokers. Morpho- metrically, they found obvious narrowing of airways less than 2 mm in diameter, which also contained excess mucus. The important study by Cosio et al. (19781, using surgically resected lungs, showed for the first time that abnormal tests of small airway function were related to abnormal morphology. There were 34 smokers and 2 nonsmokers in their group. A variety of abnormali- ties were observed, including inflammation, squamous cell metapla- sia, ulceration, fibrosis, pigmentation, and increased muscle. They developed a score that summed the observed lesions (the total pathology score), and divided their patients into four groups on the basis of this score. They showed that as the total pathology score increased, tests of small airway function (single breath nitrogen test and flows on air and helium mixtures) deteriorated, as did standard tests of pulmonary function such as the FEVl and FEFzsx. The data concerning smoking are hard to interpret, but the smoking index (number of cigarettes smoked per day times number of years smoked) increased from groups I to III and was similar in groups III 227 TABLE 2.-Occurrence of lesions of peripheral airways in patients with severe chronic airflow obstruction Authors Disease invest:gated Abnormalities found Laennec (1962) Spain and Kaufman ( 1953) Reid (1954) Emphysema Chronic bronchitis Leopold and Gough (1957) Centrilobular emphysema McLean (1958) Emphysema Anderson and Foraker (1962) Pratt et al. (1965) Anderson and Foraker (1967) Hogg et al. (1968) Mitchell et al. (1968) Bqnon et al (1969. 1970) Karpick et al. 119701 Linhartova et al. (19711 Matauba and Thurlbeck (1972) Linhartova et al. 11973, 1974, 19771 Scott and Steiner (1975) Scott c 19761 Mitchell et al. (1976) Emphysema Emphysema Centrilobular emphysema Emphysema Emphysema with severe chronic airflow obstruction Chronic airflow obstruction and severe emphysema Cm pulmonale and centrilobular emphysema Respiratory failure Emphysema Severe emphysema and chronic airflow limitation Emphysema Car pulmonale Chronic airflow obstruction Chronic airflow obstruction obstruction Obstruction to flow in peripheral airways Mural inflammation and fibrosis of bronchioles Bronchiolitia, broncbiolar oblit- eration, and mxus plugging Inflammation, fibrosis with narrowing of 60% of bronchioles supplying centrilobular space Inflammation of proximal rea- piratory bronchioles, mucus plugging, and loss of bronchioles Collapse of bronchioles due to loss of alveolar attachments Loss or distortion of the radial support of bronchioles Loss of bronchioles in patients under age 70 Inflammation and fibrosis of bronchi and bronchioles and nNKus plugging Inflammation, atrophy, goblet cell metaplasia, squamous metaplasia, and mucus plugs in bronchioles Inflammatory narrowing and fibrosis, loss of bronchioles. and mucus plugging Goblet cell metaplasia Plugging of bronchioles with inflammatory cells and mucus Loss of lumen of airways less than 2 mm in diameter due primarily to narrowing and InUCus plugs Distortion, tortucsity, and irregular narrowing of bronchioles Lack of tilling bronchioles of less than 1 mm Loss of airway lumen Chronic inflammation (r=0.48), narrowing (OB), fibrosis (0.27). goblet cell metaplasia (0.241, and fewer small airways (-0.18) 228 and IV. The lesions that were different in group II from lesions in group I were squamous cell metaplasia, inflammation, and fibrosis. Fibrosis and squamous cell metaplasia increased steadily from groups I to III. Increased muscle and goblet cell metaplasia occurred only in group IV. One extrapolation of these data is that inflamma- tion in the peripheral airways is the initial event produced in response to cigarette smoke. This inflammation leads to, or is associated with, squamous metaplasia and mural fibrosis. Goblet cell metaplasia and increase in muscle subsequently occur and are associated with decrements of function. Berend et al. (1979) did a similar study on 21 smokers and 1 nonsmoker, and added the important information that airway narrowing occurred and was associated with abnormalities of the single breath nitrogen washout test and the FEFs75. The data were reanalyzed subsequently (E&end et al. 1981b) and showed that inflammation was the lesion associated with the most abnormalities in tests of expiratory function. Airway inflammation was significant- ly related to abnormalities of the FEV1, FEFzF~x, slope of phase III of the single breath nitrogen test, and closing volume expressed as a percentage of vital capacity. The authors also noted that as the total pathology score got worse, the airways diminished in caliber in surgically derived lungs, but not in autopsy lungs. They noted that airway caliber was larger in autopsy lungs than surgical lungs, and suggested that this represented functional narrowing due to in- creased muscle tone, which was caused by release of mediators affecting the muscle directly or reflexly. Studies of lungs at autopsy have shown correlations between airway lesions and abnormal tests of function. Petty et al. (1980, 1982) have shown that correlations exist between inflammation, and increased muscle and elevations in the closing capacity; that occlusion of airways by cells and mucus, inflammation, and in- creased airway muscle are related to abnormalities of the slope of phase III of the nitrogen washout; that airway narrowing is closely related to the FEVi, FEFs75, and slightly less well related to closing capacity. Similarly, Berend et al. (1981a) showed an association between post-mortem closing capacity and both peripheral airways inflammation and a total pathology score. Decrease in maximum flow at a transpulmonary pressure of 5 cm HzO was related to inflammation and the total pathology score, but not as well related to airway narrowing (Berend and Thurlbeck 1982). Morphologic abnormalities similar to those found in autopsy lungs have been found in surgically excised lungs derive* almost entirely from smokers, and these in turn have been related to abnormal tests of small airway function. Smoking and Lesions of Peripheral (Small) Airways An increase in goblet cells was the first abnormality of peripheral airways noted in smokers. The observation was made in bituminous coal workers. In nonsmokers, about 0.66 percent of peripheral airway cells were found to be goblet cells; in smokers, this rose to about 1.0 percent (Naeye et al 1971). The critical observation, both factually and conceptually, was that of Niewoehner et al. (1974). In an autopsy study of men under the age of 40 who died suddenly elsewhere than in the hospital, they compared lesions of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls) in smokers and nonsmokers. Emphysematous lungs were excluded, and the smoking history was obtained by personal interview with close relatives, using a standard questionnaire. The researchers found that intraluminal mucus, mural edema, peribronchiolar pigment, peribronchiolar fibrosis, denuded epithelium, mural inflammatory cells, and respiratory bronchiolitis were more severe in the smokers. The last three were significantly different statistically. They empha- sized the importance of respiratory bronchiolitis, which consisted of aggregates of brown macrophages in and around the first and second order respiratory bronchioles and was associated with edema, fibrosis, and epithelial hyperplasia in adjacent bronchioles and alveolar walls. Bronchiolitis was found in all of the smokers, but in only 5 of the 20 nonsmokers, and it was the lesion that showed the greatest difference between smokers and nonsmokers. Since respira- tory bronchiolitis was found in precisely the same regions where centrilobular emphysema is found in subjects 20 years older, the researchers suggested that this lesion might evolve into emphysema. This observation fits well the proteolytic-antiproteolytic hypothesis of the pathogenesis of emphysema. Ebert and Terracio (1975) compared the peripheral airways in resected lungs of 22 smokers and 3 nonsmokers and found that the number of Clara cells (the tall nonciliated airway cells thought to be secretory, although the nature of their secretion is not completely certain) was diminished, as assessed subjectively, and the number of goblet cells was increased, as assessed quantitatively. Two laboratories have concentrated on the association between smoking and lesions of vessels as well as of airways. One has used autopsy-derived lungs (Casio et al. 1980; Hale et al 1980); the other, surgically excised lungs (Wright et al. 1983a, b, in press). The first material has the advantage that the entire lung can be examined, but has the disadvantage that agonal changes may affect the airway; the second has the advantage that agonal changes are absent and structure-functional studies can be done, but has the serious disadvantage that usually only a part of the lung is examined. Because of the wide variation in severity of emphysema from lobe to 230 lobe, emphysema in the whole lung cannot be assessed from a single lobe. Also, airway inflammation may not be evenly distributed through the airways (Berend 1981; Hale et al. 1980). Cosio et al. (1980) studied 14 nonsmokers with an average age of 71.6 years and 25 long-term smokers with an average age of 58.4 years. The total pathology score was significantly higher in the smokers; in them, but not in the nonsmokers, the total pathology score was significantly related to age. Respiratory bronchiolitis was more common in the smokers, and of the components of the total pathology score, goblet cell metaplasia (p \\ 1,. `c'.. `\ Q.. `\ <`X.. \. \x FIGURE S.-Average emphysema score in male and female nonsmokers in Montreal, Cardiff, and MaIma, by decade NOTE All The average for the three cities. SOURCE l'burlbeck et al t 1974bl 242 FIGURE b.-Average emphysema score in male and female heavy cigarette smokers (>pack per day) and ex-smokers, by decade N(3TE: All: The average for the three aties SOURCE Tburlteck et al 11974bl 243 women are more modest, with an average emphysema score of 8 to 12 from the sixth to the ninth decade. Pratt et al. (1980) studied the effect of smoking on cotton textile workers and on workers not exposed to cotton. They found that the incidence of centrilobular emphysema was 6.7 percent in non- smoking non-cotton-textile workers, 6.9 percent in nonsmoking cotton-textile workers, 26.5 percent in smoking non-cotton-textile workers, and 26.2 percent in smoking cotton-textile workers. The variation in the incidence of centrilobular emphysema involving more than 25 percent of the lung was even more dramatic-1.1,0.4, 11.0, and 12.6 percent for the respective categories. Thus, despite the limitations in interpretation of the types of emphysema and in recognition of the presence of emphysema, the association between smoking and emphysema-particularly severe emphysema-is overwhelming. In the various series referred to, of the 227 patients with severe emphysema, only 3 were nonsmokers. Summary and Conclusions 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of small airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. This lesion may be an important cause of abnormalities in tests of small airways function, and may be involved in the pathogenesis of centrilobular emphyse- ma. 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MECHANISMS BY WHICH CIGARETTE SMOKE ALTERS THE STRUCTURE AND FUNCTION OF THE LUNG 251 CONTENTS EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Introduction Effect of Smoking on Numbers and Types of Inflammatory Cells Effect of Smoking on the Morphology and Function of Inflammatory Cells Emphysema Populations Deficient in Alpha,-antitrypsin Alpha,-antitrypsin Proteolytic Enzymes Inducing Emphysematous Change Papain Pancreatic Elastase Polymorphonuclear Leukocyte Elastase Alveolar Macrophage Elastase Protease-Antiprotease Hypothesis Increased Elastase Owing Lo the Cellular Response to Smoke Number of Cells Elastase Content Release Proximity Milieu Decreased Antiprotease Owing to Oxidation Explanation for Upper Lobe Distribution Animal Models of Emphysema Spontaneous Emphysema Experimentally Induced Emphysema Oxides of Nitrogen Cadmium Salts Cigarette Smoke 253 The Effects of Smoking on Cellular and Immune Defense Mechanisms In Vitro Effects of Cigarette Smoke on Inflammatory and Immune Effector Cells The Effect of Cigarette Smoke on Antibody Production EFFECTS OF CIGARETTE SMOKE ON AIRWAY MUCOCILIARY FUNCTION Introduction Normal Mucociliary Function Cilia Mucus Mucociliary Interaction Effects of Cigarette Smoke on Mucociliary Function Short-Term Exposure Cilia Mucus Mucociliary Interaction Long-Term Exposure Cilia Mucus Mucociliary Interaction Fractionation and Filtering of Cigarette Smoke Effects of Filters Mucociliary Function in Chronic Bronchitis Cilia Mucus Mucociliary Interaction Summary and Conclusions References 254 EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Cigarette smoke is a complex mixture of several thousand different constituents that may produce physiologic and pathologic changes. This discussion focuses on the cellular and immune responses of the lung to cigarette smoke, the mechanism by which smoking can cause emphysema, and the impact of smoking on mucociliary clearance. The last 20 years have witnessed dramatical- ly increased understanding of cigarette-induced lung injury, particu- larly emphysema, thus enhancing our understanding of the process by which cigarette smoking can lead to emphysema. Introduction Inhalation of cigarette smoke markedly alters the inflammatory and immune processes in the lung, leading to increases in the total number of inflammatory cells and to changes in cell type and function. These effects of cigarette smoke on lung inflammatory cells may play a role in decreased pulmonary host defenses against various microorganisms and the development of lung cancer, chronic bronchitis, and pulmonary emphysema (USPHS 1971, 1972, 1973, 1974,1975; USDHHS 1981). Effect of Smoking on Numbers and Types of Inflammatory Cells One of the most consistently observed effects of cigarette smoking on the lung is a marked increase in the numbers of inflammatory cells, especially at sites of disease. Increased numbers of inflammato- ry cells have been seen in pathological studies of the lungs of cigarette smokers, as well as in lungs of animals exposed to cigarette smoke. In addition, increased numbers of inflammatory cells occur in bronchoalveolar lavage fluid of cigarette smokers and in lavage fluid of animals exposed to cigarette smoke. Spain and Kaufman (1953) noted inflammatory changes in the lung bronchi of cigarette smokers. Later, Anderson and Foraker (1961) described the presence of an alveolitis, and McLean (1959) described the presence of a bronchiolitis in these patients. In an autopsy study of patients with early emphysema (McLaughlin and Tueller 19711, numerous abnormal, brownish-pigmented alveolar macrophages were found in adjacent, otherwise intact parenchyma, but none were found in normal lungs. Identical pigmented macro- phages were found in the sputum of patients obtained from apparently healthy cigarette smokers. The frequency of occurrence of these macrophages in the tissue appeared to be related to the 255 number of cigarettes consumed. Niewoehner et al. (1974) evaluated the lungs of young smokers and controls of comparable age from a population that had experienced sudden nonhospital deaths. In smokers, a characteristic lesion occurred in the form of respiratory bronchiolitis associated with clusters of pigmented alveolar macro- phages. This lesion was present in the lungs of all smokers studied, but was rarely seen in nonsmokers. Lungs of smokers also showed small, but significant, increases in mural inflammatory cells and denuded epithelium in the membranous bronchioles as compared with controls. The researchers suggested that this respiratory bronchiolitis may be a precursor of emphysema and may be responsible for the subtle functional abnormalities that are observed in young smokers. Mitchell et al. (1976) also noted the presence of significant amounts of inflammation in the small airways of cigarette smoker lungs, and Cosio et al. (1978) suggested that the primary lesion in the small airways was a progressive inflammatory reaction, leading to fibrosis with connective tissue deposition in the airway walls. These lesions were closely correlated with abnormali- ties in pulmonary function. As noted above, most early investigators concentrated on the role of the increased numbers of pigmented alveolar macrophages present at disease sites in cigarette smokers. These pigmented macrophages, because of their numbers and prominent coloration on histologic sections, were initially the sole focus of research on the inflammatory response in these patients. More recently, however, Ludwig et al. (1983) evaluated the relationship between cigarette smoking and the accumulation of neutrophils in the lungs of smoking and nonsmoking humans. Human lungs were obtained from autopsies of 10 cigarette smokers and 5 nonsmokers who experienced nonhospital death. These studies indicated a marked increase in neutrophil infiltration in the lungs of cigarette smokers compared with nonsmokers, and identified the site of the accumulation as the alveolar septa. Neutrophils were found in the alveolar walls of smokers both with and without emphysema. The researchers con- cluded that a marked neutrophil accumulation occurs in the lungs of cigarette smokers, that it precedes the development of emphysema, and that it continues once emphysema is established. They further suggested that the neutrophils may play a role in the destruction of the alveolar septa of the lungs in cigarette smokers. The presence of increased numbers of neutrophils in cigarette smokers' lungs has also been documented by extracting inflammatory cells from open lung biopsies of smokers and nonsmokers (Hunninghake and Crystal 1983). A higher percentage of these inflammatory cells were neutrophils in smokers compared with nonsmokers. Finally, the association between cigarette smoking and increased numbers of inflammatory cells, including neutrophils. at disease sites has also 256 been confirmed in numerous animal studies (Frasca et al. 1971; Dahlgren et al. 1972; Rylander 1974; Park et al. 1977). Increased numbers of inflammatory cells in the lungs of smokers, as compared with nonsmokers, have also been observed by all investigators performing bronchoalveolar lavage studies (Davis et al. 1976; Demarest et al. 1979; Harris et al. 1970, 1975; Hunninghake et al. 1979a, 1980a; Hunninghake and Crystal 1983; Hunninghake and Gadek 1981-1982; Hunninghake and Moseley, in press; Reynolds et al. 1977; Reynolds and Newball 1974, 1976; Rodriquez et al. 1977; Warr et al. 1976,1977; Warr and Martin 1974,1978). Such increases have been detected additionally in lavage fluid of animals chronical- ly exposed to cigarette smoke (Davies et al. 1977; Flint et al. 1971; Holt et al. 1973). The majority of these studies have demonstrated increases in both the number of macrophages and the number of neutrophils, although Hoidal and Niewoehner (1982) found increases only in the former. The presence of neutrophils in the lungs of cigarette smokers is of interest because these cells contain elastase, an enzyme believed to be important in the pathogenesis of emphysema (Lieberman 1976; Karlinsky and Snider 1978; Kuhn and Senior 1978; Carp and Janoff 1978; Snider and Korthy 1978; Schuyler et al 1978; Janoff et al. 197'1; Hunninghake et al. 1979a; Hunninghake and Crystal 1983; Hun- ninghake and Gadek 1981-1982; Hunninghake and Mosley 1984; Laurel1 and Eriksson 1963). Alveolar macrophages have also been implicated as a source of an elastase-like metalloprotease (Harris et al. 1975; Rodriguez et al. 1977). This enzyme is not inhibited by alpha,-antitrypsin (a,AT) (Banda and Werb 19811, the major anti- elastase in the lower respiratory tract (Gadek et al. 1981). Although macrophages are clearly present in large numbers in the alveolar structures of smokers (Niewoehner et al. 1974; Harris et al. 19751, several lines of evidence suggest that neutrophils may play a significant and perhaps more important role in increasing the elastase burden of the lungs. First, neutrophils store and release significantly more elastase than do alveolar macrophages (Barrett 1977; Rodriguez et al. 1977; Levine et al. 1976). Comparative estimates of elastase production by human neutrophils and alveolar macrophages suggest that neutro- phils are at least 1,000 times more potent elastase producers (Janoff et al. 1979). Second, although alveolar macrophages of cigarette smokers have been shown to release elastase in vitro (Rodriguez et al. 19771, it is not clear whether the elastase was produced by these cells or was secreted by other types of cells, such as neutrophils, and subsequent- ly ingested by the macrophages (Janoff et al. 1977). In this regard, recent studies by Campbell et al. (1979) and McGowan et al. (1983) have shown that alveolar macrophages are capable of phagocytosing 257 neutrophil elastase via a receptor-mediated mechanism; some of the elastase remains enzymatically active for up to 48 hours. These findings suggest that alveolar macrophages may, in fact, be capable of both decreasing and increasing the protease burden of the lung. Third, once a neutrophil has left its vascular space, its lifespan is only a few hours; when the neutrophil dies, it may release at least a portion of its preformed enzymes, including elastase. Thus, when a neutrophil is present within a tissue, it is possible that the tissue will be exposed not only to the elastase secreted by the neutrophil while it is functional, but also to the elastase stored by the neutrophil and released when the neutrophil disintegrates. In this context, the finding that neutrophils represent only a small percentage of all inflammatory and immune effector cells in the smoker's lungs would not preclude the smoker's exposure to a large chronic burden of neutrophil elastase. In contrast, the alveolar macrophage has a half- life of months to years (Thomas et al. 19761, and it stores little, if any, elastase (Rodriguez et al. 1977; Levine et al. 1976). Macrophages may also play an important role in this process by secreting a potent chemotactic factor for neutrophils (Hunninghake and Crystal 1983). This hypothesis is supported by the following observation: alveolar macrophages of cigarette smokers spontaneous- ly release a chemotactic factor for neutrophils, whereas alveolar macrophages of nonsmokers do not. In addition, in vitro exposure to cigarette smoke particulates results in the release of a chemotactic factor from the alveolar macrophages of nonsmokers. The migration of neutrophils to the lung in response to the chemotactic factor may be augmented by factors in cigarette smoke. In this regard, McCusk- er et al. (1983) have shown that nicotine is a potent chemokinetic factor for neutrophils, enhancing the migration of these cells to other chemotactic factors. Once neutrophils are present in the lung, they may release elastase, because both cigarette smoke (Blue and Janoff 1978) and the macrophage-derived chemotactic factor stimu- late these cells to release the enzyme (Gadek et al. 1979a, b). The postulated release of elastase by neutrophils could also partly explain how the number of macrophages are increased in this disorder. Fragment,s of elastin (which are probably generated by the release of neutrophil elastase at sites of disease activity) are potent chemoattractants for blood monocytes, the precursors of alveolar macrophages (Senior et al. 1980; Hunninghake et al. 1981). These fragments of elastin possess no chemotactic activity for neutrophils. Effect of Smoking on the Morphology and Function of inflammatory Cells No size differences have been observed between alveolar macro- phages from smokers and those from nonsmokers when the cells are 258 fixed in suspension immediately after bronchoalveolar lavage (Table 1). Harris and coworkers (1970) observed a mean size of 23.3 pm (range, 10 to 47 pm) for nonsmokers and 26.4 pm (range, 12 to 53 pm) for smokers. Reynolds and Newball (1974), using similar methods, did not find any size differences between smoker and nonsmoker alveolar macrophages. The morphology of smoker macrophages clearly differs, however, from that of nonsmokers (Table 1). Macrophages of smokers show increased numbers of large lysosomes, phagolysosomes, endoplasmic reticulum, ribosomes, and Golgi vesicles (Golde 1977; McLemore et al. 1977; Martin 1973; Warr and Martin 1978; Rasp et al. 1978; Pratt et al. 1971; Brody and Craighead 1975). These findings are generally associated with activated mononuclear phagocytes, and these macro- phages have probably become activated by the ingestion of the particulates present in cigarette smoke. Smoker macrophages have pigmented inclusions that appear to have platelike or needlelike configurations when seen by electronmicroscopy (Golde 1977; Warr and Martin 1978; Pratt et al. 1971; Brody and Craighead 1975). Studies of the nature of these inclusions by X-ray analysis suggest they may be, at least in part, particulates of aluminum silicate (Brody and Craighead 1975). Together with in vitro studies showing that alveolar macrophages are activated following phagocytosis of particulates (Hunninghake et al. 1980a), these findings are compat- ible with the notion that macrophages of smokers are activated in vivo. Alveolar macrophages from cigarette smokers have an increased ability to generate superoxide anion (Hoidal et al. 1979a, 1980,1981), the functional effects of which include an increased capacity to kill lung fibroblasts. These observations suggest that alveolar macro- phages from cigarette smokers are increasingly able to injure lung parenchymal cells, and that they may contribute to the observed loss of lung cells in the alveoli of patients with pulmonary emphysema. A variety of other effector functions of smokers' alveolar macro- phages have also been evaluated (Table 1). Alveolar macrophages from cigarette smokers appear to have a normal or increased ability to migrate in response to chemotactic factors (Demarest et al. 1979; Warr and Martin 1974). They differ, however, from normal alveolar macrophages in several other respects: for example, increased glucose utilization has been reported in some studies (Harris et al. 1970), but was normal in others (Hoidal et al. 1979a). Oxygen consumption has been reported to be normal (Hoidal et al. 1979a), but the protein content of these cells has been increased (Harris et al. 1975; Warr and Martin 1978). Alveolar macrophages from smokers release less PGE, and thromboxane B, than normal macrophages (Laviolette et al. 1981), suggesting that cigarette smoking induces a lesion in phospholipid hydrolysis or the mecha- TABLE l.-Cigarette-smoking-induced abnormalities in the inflammatory and immune effector systems > within human alveolar structures Parameter Findings in smokers cell types present Total number of cells Percent polymorphonuclear leukocytes Percent T lymphocytes Percent B lymphocytes Lymphocyte function Response to mitogens Macrophage structure Diameter Ruffling of cell surface Number and size of cytoplasmx structures Abnormal cytoplasmlc inclusions Macrophage propertws and function Surface receptors 1gGFc C3b Phagwy&ls and killing of microorganisms Bacteria Fungi Effector and accessory cell function responsiveness to chemotactic factors Casein Activated serum Function as act-ry cell to lymphocytes Responsiveness to MIF Production of neutrophll chemotactlc factor SecretIon of superoxIde anion Secretlon of elastase Release of prostaglandm E, and thromboxane B, Miscellaneous properties and function Glucose utdlvltion Oxygen consumption Protem content Content of various enzymes Eklstase Acid protease Neutral protease Esterrise Acid phosphatase &glucuromdase Lysozyme Aryl hydrocarbon hydroxylase An@otensmsonvertmg enzyme Spreading and adherence properties Plllocytosls Content of a,-antlproteinase IIlCEased Increased Increased or normal Normal Decreased Normal Decreased Increass Pigmented inclusions, particulates with plate or needle-like confwratlon. presence of aluminum silicate NOM"1 Decreased Kormal or decreased Normal Increased Normal Decreased Decreased Increased Increased Increased Decreased Increased or normal Normal Increased Increased IllCreased Normal Increased Increased Increased Normal or increased Increased Increased Increased in presence of serum. decreased nylon adherence Decreased Increased SOURCE Adapted from Hunnmghake et al 119791 260 nism regulating hydrolysis. Smoker macrophages also appear to have increased amounts of various enzymes, including acid protease (Harris et al. 1975), neutral protease (Harris et al. 1975), esterase (Harris et al. 1975), acid phosphatase (Martin 1973!, angiotensin- converting enzyme (Hinman et al. 1979), P-glucuronidase (Martin 1973), lysozyme (Martin 1973), and arylhydrocarbon hydrolase (Cantrell et al. 1973; Harris et al. 1978; McLemore et al. 1977b, c, 1978; McLemore and Martin 1977). The functional significance of increased amounts of these enzymes is not entirely clear. In addition to its effects on the inflammatory and immune effector cells in the lung, cigarette smoke may also affect the composition of epithelial surface fluid. For example, some investigators have found that the amount of immunoglobulin G (IgG) present in lavage fluid is increased (Reynolds and Newball 1974); others have noted normal levels (Warr et al. 1977). Interestingly, cigarette smoking appears to cause a significant decrease in the secretory component of immuno- globulin A (IgA) in the lavage fluid of some people who smoke cigarettes (Merrill et al. 1980). This effect most likely indicates a subtle injury to the epithelium of the lung that produces this factor. The only additional factors that have been reported to be abnormal in lavage fluid of cigarette smokers are an increase in the amounts of fibronectin (Villiger et al. 1981) and a decrease in the function, but not the amount, of a,AT (Gadek et al. 1979; Janoff et al. 1979). This latter finding has been disputed by others (Stone et al. 1983). Emphysema A number of lines of evidence link the cellular changes described above with the development of emphysema. They include observa- tions in populations deficient in a,AT, in animal models of emphyse- ma, and most important, in human cigarette smokers. Populations Deficient in Alpha,-antitrypsin Eriksson (1965) described the characteristic features of a,AT- deficiency-associated lung disease. Approximately 60 percent of affected individuals develop symptoms of airways obstruction by age 40, and 90 percent by age 50. Excluding the influence of cigarette smoking, there is no sexual predominance of disease. Kueppers and Black (1974) found that dyspnea occurred a decade earlier in cigarette smokers (35 years in smokers versus 44 years in nonsmok- ers), and estimated that 70 to 80 percent of all PiZZ persons (where Pi= protease inhibitor) will develop lung disease. Larsson (1978) has projected that nearly 60 percent of PiZZ people will ultimately die of lung-related disease. Ore11 and Mazodier (1972) reviewed the morphologic features of a,ATdeficiency-associated emphysema and found primarily the 261 panacinar or panlobular form. Emphysematous lesions may be distributed uniformly throughout the lungs (Ore11 and Mazodier 1972), but frequently show a predominant lower lobe distribution (Greenberg et al 1973). In people genetically deficient in alAT, the increased numbers of inflammatory cells found in the lungs of smokers probably present an increased elastase burden to the lung and magnify the protease- antiprotease imbalance. This may explain the deleterious effects of cigarette smoke in this population. Kueppers and Black (1974) reviewed data on the impact of cigarette smoking in people severely deficient in a,AT and concluded that, in addition to experiencing earlier onset of respiratory symptoms and pulmonary function abnormalities, cigarette smokers die at an earlier age from respira- tory failure than similiarly afflicted nonsmokers. The increased prevalence of emphysema in populations deficient in alAT, plus the exacerbation of this lung disease by smoking, suggests that protease- antiprotease imbalance may also play a role in the development of emphysema by smokers who are not deficient in a,AT. This suggestion has resulted in a substantial body of research that has characterized a,AT, defined the nature of elastase-induced emphyse- ma, and clarified and supported the protease-antiprotease hypothe- sis of cigarette-induced emphysematous lung injury. Alpha,-antitrypsin The deficient constituent of a,-globulin was initially described by Schultze et al. (1955) as a,-3,5-glycoprotein but later renamed a,- antitrypsin (a,AT) when it was found to inhibit trypsin activity (Schultze et al. 1962). Subsequently, a,AT has been shown to inhibit a variety of proteolytic enzymes including neutrophil elastase (Ohlsson 1971), neutrophil collagenase (Tokoro et al. 1972; Ohlsson 1971), cathepsin-G (Travis et al. 1978), chymotrypsin (Travis et al. 1978; Rimon et al. 1966), plasmin (Rimon et al. 1966), thrombin (Rimon et al. 1966), Hageman factor cofactor (Crawford and Ogston 1974), coagulation factor XI (Heck and Kaplan 1974), acrosin and kallikrein (Fritz et al. 1972a, b), urokinase (Crawford and Ogston 1974; Clemmensen and Christensen 1976), and renin (Scharpe et al. 1976). Although the range of proteases inhibited by a,AT appears broad, the association rate constants of these enzymes for a,AT differ (leukocyte elastase > chymotrypsin > cathepsin-G > trypsin > plasmin > thrombin) (Beatty et al. 1980), and the inhibitory role of a,AT against enzymes with low association rate constants, such as trypsin, may be negligible. The names a,-protease inhibitor or al- proteinase inhibitor better describe this broader range of inhibitory functions and are preferred by some authors. In deference to historical usage and in accord with the recommendations of the 262 Nomenclature Meeting for this substance (Cox et al. 1983), the name a,AT has been retained in this discussion. The inhibitor a,AT is a polymorphic plasma protein (Fagerhol and Cox 1981; Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981; Fagerhol and Braend 1965) encoded by two codominant autosomal alleles and inherited as a single Mendelian trait. The basal serum concentration is genetically determined (Eriksson 1964; Kueppers et al. 1964; Fagerhol and Gedde-Dahl 1969; Talamo et al. 1966). More than 31 allelic variants or Pi types (where Pi, or protease inhibitor, is the symbol assigned the genetic locus of the a,AT allele) have been identified (Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981). The variants are designated by capital letters, B through Z, correspond- ing to their approximate electrophoretic mobility, relative to the anode, in acid starch gel electrophoresis or their relative positions on polyacrylamide isoelectric focusing. New variants are named accord- ing to the conventions established by the Fifth International Workshop on Gene Mapping and the Nomenclature Meeting for a,AT (Cox et al. 1980). The M allele (PiM) has a gene frequency of about 0.9 and is the most common Pi type in all populations tested (Kueppers 1978). The a,AT serum concentration in PiMM homozygotes is between 1.3 and 2.2 g/liter (depending on the method of measurement and the purity of standard) (Kueppers 1968; Jeppsson et al. 1978a) and, by conven- tion, defines normal. Pi types with decreased circulating levels of a,AT include (serum concentration expressed as percent normal) null 0% (Feldman et al. 1975; Talamo et al. 1973), Mmalton and Mduarte 12% (Cox 1976; Lieberman et al. 1976), Z 15% (Laurel1 and Eriksson 1963; Fagerhol and Laurel1 1970), P 30% (Fagerhol and Hauge 1969), S 60% (Fagerhol 1969), and I 68% (Arnaud et al. 1978). PiZ was the first variant recognized (Laurel1 and Eriksson 1963) and is the Pi type most frequently associated with a serum deficiency of a,AT (Kueppers 1978). Its allele frequency varies markedly between different ethnic and racial groups. In the United States, the allele frequency is greater than 0.010 in whites but nearly zero in blacks (Kueppers 1978). Approximately 1 in 2,000 whites is homozy- gous for the Z gene (Laurel1 and Sveger 1975). Although a decrease in hepatic synthesis is probably the major mechanism for quantitatively significant reductions in serum a,AT, the factors that modulate such synthesis are only partially under- stood (Morse 1978). Impaired hepatic secretion, as evidenced by the presence of intrahepatic cytoplasmic inclusions containing accumu- lations of a,AT polypeptides (Blenkensopp and Haffenden 1977), occurs in persons with the PiZ genotype. It is uncertain if these intrahepatic inclusions exert a negative feedback inhibition on the hepatocyte and thereby retard biosynthesis of a,AT. Intrahepatic inclusions are not found with the S and null Pi types (Carrel1 et al. 19821, suggesting that decreased synthesis, independent of impaired secretion, is primarily responsible for the reduced serum levels of a,AT. Catabolic studies of the PiM and PiZ proteins have identified similar half-lives in the circulation, 6 to 7 days and 5 days, respectively (Laurel1 et al. 1977; Jeppsson et al. 1978b). It is therefore unlikely that accelerated peripheral catabolism contributes signifi- cantly to serum deficiencies in a,AT. In addition to quantitative deficiencies in serum a,AT, a reduction in serum inhibitory capacity could also result from a loss in the functional activity of a,AT. Most genetic variants, however, are functionally equivalent to normal a,AT (PiMM) in their capacities to inhibit both trypsin and elastin (Billingsley and Cox 1982). The inhibitor a,AT is a low molecular weight (51,000 daltons) (Mega et al. 1980; Carrel1 et al. 1981; Chan et al. 1976; Pannell et al. 1974; Jeppsson et al. 19781 protein comprised of a single polypeptide chain containing 394 amino acid residues. Three carbohydrate side chains are attached, each containing terminal sialic acid residues (Mega et al. 1980; Carrel1 et al. 1981). The a,AT reacts stoichiometri- tally with free protease in a ratio of 1:l; one mole of a,AT inhibits one mole of protease and yields a stable complex (Cohen 1973). An in vitro study (James and Cohen 1978) found, however, that complete inhibition of elastase requires molar ratios of a,AT to elastase greater than 2.2:1. This phenomenon may be explained by elastase having two major sites of attack on a,AT. Attack against one site leads to a conformational change in a,AT and inhibition of elastase, whereas attack against the other site results in cleavage and inactivation of a,AT. The a,AT-protease complexes that form during protease inhibition are not reutilized by the body (Balldin et al. 19781, and the body supplies of a,AT are replenished via de novo synthesis by the liver. In addition to hepatic biosynthesis, a,AT is synthesized by at least two other endogenous sources. Both human peripheral lymphocytes and rat alveolar macrophages have been shown to synthesize a,AT. Ikuta et al. (1982) demonstrated that concanavalin A-stimulated monocytes interact with human peripheral lymphocytes, causing a threefold increase in a,AT synthesis. White et al. (1981) cultured rat alveolar macrophages and recovered newly synthesized radio-labeled FS)a,AT from the cell culture medium. Macrophages and lympho- cytes, by virtue of their close physical proximity to the sites of connective tissue injury, may play a significant role in defense against proteolytic destruction. The physiologic significance of extrahepatic synthesis of a,AT remains speculative, however. While certain chemical and physiological aspects of a,AT are clear, the exact biochemical mechanism by which it causes protease inhibition is uncertain. It is generally agreed that the reactive center of a,AT is located on a single serine-methionine segment peptide 264 bond on the carboxyl-terminal end (Carrel1 et al. 1982; Kurachi et al. 1981). Proteolytic Enzymes Inducing Emphysematous Change Proteolytic enzymes have been a major focus of investigation following the demonstration by Gross et al. (1965) of papain's ability to induce emphysematous changes in rats. Papain Papain, a proteolytic enzyme with a broad range of substrate specificities (Bergmann and Fruton 1941; Kimmel and Smith 1953), reproducibly causes emphysema-like lesions in a variety of experi- mental animals following aerosolization or intracheal instillation (Gross et al. 1965; Palecek et al. 1967; Goldring et al. 1968; Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969). A number of studies have helped to clarify the critical importance of elastolysis in papain-induced emphysema. Snider et al. (1974) tested amorphous and crystalline forms of papain and found that the emphysema-inducing properties of these preparations were directly proportional to their abilities to degrade and solubilize elastin. Heat inactivation of papain destroyed its emphysema-inducing capabilities. Similarly, intratracheal pretreat- ment of hamsters with human a,AT, an inhibitor of papain elastolytic activity, ameliorates papain-induced emphysematous changes (Martorana and Share 1976). Furthermore, Blackwood et al. (1973) showed that the elastolytic activities of several microbial enzymes, rather than their nonspecific protease activities, correlate best with the enzyme's ability to induce emphysematous changes following intravenous administration to rats. Snider et al. (1977) showed that enzymes lacking elastolytic activity, such as collagenase or trypsin, do not produce emphysema in hamsters. Whereas these studies support the notion that the early histologic changes induced by papain are a direct consequence of its elastolytic activity, they do not preclude the possibility that endogenous factors may contribute to subsequent disease progression. Snider and Sherter (1977) noted a gradual increase in static lung volumes in hamsters following a single intratracheal injection of pancreatic elastase. Stone et al. (1979) followed the fate of tritium-labeled pancreatic elastase and found that enzymatically active prepara- tions are retained longer within the lung than inactive preparations, and that 1qGguanidated elastase remains bound to lung matrix for at least 96 hours. This suggests that tissue-bound elastase may continue to digest elastin for extended periods of time. Martorana et al. (19821 found no progression in the mean linear intercept measurements or internal surface areas in the lungs of papain-treated dogs between 3 265 480-144 0 - 85 - 13 and 6 months after treatment. However, the mean pulmonary arterial pressure and pulmonary arteriolar resistance did increase during this interval. Papain-treated animals exhibit the expected physiologic changes of emphysema: increased RV, FRC, and TLC, decreased elastic recoil, increased static lung compliance at middle and low lung volumes, and reduced diffusing capacity (DLcoVA and Delco) (Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969; Giles et al. 1970; Johanson and Pierce 1973). Studies by Kobrle et al. (1982) have shown that following papain administration the elastic fibers are disrupted and that the elastin content of the lung initially decreases, but later returns to normal after a period of accelerated synthesis. The newly synthesized fibers are disordered; however (Kuhn and Senior 1978; Kuhn and Starcher 1980). Pancreatic Elastase The ability of porcine pancreatic elastase to rapidly hydrolyze insoluble elastin (Partridge and Davis 1955) and its commercial availability in a highly purified crystalline form have led to its extensive use as an experimental agent for inducing emphysema in animals (Karlinsky and Snider 1978). Lesions resembling human panacinar emphysema can be induced in hamsters within 2 hours of intratracheal instillation of pancreatic elastase (Kaplan et al. 1973). The severity of the lesions, as assessed by histologic or physiologic criteria, is dose related (Raub et al. 1982), with adult animals being more susceptible to pancreatic elastase than young animals (Lucey and Clark 1982). Within a few hours of intratracheal instillation in hamsters, hemorrhagic lesions develop and an influx of polymorpho- nuclear leukocytes is seen (Hayes et al. 1975; Kuhn and Tavassoli 1976). Digestion of elastin fibers is apparent in the pleura and in the alveolar walls by 4 hours, but is more extensive at 24 and 48 hours (Kuhn et al. 1976). By day 4, there is a diminution in the number of polymorphonuclear leukocytes (PMNs), but many macrophages remain (Morris et al. 1981). The hemorrhage and cellular infiltration resolves within 3 weeks, and the ensuing lesions resemble panacinar emphysema (Kuhn et al. 1976). Over 95 percent of the detectable urinary excretion of desmosine and isodesmosine, amino acid markers of in vivo elastolysis, appears within 2 days of elastase instillation; only small amounts can be detected by day 3 (Goldstein and &archer 1977). Kucich et al. (1980) developed a hemagglutina- tion inhibition assay to measure elastinderived peptides in serum, and found that elastinderived peptides could be detected in the serum of dogs for a period of 12 days following administration of a 25 to 50 mg dose of porcine pancreatic elastase and for 40 days following a 100 mg dose. Janoff et al. (1983b) found increases in urinary desmosine excretion during the first 48 hours following endobronchi- al instillation of pancreatic elastase to sheep; increases in mean linear intercepts and decreases in lung ventilation and perfusion were found after 4 weeks. All changes correlated positively with the elastase dose. Studies have shown a decrease in the lung elastin content within the first 24 hours of intratracheal injection of elastase (Kuhn et al. 1976; Ip et al. 1980; Goldstein and Starcher 1977). Physiologic studies (Snider and Sherter 1977; Snider et al. 1977) of experimental animals after pancreatic elastase administra- tion have shown increases in the lung compliances and in the volume of air within the lungs at specified transpulmonary pressures (25 and -20 cm H*O). These physiologic alterations appear to progress in severity for about 26 weeks following exposure to elastase (Snider and Sherter 1977). In spite of substantial experimental verification of ability of pancreatic elastase to induce emphysematous changes in animals following intratracheal instillation, there is little evidence implicat- ing endogenous pancreatic elastase in the pathogenesis of pulmonary emphysema in humans. A serine endopeptidase of pancreatic origin (elastase 2) has been shown to circulate in human blood (Geokas et al. 1977). However, the enzyme is rapidly bound to serum inhibitors a,AT and a,-macroglobulin (a,M) and inactivated (Gustavsson et al. 1980). Although a,Melastase complexes retain enzymatic activity against low molecular weight synthetic elastin substrates (N-succi- nyl-I-.-alanyl-Lalanyl-Lalanine-4-nitroanilide) (Twumasi and Liener 1977; Barrett and Starkey 1973); high molecular weight proteins such as elastin are prevented from reaching the enzyme and are not hydrolyzed (Barrett and Starkey 1973). Attempts to induce emphysematous changes via the intravenous injection of elastase have met with limited success. Hamsters injected intravenously with nonfatal doses of pancreatic elastase fail to show histologic changes characteristic of emphysema (Schuyler et al. 1978) and do not manifest detectable reductions in lung elastin (Ip et al. 1980). However, elastic recoil is lost at low lung volumes (Schuyler et al. 1978). Fierer et al. (1976) has noted enlargements in the airspaces of rats treated intravenously with large doses (330 U) of pancreatic elastase. They also found increases in the mean linear intercepts and rarefication of the amorphous components of elastin within the lungs. It is doubtful, however, if proportionally similar intravenous levels of pancreatic elastase occur in humans with pulmonary emphysema. Polymorphonuclear Leukocyte Elastase Polymorphonuclear leukocytes (PMN) appear to be a more plausi- ble source of endogenous elastase in the human lung than the pancreas, and are more likely to be incriminated in the pathogenesis of naturally occurring pulmonary emphysema. PMNs contain elasto- 267 lytic enzymes (Janoff 1973; Ohlsson and Ohlsson 1974; Rindler- Ludwig et al. 1974) that can be released in active form within the lung. Experimental studies have clearly demonstrated the ability of PMN elastase to degrade lung elastin and to induce emphysematous lesions in animals. Marco et al. (1971) and Mass et al. (1972) induced experimental emphysema in dogs by the administration of aerosolized crude leukocyte homogenates. Using purified human leukocyte elastase, Janoff et al. (1977) demonstrated the ability of the enzyme to digest dog lung elastin in vitro and to cause significant dilation of terminal respiratory structures when instilled into isolated perfused dog lungs. The in vivo intratracheal instillation of human leukocyte elastase in dogs produces foci of alveolar destruction within 90 minutes of administration (Janoff et al. 1977). Senior et al. (1977) studied the effects of intratracheally injected human leukocyte elastase on hamsters and found a reduction in lung elastin in treated animals, as well as mild patchy airspace dilation. Sloan et al. (1981) were able to show that purified dog leukocyte elastase could also produce emphysematous lesions in dogs when instilled endobronchi- ally. Guenter et al. (1981) developed a dog model of experimentally induced emphysema that avoided the necessity of intratracheal instillation of enzymes. They repetitively injected E. coli endotoxin intravenously, thereby inducing extensive leukocyte sequestration within the lungs of the dogs. A previous study had shown that the sequestered cells degranulate and disintegrate within the vascular bed (Coalson et al. 1970). Histologic studies of these dogs revealed mild airspace destruction and prominent intra-alveolar fenestra- tions. Alveolar Macrophage Elastase In a widely cited article (Mass et al. 1972), dog alveolar macro- phage homogenates (obtained by the method of Brain 19701, adminis- tered to two mongrel dogs produced "some dilatation and nonuni- formity in the size of the airspaces accompanied by some alveolar wall destruction" in one of the dogs. The other dog showed no evidence of emphysema. In spite of the paucity of animal data, the pulmonary alveolar macrophage (PAM) has been the focus of much investigation. Both experimental and clinical evidence is available that implicates this cell in the pathogenesis of pulmonary emphysema. Two possible mechanisms by which macrophages may mediate tissue injury are being actively studied. One mechanism involves the release of elastolytic enzymes followed by unrestrained proteolysis. The second mechanism involves either a direct or an indirect injury 268 following the release of toxic forms of partially reduced oxygen such as superoxide anions, hydroxyl radicals, and hydrogen peroxide. The ability of human alveolar macrophages to synthesize and secrete an elastolytic enzyme distinct from PMN elastase is the subject of controversy. Although human alveolar macrophages have been shown to synthesize a metalloprotease distinct from the serine protease (elastase) of the PMNs (DeCremoux et al. 19781, its hydrolytic activity against insoluble elastin substrate has not been conclusively demonstrated (Hinman et al. 1980; Levine et al. 1976). Interpretation of the observation that human alveolar macrophages raised in cell culture systems secrete an enzyme with true elastolytic activity against insoluble elastin (Rodriguez et al. 1977; DeCremoux et al. 1978) is complicated by the fact that alveolar macrophages bind and internalize PMN elastase (Campbell and Greco 1982; White et al. 1982; Campbell and Wald 1983). Hinman et al. (1980) detected a calcium-dependent metalloprotease in the culture medium and in the cell lysates of human alveolar macrophages and initially demonstrated elastolytic activity against synthetic elastin substrate and soluble elastin by both the culture medium fluid and the cell lysates. However, after 3 and 5 days of culture, no detectable activity against insoluble elastin was evident. The authors calculated that the initial elastolytic activity observed could be quantitatively explained by PMN contamination. The recognition that human alveolar macrophages internalize human PMN elastase (Campbell and Greco 1982; White et al. 1982; Campbell et al. 1979; Campbell and Wald 1983) and that the internalized PMN elastase retains enzymatic activity for at least 48 hours (McGowan et al. 1983) suggests an alternative explanation. Green et al. (1979) subcultured human alveolar macrophages for 3 months and found measurable elastase activity against solubilized elastin during the entire period. They concluded that the elastase activity appeared to be synthesized continuously rather than being internalized from external sources. In summary, human alveolar macrophages release elastolytic enzymes capable of digesting connective tissue. Whether the elastase released by these cells represents an enzyme synthesized de novo or a previously internalized PMN elastase is uncertain and requires further study. Human alveolar macrophages, especially from cigarette smokers, secrete highly reactive oxygen species (Hoidal et al. 1979a) that are :apable of directly injuring endothelial cells (Sacks et al. 1978) and `ibroblasts (Hoidal et al. 1981) and of inactivating a,AT (Carp and Ianoff 1979, Janoff 1979a). Whole cigarette smoke inhibits PMN chemotaxis in vitro in a dose- ependent manner (Bridges et al. 1977). However, when alveolar lacrophages are exposed to cigarette smoke either in vitro or in vivo, they release a PMN chemotaxic factor (Hunninghake et al. 198Oc) (see above). Protease-Antiprotease Hypothesis The protease-antiprotease hypothesis proposes that enzymatic digestion of lung parenchyma occurs as a direct consequence of a genetic or acquired imbalance of the protease-antiprotease system and that the subsequent repair of connective tissue is unable to return the structures to normal. This hypothesis derives principally from two observations: (1) people genetically deficient in a,AT (Laurel1 and Eriksson 1963), the major antielastase of the lower respiratory tract of humans (Gadek et al. 1981a), are at greatly increased risk of developing pulmonary emphysema, and (2) proteo- lytic enzymes produce physiologic and anatomic lesions resembling emphysema when administered to experimental animals (Gross et al. 1965). Attempts to integrate the clearly established relationship of cigarette smoking and pulmonary emphysema with the protease antiprotease hypothesis have led in-Testigators to search for ways in which smoking perturbs this balance. Increased Elastase Owing to the Cellular Response to Smoke At least five variables, aside from the genetically determined level of antiprotease activity, could influence the elastase burden of the lungs. These variables include (1) an increase in the number of elastase-containing cells within the lung, (2) an increase in the quantity of prepackaged or newly synthesized elastase per cell, (3) the quantity of elastase released from the cells, (4) the proximity of the elastase to suitable substrate, and (5) the extracellular milieu (i.e., pH, ionic strength, and factors such as platelet factor 4). Number of Cells As discussed earlier, the human cigarette smoker has increased numbers of alveolar macrophages in the bronchoalveolar lavages compared with nonsmokers (Rodriguez et al. 1977; Harris et al. 1975; Reynolds and Newball 1974; Hoidal and Niewoehner 1982). Holt and Keast (1973b) found sustained elevations of pulmonary macrophages in mice exposed to cigarette smoke. Cigarette smoke has been shown to recruit PMNs into the airways (Kilburn and McKenzie 1975; Rylander 1974) and to induce alveolar macrophages to release a chemotactic factor for PMNs (Hunninghake et al. 198Oc). The circulating PMNs are reported to be increased in cigarette smokers (Corre et al. 1971; Galdston et al. 1977). Hunninghake et al. (198Oc) and Reynolds and Newball (1974) found increased numbers of PMNs in the lavage fluid of smokers, but Hoidal and Niewoehner (1982) reported similar numbers of PMNs in the lavages of cigarette 270 smokers and nonsmokers. Hunninghake and Crystal (1983) obtained isolated cell suspensions from the bronchoalveolar lavage fluids and from open lung biopsies of nonsmokers and cigarette smokers with both normal lung parenchyma and sarcoidosis. They found a significantly increased number of neutrophils and macrophages in the lavage fluid and in the biopsy specimens from cigarette smokers as compared with nonsmokers, both in patients with normal lung parenchyma and in those with sarcoidosis. Elastase Content Harris et al. (1975) found an increase in the elastase-like esterase and protease activity of macrophages obtained from smokers as compared with nonsmokers. Galdston et al. (1977) found the PMN elastase levels of circulating PMNs to be elevated in patients with chronic obstructive lung disease and suggested that the intracellular elastase levels may be genetically determined (Galdston et al. 1973). Other investigators (Lam et al. 1979; Rodriquez et al. 1979) reported similar findings, but Kramps et al. (1980) failed to find any correlation between the PMN elastase levels and obstructive lung disease in PiZZ patients, although they did note a difference in PiMM patients. Lanky et al. (1980) demonstrated that dogs infected with Type 3 pneumococcus had increased PMN elastase-like esterase activity within their cells, suggesting an acute phase reaction. Release A variety of mechanisms may lead to the extracellular release of lysosomal contents. These include cell lysis, regurgitation during phagocytosis, reverse endocytosis, humoral mediation, and cytocha- lasin B treatment of cells (Klebanoff and Clark 1978). Wright and Gallin (1979) showed that migration of PMNs is associated with the leakage of various enzymes. Sandhaus (1983) found that migrating human neutrophils degrade elastin in vitro in the presence or absence of human a,AT. A similar mechanism may occur during neutrophil migration in vivo. Hutchison et al. (1980) found that the soluble fraction of cigarette smoke suppressed the release of lysoso- ma1 enzymes (acid phosphatase and acid ribonuclease) from PMNs obtained from healthy persons, but not from the PMNs of emphy- sematous patients. Blue and Janoff (1978) demonstrated that the water-insoluble fraction of cigarette smoke has a cytotoxic effect on PMNs in vitro and causes them to release their lysosomal contents, including beta-glucuronidase, acid phosphatase, and elastase. Eliraz et al. (1977) found that canine alveolar macrophages and PMNs, when stimulated with the water-soluble fraction of cigarette smoke, secrete elastase. Abboud et al. !1983), however, compared the release of elastase and 8-glucoaminodase from PMNs obtained from ciga- 271 rette smokers and with that from nonsmokers and found no differences. In vitro stimulation of these cells by ?ither phagocytosis or chemotactic polypeptides did not alter the results. These research- ers concluded that chronic smoking does not affect neutrophil elastase release in vitro and that among smokers there is no significant relationship between in vitro neutrophil elastase release and abnormalities in lung function. They speculated that some of the differences between studies may be related to experimental condi- tions, such as the concentrations of cigarette smoke. Because the mechanisms involved in the release of intracellular contents are complex and the representativeness of in vitro condi- tions to in vivo events is uncertain, definite conclusions await further studies. Proximity Elastolytic activity is conditioned by the absorption of elastase onto elastin substrate (Robert and Robert 1970); the adsorption, in turn, results from the electrostatic attraction between negatively charged carboxylate groups of elastin and positively charged groups of elastase (Hall and Czerkowski 1961; Gertler 1971). Campbell et al. (1982) found that a,AT has less inhibitory activity against PMN elastase derived from cells in contact with substrate than against PMN elastase free in solution. They reasoned that the partial exclusion of protease inhibitors from the PMN-connective tissue interface may account for this phenomena and may be an important factor in elastase-mediated injury. Focusing more on the macroenvi- ronment within the lung, Janoff et al. (1983c) found that the bronchoalveolar lavage fluids of young asymptomatic cigarette smokers contain significantly more elastase activity than the lavage fluids from nonsmokers. Kucich et al. (1983) found that the serum lung em&in-derived peptides were elevated in some smokers and most patients with COLD, suggesting that elastolysis may be taking place in smokers and COLD patients. Milieu A number of in vitro experiments have examined the chemical and physical conditions that modify neutrophil elastase kinetics. Lesti- enne and Bieth (1980) demonstrated that human leukocyte elastase activity is activated in the presence of substrate excess, hydrophobic solvents, and increasing ionic strength. The adsorption of sodium dodecyl sulfate (SDS), a hydrophobic, anionic ligand, onto the surface of elastin enhances the elastolytic activity of pancreatic elastase (Kagan et al. 1972). Lonky et al. (1978) showed that platelet factor 4 (PF,) in physiologic concentrations is capable of in vitro stimulation of human neutrophil elastase (HLE) against lung elastin. Low doses of HLE instilled intratracheally in hamsters failed to induce physiologic, morphologic, or biochemical changes, but following the addition of PFI, a significant injury was evident, and the elastin content of the lung was lowered by 20 percent (Lonky et al. 1978). Boudier et al. (1981) demonstrated that human leukocyte cathepsin- G, an enzyme in the azurophilic granules that possesses little intrinsic elastolytic activity, stimulates the rate of solubilization of human lung elastin by HLE. The elastolytic activity increased by more than five times the HLE rate when the HLE-cathepsin-G mixture was present in equimolar concentrations. The relevance of these findings to the physiologic conditions that prevail in vivo requires further study. Laurent et al. 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LOW YIELD CIGARETTES AND THEIR ROLE IN CHRONIC OBSTRUCTIVE LUNG DISEASE 329 480-144 0 - 85 - 12 CONTENTS Introduction Problems of Measurement by Machine Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Epidemiologic Studies Mechanisms of Lung Damage Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Smoking Behavior Carbon Monoxide Uptake Nicotine Uptake Role of Tar Content Variations in Pattern of Cigarette Smoke Inhalation Use of Additives in Low Tar and Nicotine Cigarettes Research Recommendations Summary and Conclusions References 331 Introduction Following the initial reports in the early 1950s linking cigarette smoke with lung cancer, the pathogenic role of cigarette tar content received considerable emphasis. Because the tar fraction of the smoke contained the bulk of the carcinogenic effect of whole smoke, and because lung cancer risk was closely related to other measures of total smoke exposure (number of cigarettes smoked per day, depth of inhalation, etc.), it was suggested that risk might be related to the amount of tar generated by different cigarettes. This prompted health authorities to advise smokers who were unable to quite smoking to switch to low tar cigarettes (U.S. Senate 1967; Health Department of the United Kingdom 1976). To facilitate this process, the Federal Trade Commission published smoking-machine assays of the tar and nicotine yield of different cigarette brands (Pillsbury et al. 1969). This approach to low tar and nicotine cigarettes was based on the assumption that smoking lower yielding brands, as deter- mined by a smoking-machine, would result in a proportional reduction in the lung's exposure to these toxic substances. This approach to "safer" cigarette smoking has been promoted by the tobacco industry and apparently accepted by the smoking public, as evidenced by the escalation in sales of low tar and nicotine cigarettes. However, there is increasing evidence that this concept of a "less hazardous" cigarette is misleading; although definitive studies are still awaited, it appears that switching from regular to low tar and nicotine cigarettes may not substantially reduce the risk of chronic airflow obstruction. Problems of Measurement by Machine The first step in evaluating the relative health risks of different cigarettes is to establish some standardized measure of the toxic substances in different cigarettes in order to facilitate comparison. Quantifying each of the several thousand constituents of cigarette smoke for each brand of cigarette, and assessing the changes in these constituents as the manufacturing and agricultural processes change, would be a truly herculean task; therefore, a more modest goal of quantifying tar and nicotine yields was accepted. To date, the yields determined by the Federal Trade Commission have been the most widely adopted. These measurements are obtained with a laboratory smoking-machine, which consists of a syringe pump that takes a 35 ml bell-shaped puff from a cigarette, over a 2-second period, once per minute until a predetermined butt length is reached, either 23 mm for nontiltered cigarettes or 3 mm longer than the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969). These parameters are based on observations of smoking patterns in seven subjects in Europe in 1933 (Kozlowski 1983). Today's cigarette 333 is markedly different from that smoked in 1967 when these parameters were established, yet the same parameters are still employed. Measurements obtained using these parameters indicate a marked reduction in the tar and nicotine yield of cigarettes over the last decade (Figure 1). In addition to the actual tar and nicotine yield of the tobacco, the yield measured by a smoking-machine is influenced by many factors, including cigarette length and diameter, porosity of the cigarette paper, presence of a ventilated or an unventilated filter, butt length, number of puffs, interpuff interval, puff volume, puff duration, puff pressure profile, and frequency of puffing at different stages of cigarette consumption. The number of puffs is important in determining the tar yield of a cigarette, and the number of puffs taken from some brands with the official smoking- machine has significantly declined in recent years (Kozlowski 1981). Since puffs are taken at l-minute intervals, a more rapidly burning cigarette will have a smaller number of puffs. The burning time of the cigarette is determined by porosity of the cigarette paper, the- amount of tobacco in the cigarette, and the diameter of the cigarette column. In a survey of Canadian cigarettes between 1969 and 1974,- Kozlowski et al. (1980b) noted a significant reduction in the number- of puffs taken in the official assays over this time period, which was strongly correlated with a reduction in tar yield. Omission of the last- few puffs can markedly affect tar yield, because tar delivery- increases with each puff, and the last few puffs from a cigarette can contain twice as much tar as the first few puffs (Wiley and Wickham 1974). Currently published yields do not indicate the number of puffs taken, which may range from 7 to 12 and may result in a marked variation of the tar yield. Ventilated cigarette filters, which cause inhaled smoke to be diluted with air, are one of the major methods of achieving low tar yields (Gori and Lynch 1978). Cigarettes with ventilated filters constituted about 25 percent of all cigarette sales in the United States in 1979 (Hoffmann et al. 1980). During systematic interviews, Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar smokers block these filter perforations with their fingers or lips, a feature unaccounted for by smoking-machines. This hole blocking increased the yield of toxic products by 59 to 293 percent. If a person smokes a cigarette in a manner identical to the smoking-machine, the delivery of tar and nicotine to the mouth will be the same as that estimated by the machine. Human smoking patterns are diverse, however, and show considerable variation from the machine parameters; puff volumes range from less than 20 ml to more than 90 ml (Tobin and Sackner 19821, compared with the fixed 35 ml volume employed by the machine. Differences in puff profile from the bell-shaped puff used by the machine also alter cigarette 334 Tar mg 100 -' 1950 1955 1960 1965 1970 1975 1980 FIGURE l.-U.S. sales-weighted average tar and nicotine yields SOCRCE Amencan Cancer Scaety 11981 I yield. Numerous studies indicate that smokers compensate for lower yielding cigarettes by altering their style of smoking. For each different cigarette brand, smokers may have a different smoking oattern. To provide more meaningful information, smoking-ma- :hines should be designed to reproduce variations in the manner of smoking each cigarette brand, and their assays should provide both m average and a range of tar and nicotine yields depending on the ndividual pattern of smoking (USDHHS 1981). Many investigators have examined the relationship between the nachine-determined nicotine yield of a cigarette and the concentra- ion of nicotine or its metabolites in blood or urine. A fair correlation vas observed in some studies (Goldfarb et al. 1976; Herning et al. 9831, but most studies have revealed a poor correlation (Russell et -1. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983). Jachinedetermined nicotine yield accounts for only from 4 (Russell t al. 1980) to 25 percent (Herning et al. 1983) of the variation in lood nicotine concentration, whereas 50 to 60 percent of the ifferences in blood nicotine levels are attributable to individual smoking behavior. The overriding importance of the pattern of smoking in determining nicotine delivery from a cigarette was underlined in a recent study demonstrating that the nicotine content of the unburned tobacco was similar for cigarettes with high and low nicotine yields determined by smoking-machine assays (Benowitz et al. 1983). The concept of providing the smoker with information on cigarette yield need not be abandoned. Smoking-machines can be designed to control the puff number, puff volume, puff pressure profile, puff duration, puff interval, butt length, position of the cigarette during and between puffs, and "restricted" or "free" smoking, i.e., whether the butt end is closed or open Kreighton and Lewis (1978a, b). These parameters should be determined and used to obtain an average and a range of yields for each brand. Measurement of cigarette yield should include assays not only of tar and nicotine but also of carbon monoxide and other toxic substances, because compensatory smok- ing behavior may alter the exposure to each substance beyond that expected on the basis of tar and nicotine delivery. Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Cigarette smokers account for the vast majority of deaths from chronic obstructive lung disease (COLD) (Peto et al. 1983), and the relative risk for the effects of smoking on mortality from COLD is even greater than that for lung cancer (see the chapter on Mortality in this Report). Chronic obstructive lung disease in smokers may take the following three forms: (1) cough and mucus hypersecretion, (2) airway obstruction, and (3) emphysema. Frequently the three components coexist, as all are related to cigarette smoking, but the agents in cigarette smoke responsible for each type of lung injury may be different. Over the past 25 years, considerable progress has been made in our understanding of the role of cigarette smoking in the pathogenesis and natural history of COLD, but most of the available data have not related lung function to cigarette yield. Epidemiologic Studies The cardinal importance of cigarette smoking in the pathogenesis of COLD has been repeatedly documented, and generally the severity of disease increases with increasing cigarette consumption (Ferris et al. 1976). Because of this dose-response relationship, it has been hoped that a reduction in cigarette yield by filtration or other means would reduce the risk of disease (Gori 1976). Available epidemiologic studies of the effect of low yield cigarettes on the development of COLD have shown variable results, which reflects 336 marked differences between the studies in terms of the population studied, sample size, variation in cigarette brands, reference period of the study, criteria of respiratory involvement, and type of statistical analysis, and whether the study was of a cross-sectional or a longitudinal design. Separating the studies by the three compo- nents of smoking-induced COLD indicates that there is a growing body of data on the effect of cigarette yield on the development of mucus hypersecretion and airway obstruction, but currently no information on the development of emphysema. Several studies have examined the effect of cigarette yield on respiratory symptoms and have observed a relationship between reduction in cigarette yield and the prevalence of cough (Comstock et al. 1970: Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et al. 1978; Schenker et al. 1982) and phlegm production (Comstock et al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et al. 1980b). Tar yield was not defined in some of these earlier studies (Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne and Fry 19781, but instead a comparison was made between smokers of plain cigarettes and smokers of filter-tipped cigarettes. The tar yield was specified in some studies: in the recent study by Schenker et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman and Fletcher (19761, from 17 to 20 mg; and in the studies by Higenbottam et al. (1980b1, from 18 to more than 33 mg, higher than that observed in many of today's cigarettes. In a cross-sectional survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial effect of low tar cigarettes on phlegm production was lost when subjects smoked 20 or more cigarettes per day, as their prevalence of phlegm production increased to that observed in higher tar cigarette smokers. In contrast, in another cross-sectional study of 5,686 women (Schenker et al. 19821, cigarette tar content was a significant risk factor for chronic cough and of borderline significance for phlegm production; this effect of cigarette tar content was indepen- dent of the number of cigarettes smoked per day. Chronic cough or phlegm production was approximately twice as common in smokers of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10 mg) smokers. In the latter study, however, multiple logistic regres- sion analysis indicated that the risk of chronic cough and phlegm production is more strongly affected by daily cigarette consumption than by tar content: these symptoms were 4.5 times more common in smokers of 25 or more cigarettes per day than in smokers of less than 15 cigarettes per day. A small number of studies have examined the importance of cigarette yield on change in pulmonary function. In a prospective study of 680 men, Comstock et al. (1970) noted that smokers of plain cigarettes, compared with smokers of filter-tipped cigarettes, had a lower FEV, at entry into the study. Followup measurements showed 337 I a23 24-27 2E32 .33 Tar per cigarette Prv$ FIGURE 2.-Relationship between mean FEVI of asymptomatic smokers (adjusted for height and weight) and tar yield of cigarettes, by number of cigarettes smoked per day SOURCE: Hlgenbottam et al rlS&Wbi. a greater mean reduction of FEVl in users of filter-tips, so that the reduction was similar in the two groups after 5 to 6 years of followup. Unfortunately, the variance of the data was not stated, and tests of statistical significance were not performed. In another longitudinal survey of 1,355 men, Sparrow et al. (1983) determined the effect of cigarette tar content, which ranged from less than 16 mg to more than 22 mg, on pulmonary function. Multiple regression analysis indicated that tar content did not significantly influence baseline spirometry or repeat measurements after 5 years of followup. Cross- sectional epidemiologic surveys also indicate no relationship be- tween abnormal pulmonary function and the use of filter-tipped versus plain cigarettes (Beck et al. 1981) or cigarette tar content (Higenbottam et al. 1980b) (Figure 2). Interpretation of these studies as evidence that cigarette tar and nicotine yield is not an important factor in the development of COLD is premature. First, cross-sectional studies are limited in their capability of defining the natural history of a disease. Second, COLD has a very slow progress, and Fletcher et al. (19761 suggest that a span of approximately 8 years is necessary to establish rates of change of spirometric values with sufficient confidence even to distinguish between smokers and nonsmokers. Third, we have no information on the baseline pulmonary function of smokers at the time they choose between high or low tar and nicotine cigarettes. Significant differences in pulmonary function have been observed between young adults who decide to smoke and those who avoid cigarette smoking (Tashkin et al. 19831, and it is possible that similar 338 function differences may exist in subjects who choose between high or low tar and nicotine cigarettes. Fourth, the yield of tar and nicotine used in many of these studies does not lie in the same range as that produced by many of today's cigarettes. However, the possibility that cigarette tar content is related to the development of cough and phlegm, but not of dyspnea or airflow obstruction, is consistent with current concepts of COLD. In a study of 792 men followed over an g-year period, Fletcher et al. (1976) observed that cigarette smokers were susceptible to two distinct chronic lung diseases-mucus hypersecretion and chronic airflow obstruction. This has recently been confirmed in a large prospective study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years, which showed that the risk of death from COLD was strongly correlated with initial degree of airflow obstruction, but bore no relationship to initial mucus hypersecretion. Given the evidence that mucus hypersecretion may depend on the tar fraction of cigarette smoke, while development of airflow obstruction is more closely linked to the ilumber of cigarettes smoked, Higenbottam et al. (1980b) reasoned that these differences might be due to a reduction in the particulate phase products, without a decrease in the gas phase products, in the low tar cigarettes. They hypothesized that tar droplets and soluble gases, such as sulfur dioxide and hydrogen cyanide, are more likely to be deposited or absorbed in the large airways where mucus is produced. The smaller airways, the earliest site of airflow obstruction, are exposed to a lower concentration of tar, but to a full concentration of insoluble gases such as nitrogen dioxide and ozone. This line of reasoning is in agreement with several studies showing a reduction in lung cancer with the use of low tar and nicotine cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington 1981; Hammond et al. 1976). The tar fraction is the component of cigarette smoke particularly linked with the development of both lung cancer and mucus hypersecretion. Although clinicians have long linked chronic bronchitis (mucus hypersecretion) with emphyse- ma, recent evidence indicates that mucus hypersecretion is not predictive of airflow obstruction, but is significantly greater in those smokers who develop lung cancer (Pete et al. 1983). Mechanisms of Lung Damage Studies of the mechanism of cigarette-smoke-induced lung damage have contributed significantly to the present understanding of COLD. Cigarette smoke may initiate and aggavate lung injury by a number of mechanisms and may also interfere with the lungs' defense responses. These mechanisms include the prot.ease-ir$$bit,or imbalance theo- ry for the pathogenesis of emphysema whereby alveolar wall 339 digestion results from an excess of proteases, a deficiency of their inhibitors, or a combination of both factors (see the chapter on Mechanisms in this Report). The sources of endogenous proteases include polymorphonuclear neutrophils and alveolar macrophages, both of which are found in increased number in the lungs of cigarette smokers. Protease release from both macrophages and neutrophils is increased in the presence of cigarette smoke (Rodriquez et al. 1977; Blue and Janoff 1978). In health, proteases are continually inhibited by al-antitrypsin, whereas proteases cause unimpeded digestion of lung tissue in patients with al-antitrypsin deficiency, with a markedly increased risk of emphysema. In addition to increasing the protease burden, cigarette smoke causes a functional inhibition of al- antitrypsin through the action of oxidants in cigarette smoke (Janoff et al. 19791. The relative potency of smoke from cigarettes of varying tar and nicotine yields in stimulating protease production and release and in inhibiting al-antitrypsin has received scant scientific investigation. Travis et al. (1980) tested the effect of both filtered and unfiltered cigarette smoke on the elastase inhibitory activity of al-antitrypsin. Filtered smoke reduced elastase inhibitory activity by 3 percent, and a 19 percent reduction was observed with unfiltered smoke; the tar content of the respective smokes was not stated. The researchers reasoned that this small in vitro effect would be greatly magnified by in vivo conditions in the lung, particularly through its huge surface area. In addition to examining the effect of filters, Cohen and James (1982) recently examined the effect of tar and nicotine content on the elastase inhibitory capacity of al-antitrypsin. The oxidant capacity of cigarette smoke was also examined using a chromogenic electron donor. Aqueous condensates of cigarette smoke were obtained from a variety of brands ranging in tar content from about 1 mg to more than 20 mg. Reported tar and nicotine content correlated well with the amount of measured oxidants and the ability of a brand to reduce the elastase inhibitory capacity of al-antitrypsin. Filters were found to remove 73 percent of the oxidants from the aqueous smoke solutions. While these findings suggest that low tar and nicotine or filter-tipped cigarettes could reduce a smoker's predisposition to enzymatic lung damage and consequent COLD, it should be noted that neither study examined the effect of lower yield cigarettes on protease production. Morosco and Gueringer (1979) demonstrated a greater increase in elastase in dogs exposed to high nicotine cigarette smoke compared with low nicotine cigarette smoke. More important, these studies have not taken into account the compensatory changes in smoking pattern likely to result with lower yield cigarettes. The airway response to acute exposure to cigarette smoke has been examined by several investigators employing spirometry (Da Silva and Hamosh 19811, body plethysmograph (Nadel and Comroe 1961j.I 340 and breathing pattern analysis (Tobin et al. 1982a). Airway narrow- ing has been consistently observed by some investigators (Nadel and Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a variable response (Higenbottam et al. 1980a; Rees et al. 1982). In some studies, the acute airway response was unrelated to cigarette yield (Higenbottam et al. 1980a), but in most investigations (Robert- son et al. 1969; Tobin et al. 1982a; Rees et al. 1982), smoking a low tar or filter-tipped cigarette induced less acute bronchoconstriction. The acute airway response is probably localized to the larger airways, as acute cigarette exposure resulted in no change in the nitrogen washout test of small airway function (Da Silva and Hamosh 1973; Tobin et al. 1982al. These observations on the relative bronchocon- strictor response of various types of cigarettes may be important in our understanding of why some smoking novitiates persist with the habit despite the initial unpleasant reactions (Tashkin et al. 1983), but it is unlikely that repeated episodes of smoking-induced acute airway narrowing finally result in COLD. Future studies examining the mechanism of smoking-induced lung injury must not only take into account the range of cigarette yields, as determined by a smoking-machine, but also consider variations in smoking behavior. Puff volumes may vary considerably with nomin- al cigarette tar and nicotine content, thus altering the relative amount of various toxic substances yielded by different cigarettes. Similarly, inhalation profiles are of a diverse nature (Tobin et al. 1982b) and are likely to significantly alter the distribution, penetra- tion, and retention of cigarette smoke constituents in the lungs. Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Low tar and nicotine cigarettes have gained considerable populari- ty among the smoking public, partly on the premise that a reduction in the nominal tar and nicotine yield results in a proportional reduction in the health hazards of cigarette smoking. The validity of this approach to cigarette smoking is contingent on the accuracy of smoking-machines in reflecting the actual manner of puffing and also on the smoker not altering smoking behavior to compensate for variations in nominal tar and nicotine content. Should smokers develop compensatory alterations in their smoking behavior, this would not only reduce the relevance of the smoking-machine assays but might also alter the proportionate delivery of the different toxic substances in cigarette smoke and expose the smoker to concentra- tions beyond those predicted by the smoking-machine. 341 Smoking Behavior Nearly 40 years ago, Finnegan et al. (1945) studied the effect of alterations in cigarette nicotine content on smoking behavior and noted no change in cigarette consumption. It is only in the last decade, with the increasing popularity of low tar and nicotine cigarettes, however, that this question has attracted signEcant interest. The results of 38 studies examining alterations in smoking behavior with a reduction in cigarette yield are shown in Table 1. Considerable differences can be observed between the studies, partly reflecting variations in the level of cigarette yield reduction, alterations in other cigarette constituents, type and duration of switching procedure, parameters evaluated, and techniques used in their measurement. Most studies agree that smokers rarely increase their daily cigarette consumption upon switching from higher to lower yield brands. Reports are almost equally divided as to whether a smoker increases the number of puffs per cigarette or shows no change on switching to a lower yielding brand. There is an almost unanimous consensus that smokers take a larger puff volume from a lower yielding brand. Studies of puff volume also indicate huge variation between individual subjects (Guillerm and Radziszewski 1978; Hern- ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and that considerable increases in puff volume may occur on switching from a higher to a lower yielding brand, with certain subjects increasing their puff volume by up to 75 percent (Tobin and Sackner 19821. This compensatory increase in puff volume may be observed within a single experimental session (Tobin and Sackner 1982) and maintained over several weeks Rawbone et al. 1978; Stepney 1981). Full compensation for a lower yielding cigarette is generally not achieved by smokers taking a large puff volume (Rawbone et al. 1978; Herning et al. 1981; Tobin and Sackner 1982). Instrumentation is required to quantitatively assess the pattern of smoking, but it is important to realize that such instrumentation may, in itself, alter usual smoking behavior. Puff volume has been almost universally measured by using a specialized cigarette holder incorporating different flowmeter designs (Frith 1971; Adams 1977; Rawbone et al. 1978). These devices consist of two tubes connected to a pressure transducer that measures the pressure drop across a small resistance (a filter insert) in the holder; the flow measured is integrated to obtain volume. Use of a cigarette holder has been shown to increase the rate of puffing and puff volume, compared with measurements made with the cheek inductive plethysmogra- phy coil (Tobin and Sackner 1982). Unlike the compensatory increases in puff volume, measurements of the subsequent inhalation volume-which includes the volume of smoke mixed with air inhaled into the lung-have shown no change 342 TABLE l.-Effect of smoking low yield cigarettes on smoking pattern (`0 paramrters Nlcotme parameters ~____ Number Number Volume Durat Km Relationship Nlcotinr'rotlninr Mouth Relationship Reference Expenmental of cigs of Puff of of Expwd to level CCpOS"W LO First author year de@ smoked puffs/cig volume mhalatmn mhalatlon C'OHb (`0 nominal yield tblood!ur~ne/salw;i) Index normal yield F1llIIegaIl I945 Ashton 1970 Fnth 1971 (bhen 1971 Rwssell 1973 Turner 1974 Russell 1975 Coldfarb 1976 FO&8 I976 Adams 1977 Wald 1977 Sutton I978 R&s&one 1976 Schulz 197X (`wghtnn 1978a.b Adams 1978 (;udlerm 1978 clamk 1978 Ashton 1979 tiarfinkrl 1979 HI11 19fUl RobInson I980 Russell 1980 Hrnnmgtield 1980 Wald 19&I cl3 NC VCF CS CS cs t CS cs I CS f CS cs NC svs VCF NC C'S CS NC s CS cs CS CS NC svs NC cs svs svs VCF NC svs NC 1 /1N( NC NC I NC i N( t t 1 NC NC t t NC PcKJr (hod PO0 I 1 POW E TABLE I.-Continued Dr- CO paramrten Nicotme parameters NUdW NUdW Volume rhmitml Belatlonshlp Nwtmeicotinme Mouth Belatlonship Reference Experimental of CITY of Puff of of EXPlWd to level exposure t4, Fwst author year design smoked puffs/cig volume lnhaletwn lnhalatlon COHb (`0 nominal yleld ibloodod/urme/saliva~ Index normal yield Hernmg 1981 cs NC' I t Wtlld 19R1 svs NC I Poor Stepney 1981 cs NC t f I Fair I I Jaffe 1981 svs NC/ 1 NC PCXJr Tobin 1982 cs NC I NC NC Battig 1982 svs NC t NC Sutton 1982 svs t coed Poor Griffith8 1981 CS NC t Jaffe 1982 cs NC/ 1 NC Poor Feyrrabend 1982 svs Poor HtTWlg 1983 cs FHIT Benowitz 19n3 svs NOTE Cs controlled swtchmg. VCF - var,able c,garette filters. SVS a~wntaneo~rs voluntary wltchw. NC = no change. T - mcreaee. ; = dexeaee. CO - ctlrbon monvx,dr on switching to a low yield cigarette. Likewise, in one short-term study (Tobin and Sackner 1982), duration of inhalation showed no relationship to nominal cigarette yield. Perhaps compensatory changes in inhalation parameters require a longer period of time than puff volume does. Measurement of carboxyhemoglobin (COHb) concentration has been proposed as an index of the pattern of inhalation (Wald et al. 1975, 1978). While COHb provides valuable information on the amount of carbon monoxide absorbed from the lung during compen- satory alterations in smoking behavior, it is an indirect index and provides complementary information on cigarette smoke inhalation rather than replacing direct measurements of the volume of inhalation. Carbon Monoxide Uptake Unlike tar and nicotine, which are present in the particulate phase, carbon monoxide (CO) is a constituent of the vapor phase of cigarette smoke. For this reason, cigarettes purported to produce a low tar and nicotine yield may not necessarily provide a lower yield of carbon monoxide. Compared with tar and nicotine yield, carbon monoxide yield is more dependent on cigarette design, including such features as paper porosity and perforations in the filter tips. These factors regulate the dilution of smoke with air and the burning profile of the cigarette, and thus can significantly reduce carbon monoxide yield. Wald (1976) showed that the carbon monox- ide yield of filter-tipped cigarettes was 28 percent higher than that of plain cigarettes, although the average nicotine yield was lower in the filter-tipped cigarettes. He reasoned that smoke passing through a cigarette is diluted by air entering through the porous cigarette paper. However, the filter of filter-tipped cigarettes is surrounded by relatively nonporous paper, resulting in a higher content of carbon monoxide exiting from the proximal cigarette end. Perforations in the filter tip circumvent this problem and significantly reduce carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973). Many investigators have measured COHb or carbon monoxide concentration in expired gas following cigarette smoking and compared the levels achieved in smoking brands with different nominal yields (see Table 1). An increase, decrease, or no change in carbon monoxide intake has been observed, depending on relative differences in cigarette design and experimental procedure. As expected, unventilated filter-tipped cigarettes produced higher COHb levels than those observed with unfiltered cigarettes (Wald et al. 1977). This is in agreement with information provided by smoking-machine assays (Wald et al. 19731, but the use of ventilated filter-tipped cigarettes may produce COHb levels similar to those observed with unfiltered cigarettes despite lower carbon monoxide 345 yields on smoking-machine assay (Wald et al. 1977). Comparison of cigarettes with a marked difference in nominal carbon monoxide yield usually results in a lower COHb level when the lower yielding brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton et al. 1978; Ashton et al. 1979); but over the range of different carbon monoxide yields there is a poor correlation between levels of COHb and measured carbon monoxide yield. Similar information has been observed using expired carbon monoxide concentrations. Nicotine Uptake It has been long considered that nicotine might serve as a primary reinforcer of cigarette smoking and that smokers might adjust their smoking behavior to regulate their level of nicotine intake. Several investigators have measured the blood, urinary, or salivary levels of nicotine or its major metabolite cotinine during the smoking of cigarettes of varying nominal nicotine yields (see Table 1). A reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976; Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al. 1979; Hill and Marquardt 1980) cotinine levels has generally been observed on switching to a cigarette with a lower nominal nicotine yield. However, smokers show variable degrees of compensation for the lower yield, as there is generally a poor relationship between nominal nicotine yield and measured blood nicotine levels (Russell et al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). Relating nominal nicotine yield and blood nicotine levels, Ashton et al. (1979) estimated that smokers compensated for about two- thirds of the difference in nominal yields when they switched from medium nicotine cigarettes to high or low nicotine brands. Using a stepwise multiple regression analysis of nicotine yield and blood nicotine concentration, Russell et al. (1980) observed a significant, but very weak, correlation (r = 0.21) between the two measurements, but the nominal nicotine yield of the cigarettes accounted for only 4.4 percent of the variability in blood nicotine concentrations. The use of absolute rather than logarithmic analysis in this study has been criticized (Kozlowski et al. 1982; Herning et al. 19831, and the criticism involved the problems of trying to predict doses to individuals rather than the dose to groups. In another study using log-linear regression analysis (Herning et al. 19831, a better correla- tion was observed between nominal nicotine yield and the increasing blood nicotine after smoking (r=0.5), but this study used Kentucky reference cigarettes rather than commercial brands, and these low yield cigarettes have less nicotine in the unburned tobacco than commercial low yield brands. Such a relationship still accounted for 346 only 25 percent of the individual differences in blood nicotine levels, whereas 50 to 60 percent was accounted for by individual differences in smoking behavior (Herning et al. 1983). Additional information on compensatory alterations in nicotine intake has been provided by studying the mouth exposure index, which is calculated from analysis of cigarette butts for nicotine content and a knowledge of the retention efficiency of the filter tip (Ashton and Watson 1970). Because the amount of nicotine retained by a filter is proportional to the amount that passes through, it is possible to estimate the amount of nicotine presented to the smoker from the nicotine content of the filter. Results using this index have revealed a greater variation between individual studies (see Table 1) than obsewed with blood nicotine measurements. This may be related to the fact that filter efficiency is usually determined by a machine, but retention of nicotine is also dependent on the way the cigarette is smoked; therefore, the retention efficiency of the filter may vary between smokers. Role of Tar Content The observations that smokers adapt their smoking behavior according to the nicotine delivery of a cigarette and that many of the toxic effects of smoking appear to be related to tar rather than nicotine content has led to the suggestion that altering the tar to nicotine ratio might produce a cigarette less hazardous to health (Russell 1976; Stepney 1981). A cigarette with a medium nicotine, low tar, and low carbon monoxide yield might be advantageous. While nicotine has been the component most extensively studied, it may not be the only substance responsible for the addictive power of tobacco. It is not possible to separate the effects of tar and nicotine in most studies, as their respective yields usually show a very close correlation. Using research cigarettes providing three different yields of nicotine and two different yields of tar, Goldfarb et al. (1976) found evidence of compensation for nicotine but not for tar content. The authors urged cautious interpretation of the results because of the limited range of tar yields examined. Examining a large number of subjects smoking cigarettes of varying tar and nicotine yield, Wald et al. (1981) found that both tar and nicotine were significantly related to blood COHb, taken as an index of cigarette smoke inhalation. Two- way analysis of variance of the data indicated that after allowing for the effect of either tar or nicotine yield, the COHb index was no longer significantly influenced by the other. A cross-over study of medium tar smokers who were switched to low nicotine, low tar cigarettes and medium nicotine, low tar cigarettes has been reported by Stepney (1981). While the intake of carbon monoxide was least with the medium nicotine, low tar cigarette, the mouth exposure 347 index to tar was similar among the brands. Indeed, the pattern of smoking adopted by the subjects was more effective in reducing the difference in tar delivery between the cigarettes than in compensat- ing for nicotine delivery. Further evidence indicating the importance of cigarette tar delivery in-determining smoking behavior was reported by Sutton et al. (1982). Using multiple regression analysis, they observed that when nicotine yield was controlled, smokers of lower tar cigarettes had higher blood nicotine levels than smokers of higher tar cigarettes, indicating that they inhaled a greater volume of smoke. In contrast, when tar yield was controlled, smokers of lower nicotine cigarettes had lower blood nicotine concentrations than smokers of higher nicotine cigarettes, indicating that they inhaled less smoke. These results suggest some compensation for tar over and above any compensation for nicotine. It may be that ncnpharmacologic, sensory stimulation by factors such as the flavor of cigarette smoke may be more important than nicotine in determining smoking behavior. These new observations, especially on the role of tar delivery, require further investigation. Most published research consists of controlled switching experiments in which the subject smokes cigarettes of varying yields (see Table 1). Further studies of smoking behavior in sutjects who have voluntarily chosen cigarettes of different yields are needed. The absence of an acceptable, palatable "standard" research cigarette continues to be an impediment to research in this area. Variations in Pattern of Cigarette Smoke Inhalation While cigarette smoking is the single most important factor in the development of COLD, the majority of smokers never develop clinically significant airflow obstruction (Fletcher et al. 1976). Despite the clear dose-response relationship between number of cigarettes smoked and death from COLD, attempts at identifying the indi-Jidual susceptible smoker on the basis of number of cigarettes smoked have had very limited success. Another approach to identifying the susceptible smoker is to study the manner of smoking, as this is probably a major determinant of the lung's exposure to cigarette smoke. Cigarette smoking consists of two phases: initially, the smoker takes a puff into the mouth, and after a variable 1 to 4 second pause, the smoke mixed with air is inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al. 1980a; Tobin and Sackner 1982). Individual differences in the pattern of cigarette smoking such as the size of the puff volume, the duration of holding the smoke in the oral cavity before inhalation, and the depth and duration of inhalation are among the important factors determining the relative concentration of smoke constituents 348 that reach the lung. Despite its significance in determining the distribution and deposition of cigarette smoke, the mode of inhala- tion following the puff has received scant scientific investigation. A number of epidemiologic studies have examined the relationship between cigarette smoke inhalation, based on the smoker's subjec- tive estimation, and the severity of pulmonary disease. Results of these studies are conflicting; some investigators repcrted an associa- tion between smoke inhalation and the presence of mucus hyperse- cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and decline in pulmonary function (Ferris et al. 1976; Bosse et al. 19?5), and others observed no relationship between inhalation and pulmo- nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The inconsistencies in these epidemiologic studies may be due to the smokers' inability to accurately describe their inhalation pattern. There are three reports of the relationship between subjective estimations of cigarette smoke inhalation and direct objective measurement. Rawbone et al. (1978) found that the rating on a visual analog scale was a good predictor of inhalation volume (r=0.65). Conversely, Tobin et al. (1982a) noted no relationship between inhalation volume and the smoker's perception of depth of inhalation, indicated on a visual analog scale (i-=0.04); a similar finding was reported by Adams et al. (1983) (i-=0.04). Standardizing the inhaled volume for vital capacity did not improve the relation- ship. Other investigators using measurements of COHb observed a weak relationship between self-estimated inhalation and COHb concentration (Stepney 1982; Wald et al. 1978). Measurements of COHb reflect the amount of cigarette smoke absorbed by the long. In addition to being affected by the depth of inhalation, COHb concentration is influenced by the varying carbon monoxide yields of different cigarettes, the number of puffs per cigarette, puff volume, pulmonary function-particularly diffusing capacity and alveolar ventilation-and hemoglobin concentration (Wald et al. 1978; Ric- kert et al. 1980). Therefore, it yields valuable complementary information, but it does not provide a direct measure of the pattern of inhalation (Tobin et al. 1982a; Guyatt et al. 1983). Direct measurements of the pattern of cigarette smo!ce inhalation have been reported for a small number of smokers. Initially, the puff from the cigarette is taken into the molrth, and after a variable pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et. al. 1978; Higenbottam et al. 1980a; Tobin and Sackner 1982; Tobin et al. 1982a; Adams et al. 1983). Higenbot,tam et a1,(1980a) reasoned that this pause, while holding the smoke in the mouth, minimized the irritant qualities of cigarette smoke. In a group of five subjects who were requested to inhale smoke directly into%eii lungs, withoslt an intervening pause in the mouth, consistent acute airway narrowing was observed. In contrast, smokers adopting the usual two-phase 349 smoking pattern showed a variable airway response. The authors suggested that buccal absorption of water-soluble compounds, such as sulfur dioxide and acrolein, together with precipitation of tar, minimized the irritating qualities of cigarette smoke. They observed no relationship between the acute airway response and amount of smoke inhaled in the regular two-phase smokers, although there appeared to be a relationship in those directly inhaling smoke into their lungs. However, there is a marked discrepancy in the inhala- tion volumes reported in this study compared with the values reported in other studies of cigarette smoke inhalation, probably due to the inaccuracy of the magnetometers employed for the measure- ments; therefore, a statement regarding the relationship between depth of smoke inhalation and the acute airway response may be misleading. The report that acute airway narrowing is uncommon after cigarette smoking is in disagreement with the findings of several investigators who have observed bronchoconstriction to be a common phenomenon after acute smoke exposure (Nadel and Comroe 1961; Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a); however, it is certainly plausible that the response is greater in smokers who inhale smoke directly into the lungs than in two-phase smokers. The frequency of direct inhalation of cigarette smoke into the lungs is unknown. In a small study of 10 smokers, Tobin and Sackner (1982) observed 1 subject who showed an approximately 50 ml expansion of the abdominal compartment simultaneously with taking the puff from the cigarette. Adams et al. (1983) studied the relationship between puffing, cigarette smoke inhalation, and partitioning of airflow between the nose and mouth in 10 smokers. After taking the puff into the mouth, two subjects actively exhaled 80 ml and 200 ml volumes, respective- ly, before the subsequent inhalation. In this situation, the volumes of smoke might be expelled from the mouth, and little, if any, would be available for subsequent inhalation into the lungs. The frequency of this smoking pattern was not given, but another report from the same laboratory (Rawbone et al. 1978) indicated that it was uncommon. There was marked intersubject variation in the parti- tioning of airflow between the nose and mouth during smoking, with four subjects inhaling almost exclusively through the mouth, four inhaling predominantly through the nose, and the other two demonstrating both patterns of inhalation. The importance of factors in determining whether cigarette smoke is inhaled as a bolus followed by a subsequent "chaser" of air or is evenly distributed throughout the inhaled volume of air remains to be determined. Considerable discrepancies exist between published reports of the volume of air mixed with smoke that is inhaled into the lungs, with reported mean inhalation volumes of 34 to 152 ml (Higenbottam et 350 3c 1 Sum 1, I1 1 I III1 1 I 10 20 30 40 5c 60 FIGURE 3.-Pattern of inhalation of cigarette smoke mixed with air, in two smokers SOURCE Modified from Tobm et al c 1982b! al. 1980a), 450 to 485 ml (Guillerm and Radziszewski 1978), 389 to 1,136 ml (Adams et al. 1983), 750 to 2,000 ml (Rawbone et al. 1978), and 170 to 1,970 ml (Tobin et al. 1982b). A major factor in the discrepancies between these studies is probably the inaccuracies inherent in some of the methods employed in the measurements, as discussed by Tobin and Sackner (1982). When inhalation volumes are standardized for body size by relating them to vital capacity, marked interindividual variation is still observed (Figure 3), with inhalation- al volumes ranging from 9 to 47 percent of the vital capacity and a group mean value of 20 percent (Tobin et al. 1982b). Smokers show considerable variation in inhaled volumes while smoking a single cigarette. The volume of inhalation bears no relationship to cigarette consumption in terms of pack-years (Tobin et al. 1982b). Similarly, duration of inhalation shows considerable variation between sub- jects, with mean individual values ranging from 1.7 to 7.3 seconds (Adams et al. 1983; Tobin et al. 1982b). Repeat measurements at intervals of up to 10 months apart indicate that individual subjects tend to maintain a fairly constant inhalation volume, duration of inhalation, and associated breathhold time (Tobin et al. 1982b; Adams et al. 1983). The pattern of cigarette smoking shows a wide degree of intersub- ject variability, including differences in the number of puffs, puff volume, holding pause in the mouth, exhalation of smoke from the mouth before inhalation, partitioning of airflow between the nose and mouth, and volume and duration of inhalation. Given this degree of variation, it is not surprising that smokers might show wide differences in their individual susceptibilities to lung injury. In a study relating inhalation volume-standardized for vital capaci- ty-to the time-volume and flow-volume components of a forced vital capacity maneuver, no significant correlation was observed (Tobin et al. 1982b). Although this lack of a relationship might be interpreted as indicating that the pattern of smoking is unimportant in the development of lung disease, it may also reflect the fact that pulmonary function was normal or near normal in the majority of subjects and that the study was of a cross-sectional design. Use of Additives in Low Tar and Nicotine Cigarettes The nominal tar and nicotine yield of cigarettes has continually decreased since the time of the initial reports linking smoking with lung cancer (USDHHS 1981). In 1954, the average tar yield per cigarette was 38 mg, and in 1980 it was less than 14 mg. Initially, tar reduction was achieved by decreasing the cigarette tobacco content or removing tar by smoke filtration, both of which probably resulted in a lower smoke exposure. Since 1971, the reduction in tar yield has exceeded the relative reduction in the weight of tobacco per cigarette; this difference has increased since 1975 (USDHHS 1981). Manufacturing technology has progressed beyond simple reduction in tobacco content: the yield and composition of smoke can be modified by genetic modification of the tobacco leaf (Tso 1972a), changes in its cultivation and processing (Tso 1972133, changes in the porosity of cigarette paper, and alterations in filter design (Kozlow- ski et al. 1980b). When initially introduced, lower yield cigarettes lacked palatabili- ty and acceptability. Advertisements for the current low tar and nicotine cigarettes emphasize their flavor, presumably achieved by the use of additives in the processing of the tobacco. Additives employed may include artificial tobacco substitutes (Freedman and Fletcher 1976), flavor extracts of tobacco and other plants, exogenous enzymes, powdered cocoa (Gori 19771, and other synthetic flavoring substances. Perhaps more additives are being used in the new lower tar and nicotine cigarettes than in the older brands, and new agents may also be in use. Some of the substances, such as powdered cocoa, have been shown to further increase the carcinogenicity of tar (Gori 19771, and others may result in increased or new and different health risks. The pyrolytic products of these additive agents may produce novel toxic constituents. A characterization of the chemical composition and adverse biologic potential of these additives is urgently required, but is currently impossible because cigarette companies are not required to reveal what additives they employ in the manufacture of tobacco (USDHHS 1981). No government agency is empowered with supervisory authority in the manufacture of tobacco products. With this lack of basic information and the usually prolonged latent period before manifestation of the adverse effects of smoking, it is likely that a long time period will elapse before we know the hazards of the new cigarettes in current use. Research Recommendations 1. Longitudinal epidemiologic studies are needed to determine the risk for pulmonary symptoms and dysfunction in smokers of cigarettes with the low tar and nicotine yields found in currently popular brands. 2. Further research is needed to determine the relative potency of high and low tar and nicotine cigarettes in inducing elastase release and producing functional inhibition of al-antitrypsin activity. 3. Development of an animal model of cigarette-smoke-induced emphysema would be advantageous in determining the relative risk of lung injury of cigarettes of different composition. 4. More information is required on the smoking behavior of smokers who have voluntarily switched from high to low tar and nicotine cigarettes. 5. The role of cigarette tar, as opposed to nicotine content, in determining smoking behavior needs to be defined. 6. Standard research cigarettes of varying tar and nicotine contents that are palatable and acceptable to smokers need to be developed. 7. The role of variation in smoking behavior in determining susceptibility to lung injury needs to be defined. Studies are required to determine the effect of smoking patterns on the distribution and penetration of the smoke aerosol into the lung. 8. More information is needed on the composition and adverse biologic effects of flavor additives in cigarettes and their pyrolytic products. Summary and Conclusions 1. The recommendation for those who cannot quit to switch to smoking cigarette brands with low tar and nicotine yields, as determined by a smoking-machine, is based on the assumption that this switch will result in a reduction in the exposure of the 353 lung to these toxic substances. The design of the cigarette has markedly changed in recent years, and this may have resulted in machine-measured tar and nicotine yields that do not reflect the real dose to the smoker. 2. Smoking-machines that take into account compensatory changes in smoking behavior are needed. The assays could provide both an average and a range of tar and nicotine yields produced by different individual patterns of smoking. 3. Although a reduction in cigarette tar content appears to reduce the risk of cough and mucus hypersecretion, the risk of shortness of breath and airflow obstruction may not be reduced. Evidence is unavailable on the relative risks of developing COLD consequent to smoking cigarettes with the very low tar and nicotine yields of current and recently marketed brands. 4. Smokers who switch from higher to lower yield cigarettes show compensatory changes in smoking behavior: the number of puffs per cigarette is variably increased and puff volume is almost universally increased, although the number of ciga- rettes smoked per day and inhalation volume are generally unchanged. Full compensation of dose for cigarettes with lower yields is generally not achieved. 5. Nicotine has long been regarded as the primary reinforcer of cigarette smoking, but tar content may also be important in determining smoking behavior. 6. Depth and duration of inhalation are among the most impor- tant factors in determining the relative concentration of smoke constituents that reach the lung. Considerable interindividual variation exists between smokers with respect to the volume and duration of inhalation. This variation is likely to be an important factor in determining the varying susceptibility of smokers to the development of lung disease. 7. Production of low tar and nicotine cigarettes has progressed beyond simple reduction in tobacco content. Additives such as artificial tobacco substitutes and flavoring extracts have been used. The identity, chemical composition, and adverse biologi- cal potential of these additives are unknown at present. 354 References ADAMS, L., LEE, C., RAWBONE, R.. GUZ. A. 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PASSIVE SMOKING 361 480-244 0 - 85 - 13 CONTENTS Introduction Differences in Composition of Sidestream Smoke and Mainstream Smoke Measurement of Exposure Acute Physiologic Response of the Airway to Smoke in the Environment Symptomatic Responses to Chronic Passive Cigarette Smoke Exposure in Healthy Subjects Respiratory Infections in Children of Smoking Parents Pulmonary Function in Children of Smoking Parents Pulmonary Function in Adults Exposed to Involuntary Cigarette Smoke The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD Summary and Conclusions References 363 Introduction This chapter explores recent data that relate involuntary cigarette smoke exposure to the occurrence of physiologic changes, symptoms, and diseases in nonsmoking adults and children. Health effects related to fetal exposure in utero, a subject that has been extensively studied, are not discussed, although instances where such exposure may relate to potential development are pointed out. The interested reader is referred to several excellent recent reviews for a more complete treatment of this issue KJSDHEW 1979; USDHHS 1980; Abel 1980; Weinberger and Weiss 1981). Differences in Composition of Sidestream Smoke and Mainstream Smoke Involuntary (passive) smoking is defined as the exposure of nonsmokers to tobacco combustion products from the smoking of others. Analysis of the health effects of passive smoking requires not only some knowledge of the constituents of tobacco smoke, but also some quantitation of tobacco smoke exposure. Tobacco smoke in the environment is derived from two sources: mainstream smoke and sidestream smoke. Mainstream smoke emerges into the environment after having first been drawn through the cigarette, which filters some of the active constituents. The smoke is then filtered by the smoker's own lungs, and exhaled. Sidestream smoke arises from the burning end of the cigarette and enters directly into the environ- ment. Differences in the temperature of combustion, the degree of filtration, and the amount of tobacco consumed all lead to marked differences in the concentration of the constituents of mainstream smoke and sidestream smoke (USDHEW 1979; Sterling et al. 1982; Brunneman et al. 1978; National Academy of Sciences 1981; Rylander et al. 1984). Many potentially toxic gas phase constituents are present in higher concentration in sidestream smoke than in mainstream smoke (Brunneman et al. 1978) (Table 11, and nearly 85 percent of the smoke in a room results from sidestream smoke. Smaller amounts of smoke are contributed to the environment from the nonburning end of the cigarette by diffusion through the paper wrapping and by the smoke exhaled by the smoker. Therefore, both active and passive smokers may be similarly exposed to sidestream smoke. Mainstream smoke is inhaled directly into the lungs and is diluted only by the volume of air breathed in by the smoker when he or she inhales. Sidestream smoke is generally diluted in a considera- bly larger volume of air. Thus, passive smokers are subjected to a quantitatively smaller and qualitatively different smoke exposure than active smokers. The quantification of the exposure of a passive smoker to these sidestream smoke constituents is often difficult. Factors such as the type and number of cigarettes burned, the size of the room, the ventilation rate, and the smoke residence time are all important variables in determining levels of exposure. Thus, no single variable accurately characterizes exposure to smoke constitu- ents. Repace and Lowrey (1980, 1982, 1983) have shown that, to a reasonable approximation, exposure to the particulate phase is predicted by the ratio of the smoker density to the effective ventilation rate of the area in which the smokers are located. Measurement of Exposure Levels of indoor byproducts of tobacco smoke, with measurements made under realistic exposure conditions, are presented in Table 2. Among the constituents that have been measured, nitrogen oxide, carbon monoxide, nicotine and respirable particulates, nitrosamines, and aldehydes have been shown to be significantly elevated indoors as a result of cigarette smoking. Nitrogen oxide is rapidly oxidized to nitrogen dioxide (NOZ) in air, and reaches equilibrium with outdoor levels of NOa, provided there are suitable air exchange rates and no other indoor sources, such as a gas stove. The particulate concentra- tion indoors clearly increases with increasing numbers of smokers, although the background level is determined by the outdoor level. The conclusions from the few studies that actually measure ventila- tion rates during exposure suggest that under "normal" air circula- tion conditions, carbon monoxide (CO) levels will be relatively low, but still may exceed the ambient air quality standard of 9 ppm (NIOSH 1971). However, even modest reductions in ventilation rates can lead to CO accumulation. A variety of measures have been utilized to quantify the nonsmok- er's exposure to tobacco smoke. No single measure has been uniformly accepted as characterizing the level of smoke. Nicotine is the most tobacco-specific of these measures, but it is relatively complicated and expensive to measure and settles out of the air with the particulate phase, making it a poor measure of gas phase constituents. In addition, nicotine may rapidly deposit on surfaces and subsequently evaporate into the environment (Rylander et al. 1984), making it a poor measure of acute smoke exposure levels. Measurements of total particulate matter are a broader measure of smoke exposure, particularly if the measurements are limited to particles in the respirable range and to environments without other major sources of respirable particles. The smoke particles also settle out of the air and therefore may not reflect the levels of gas phase constituents, and a wide variety of other dusts may contribute particulates to the air, particularly in the occupational setting. A number of authors have measured levels of CO. This measurement is relatively simple and a measure of absorption (carboxyhemoglobin) 366 TABLE l.-Ratio of selected constituents in sidestream smoke (SS) to mainstream smoke (MS) a.9 phase aJn#tituenta MS s/MS ratio Particulate phase constituents MS ss/Ms ratio Carbon dioxide Carbon monoxide Methane Acetylene Ammonia Hydmgen cyanide Methylfuran Acetnnitrile Pyridine Dimethylnitwamine 8.1 TM 2.5 Water 3.1 Toluene 0.8 Phenol 73.0 Methylnaphthalene 0.25 Pyrene 3.4 Benuo(a$wne 3.9 Aniline 10.0 Nicotine 52.0 SNaphthylamine 1.3 2.4 5.6 2.6 28 3.6 3.4 30 2.7 39 Adapted from U.S. Department of Health. Education. sod Welfare (1979). TABLE 2a.-Acrolein measured under realistic conditions Study Type of premisea Ventilation Monitoring conditions MMtl Badre et al. (1978) cafea Room Hospital lobby 2 train compartmenta cm Fischer et al. (1978) and Weber et al. (1979) Rentaurant Restaurant Bar cafeteria Varied Not given 18 smokera Not given 12 to 30 smokenr Not given 2 to 3 smokers Not given 3 emokem Natural, open 2 smokers Natural, closed 50-M/470 m' 60-lCW440 m' 3&40/50 m' &I-150/574 m' Mechanical Natural Natural. open 11 ehanges/hr loo mL sample.8 loo mL Bamples 100 mL samples loo mL .samples 100 mL Eamplea loo mL samples 27 x 30 min samples 29 x xl mill samples 28 X 30 min samples 24 x 30 mill samplea 0.03-0.10 mg/m' 0.185 mg/m' 0.02 mglm O.Ou).lZ mg/m* 0.03 mg/m' 0.30 mg/ms 7 wb 8 wb 10 Ppb 6 wb (5 ppb nonsmoking section) TABLE 2b.-Aromatic hydrocarbons measured under realistic conditions Study Ventilation Monitoring conditions Levels Nommokmg controls Mean Range Mean Range Badre et al. (1978) cafes Room Train compartmenta car cafea Varied Not given 100 mL samples 004-1.04 Room 18 smokers Not gwen 100 mL samples 0 215 Train compartmenta 2 to 3 smokers Not given 100 mL samples 1.87 car 2 smokers Natural, clceed 100 mL samples 0.50 Elliott and Rowe (1975-l ArHla Galuskinova (1964-l Restaurant Varied Not given 100 mL samples 005-0.15 18 smokenr Not given 100 mL samples 0109 2 to 3 smokers Not given 100 mL eamplea 0.024 10 3 smokers Natural, open 100 mL samples 0.04 2 smokers Natural, closed 100 mL samples 0 15 8,647-10,786 people Mechanical 12,000-12.8-44 people Mechanical 13,W14J77 people Mechanical Not given Not given Not given Not given Not given Separate non- activity days 20 days m .3ummel 18 days in the fall Benzene (n&m') Toulene (mglm') Etenxjajpyrene (,ng/m') 71 99 21.7 0 69 6.2 282-144 Y TABLE 2b.-Continued a Level0 Nonsmoking controls lLpe of Monitoring Study premises ~UpancY Ventilation conditiona MSII Ranse Mean bnge Just et al. (1972) Coffee houses Not given Not given 6 hr continuous 0.25-10.1 4.M.3 (outdcom) Berw$ehymne (nglm') 3.3-23.4 3.0-5.1 (outdoord Benz&&erylene (w/m') 5.9-10.5 6.9-13.8 (outdoors) Perylene (rig/m') 0.7-1.3 0.1-1.7 (OUtd~Ia) Perry (1973 14 public placee Not given Not given 4.1-9.4 2.C7.0 (outdoors) Anthanthmne (ng/m") O.Sl.9 0.61.8 (outdoors) Coronene (ng/m') OS-l.2 1.0-2.8 Phenols C&m') samples, 5 outdoor locations 7.4-11.5 Benzo(aipyrene (r&m') < 20-760 <2O-QJ TABLE 2c.-Carbon monoxide measured under realistic conditions Study Type of pmllliSW Ventilation MOd.OliDg conditions Levels @pm) Nonsmoking controls @pm) MWll Ranse Mean Badre et al. (1978) Gcafea Room Hospital lobby 2 train compartments car Can0 et al. Submarines (19703 66 m' ChappeU and Parker (1977) 10 OfflQs 15 rwtaurant.9 14 night&be and taverna Tavern Varied 18 smokers 12 to 30 smokers 2 to 3 smokers 3 smokers 2 smokers 157 cigfuettes per &Y 94-103 cigarettes per bY Not given Not given Not given Not given Not given Not given Not given Not given Natural, open Natural, cloeed Yea Yea values not given valuee not given valuw not given Artificial offia? 1440 ft' Natural, open 20 min samples 20 min @amplea 20 min samples 20 min Bamplea 20 min enmplee 20 min aamplee 17 x 2-3 min WIllpleS 17 x 2-3 min samples 19xMmin WlUPlW 16 x W min BampleS 2x2-3min SampIeS 2-3 mill eamples 3ominafter smoking 50 5 1.4 20 (40 PPm (40 wm 2.5 + 1.0 4.0 k 2.5 13.0 Ik 7.0 8.5 1.5-4.5 l.cL9.5 3.0X9.0 2.5 + 1.0 1.5-45 (outdoom) 2.5 f 1.5 1.a5.0 (outdoom) 3.0 + 2.0 1.0-5.0 35 @?ak) 10.0 (peak) 1.0 : TABLE 2c.-Continued Levels @pm) Nonsmoking controls (ppm) lLpe of Monitoring Study premieee ~F-7 Ventilation conditions Mean Ranse MWIl Range C&urn et al. (19653 Cuddeback et al. (1976-I U.S. Dept. of Transportation U971P Elliott and Rowe (1975F Fisher et al. (1978) and Weber et al. (2979) Codin et al. Ferryboat Not given Not given 11 grab eamplee 18.4 + 8.7 3.0 f 2.4 (nonsmoking room) (197.8 Theater foyer Not given Not given Glnh samplea 3.4 + 0.8 1.4 _t 0.8 (auditorium) Rooms Not given Not given Tavern 1 10-294 people 6 changeslhr Tavern 2 Not given l-2 che.ngea/hr I8 military Plan= 8 domestic ph.W 165-219 people 27-113 people Mechanical Arena 1 11.806 people Mechanical Arena2 2,ooO people Natural Ewtaurant 50-W/470 m' Mechanical R&aurant 60-lW440 m' Natural Bar 3J-i0/50 m' Natural, open Cafeteria W-150/574 m' 11 changea/hr Not given Nonsmokers' rooma 8 hr continuous 2 hr after smoking 8 hr continuous 2 hr after smoking 6-7 hr continuous 1 `I,-2'1, hr continuoue Not given Not given Nonsmoking srens 27 x 30 min Lwnplee 2SX3OlUiIl SampIeS 28X3Oti SampIeS 24X3Oti Nonsmoking rwm 11.5 -1 17 -12 4.3-9.0 lo-12 -3-22 <2-5 9.0 25.0 5.1 2.1-9.9 2.6 1.43.4 4.8 2.4-9.6 1.2 0.7-1.7 2.2 + 0.98 0.445 2 (outdoorL3) Values not given Values not given 3.0 (nonactivity day) 3.0 (nonactivity day) 9.0 4.8 (outdcmrs) 1.5 (outdoolB8) 1.7 (outdwrs) 0.4 (outdoors) 0.5 0.3-0.8 TABLE Lc.-Continued Study m of premises Ventilation Monitoring conditions Levels @pm) Nonsmoking controls (ppm) MWUl Ranse MWll Range Harke (1974a) Harke and Peters (19747 Harnwen and Effenherger f lY57v Perry t IY 7s Portheine I I.V71lS Sebhen et al (IH771 officed oflie car -72 m' -78 ma 2 smokers (4 cigs) 236 m'/hr Natural Natural Mechanical 14 public Pla= Rams Not given Not given One grab sample <: 10 Not given Not given Not given 625 9 night&be Not given 14 restauranta 45 rwtaurante 33 stmw 3 hospital lobbies 1-18 smokers Natural Not given O-40 Not given Not given Not given Not given Not given Not given Not given Not given 30 min samples 30 min samples Samples 77 x 1 min BarnpIeS outdmrs Spot checks Spot checks Spot checks Spot checks < 2.5-4.6 < 2.sJ.o 42 (peak) (Nonsmoking rums) 13.5 @eak) 32 @eak) (Nonsmoking runs) 15.0 @?ak) 13.4 6541.9 9.2 3.0-35.0 9.9 + 5.5 Values not given 8.2 f 2.2 7.1 + 1.7 (outdoom) 10.0 + 4.2 11.5 f 6.9 (outdoora) 48 Values not given Y TABLE 2c.-Continued IP Levels @pm) Nonsmoking controls @pm) Type of Monitoring Study pmilliSW &UpaneY Ventilation condition8 MWll Raose Mean seiff (1973) Intercity bus Not given 15 changeE/hr, 23 cigarettes burning wntiuuolWly 3 cigarettea burning continuously 33 wm 18 wm Slavin and Hertz (1975) 2 conference moms Not given 8 changealhr Continuous. morning 6 changeelhr Continuous, morning 8 (pdd 10 @& l-2 kleparate nonsmoking day) l-2 heparate nonsmoking day) &dkOWSki et al. (1976) 25 officea Not given Not given continuous 2.78 + 1.42 2.59 f 2.23 bqarate nonsmoking offi9s) `Thrseciganttesandooecigarsmokedin20minutee. whe Drager tube used is accurate only within f 25 percent. = The M6A Monitaire Sampler ubed in acnuate only within f 7.5 percent dAbout 40 t&srettw/day were smoked. o Ahout 70 cigar&Am/day were smoked. `Four filter cigar&m were smoked. rNoerperimentaldeacriptiongiven. TABLE U-Nicotine measured under realistic conditions Study nw of premises Ventilation Monitoring conditions Nonsmoking Levels Q/m') wntmls Mt?.tUl Range Man Range Badre et al. u978l Gcafea Boom Haspitnl lobby 2 train compartmenta car Can0 et al. (2970) Harmsen and Effenberger (f96Tl HindaandFirst (197.P Submarines 66m' Train Train Not given BIU Not given Bus waiting room Not given Airline waiting room Not given Ftastaurant Not given Cocktail lounge Not given Student lounge Not given Weher and Fischer m8w 44 oftk!s Varied Varied 18 smokers 12 to 30 smoker9 2 to 3 smokera 3 smokers 167 cigarett4w per day 94-103 cigarettea Per day Not given Not given Not given Not given Not given Natural, open Natural, clawed YeS YeS Natural. cloeed Not given Not given Not given Not given Not given Not given Not given Varied 50 min BarnpIe 25-52 50 min sample 500 50 min aample 37 50 min sample 3640 50 min anmple 65 50 min sample 1010 32 palm' 1535 palm' 30-45min samplea 2'/, hr aamplen 4.9 2'1, hr aamplea 6.3 2'1, hr aample 1.0 2'1, hr samples 3.1 2'1, hr samples 5.2 2% hr samples 10.3 2'1, hr samples 2.6 07.9.1 Values not given Values not given Values not given Values not given Values not given Values not given Valuea not given 140 x 3 hr samples 0.9 + 1.9 13.8 &AK) Values not given TABLE 2e.-Nitrogen oxides measured under realistic conditions Study Tvpe of premises Ventilation Monitoring conditiona Nonsmoking Levels - controls (ppb) Mf?iUl Ranse MMl Range Fischer et al (1978) and Weber et al. 11979) Restaurant Restaurant Bar cafeteria f&60/470 ma 6&100/440 m' 3@-40/50 m' @J-150/574 m" Mechanical 27xZOmin SampleS Natural 29X3Omin @amplea N8tld. 28x3Omin open SampIeS 11 changee/hr 24 X 30 min Eamplen Otber-non- smokers rcom NO,: 76 59-106 NO 120 %218 NO,: 63 2499 NO: 80 14-21 NO,: 21 l-61 NO: 195 NO,: 58 66-414 35-103 NO: 9 2-38 63 (outdwra) 115 (outdoors) 50 (outdoore) 11 @&atdoors) 48 (outdml8) 3 4-l (outdoora) 34 (outdoolB) 4 (outdooIB) NO,: 27 1.544 NO: 5 2-9 Weber and Fischer (198OP 44 OffIces Varied VlU%d NO,: 2.4 + 22 115 (peak) Values not given samples NO: 32 + 60 280 @eak) Values not given tintml values (unoccupied rooms) have been subtract& TABLE 2f.-Nitrosamines measured under realistic conditions Study Ventilation Monitoring conditions Levels (ng/L) MWII Range Brunneman and Hoffmann 11978) Train bar car Train bar car Brunneman et al (1977) Bar sporta hall Betting parlor Discotheque Bank House House Not given Mechanical 90 min continuous 0.13 Not given Natural 90 min continuous 0.11 Not given Not given Not given Not given Not given Not given Not given Not given Not given Not given Not given Not given Not gwen Not given 3 hr continuous 3 hr continuous 90 min continuous 2'1, hr continuous 5 hr continuous 4 hr continuous 4 hr continuous N-Nitroedimethylamine 0.24 0.09 0.05 0.09 0.01 `: 0.005 ~-0003 Y TABLE 2g.-Particulate8 measured under realistic conditions Study ~UpancY (active smokers per 100 mrl Ventilation Monitoring condition8 bid Levels (pg/m') Mean Std. dev. Nonemoking controls C&m') Mean Std. dev. Bepace and Cocktail party 0.75 Natural 15 351 + 38 24 b-Y Lodge hall 1.26 Mechanical 50 697 f 26 60' w3~ Barandgrill 1.78 Mechanical 18 589 k28 63' Firehow bingo 2.11 M&hIliCd 16 417 3I 63 51' Pizzeria 2.94 Mechanical 32 414 + 58 40' Bar/cocktail lounge 3.24 Mechanical 26 334 f120 50' Church biio game 0.47 MeLhUlhl 42 279 * 18 30 Inn 0.74 MdWliCd 12 239+9 22' Bowling alley 1.53 Me&IlOiCal 20 al2 + 19 49' Hmpital waiting room 2.15 M8ZtiCd 12 187 f 52 58' Shopping plaza restaurant Sample 1 0.18 M&MliCd 18 153 + 8 59' Sample 2 0.18 MeChanical 18 163 f 4 36' Barbeque restaurant 0.89 Mechanical 10 136 f 17 40' Snndwich restaurant A Smoking section 0.29 Md8lhXl 20 110 f 36 40' Nonsmoking section 0 MedUUlid 20 55t 5 30 F&food restaurant 0.42 Me`hIliCd 40 109 * 38 24' sporta arena 0.09 I MWtid 12 94 f 13 55' Neighborhood restaurant/bar 0.40 Mechanical 12 93 + 17 5.5' Hotel bar 0.59 MdaIlk.d 12 93 * 2 30 Sandwich restaurant B Smoking &ion 0.13 M@hItiCd 8 86f7 55 Nonsmoking section 0 M@hllical 21 51 Roadside restaurant 1.12 Mechanical (9.5 ach') 18 107' 30 Cmference room 3.54 Mechanical (4.3 ach') 6 1947' 55 TABLE 2g.-Continued Study -vaw btive smokera per loo n-l31 Ventilation Monitoring conditions bin) Levels @g/m') Mean Std. dw. Nonsmoking controls Q&m') Mean Std. dev. F&pace and Dinner theater h-Y Reception halJ (1982l Bingo ball 0.14 1.19 0.93 ' 0.93 a Mechanical MeCbEUhl Netural Mechanical W39 ach') 44 145 t- 43 47 c 10 20 301 + 30 33' 2 1140 40' 6 443' 40' `Sequential outdoor measurement (6 minute average). `Esltiited. ' Air dmngea per hour. o Equilibrium level BI determioed from ooncantration VI. time CUM. E TABLE 2g.-Continued .-.-* .- Levels @g/m') Nonsmoking controls (pg/mJ) Type of Monitoring Study pmmises ~UpaneY Ventilation conditions MHUI Range Mean iiancJe Cuddleback et al. Tavern (29767 U.S. DetBt. of Not given Tavern Not given 18 military planes 16219 people 8 domestic plaaes 27-113 people 6 changeelhr 4xahr 1-2 changedbr 8 hr continuous Mechanical 12 x 6-l hr SampIeS Mechanical 24 x I'/,-2'1, hr SallIpleS Dcckery and Spengler (1981) Elliott and Rowe (1975) Hamrwn and Effenberger (1957) Just et al. (1972) Neal et al. (1976) Residences Not given AlWUIl 11,806 people Arena2 Zoo0 people Arena 3 (smoking 11,COO people prohibited) Train0 15-120 people 4 coffee houeee Not given Hospital unit Hospital unit Not given Not given 310 986 Not given Varied 2-4 hr samples 32 MeChanical Natural Ml?&Mlical During activities 323 42 (nonactivity day) hrring activities 620 92 (nonactivity day) During activities 148 11 (nonactivity day) Natural Not given Nonsmokere' cam Not given 6 hr averages 48 hr samples 48 br Barnplea 1150 21 f 14 40 It 21 < lo-120 particleelcm' 20-15 particles/cm" 500-1900 510 (outdootn) 10&1900 MB 13 f 25 13-19 12 + 25 TABLE Zg.-Continued Levels (pg/m') Nonsmoking controls f&m') Type of Monitoring Study premises @CUpaneY Ventilation conditions Mean Ranse Mean Range Spender et al. Residences 2+ smokers Natural 24 hr samples 70 t 43 UW) 21 + 12 (outdoors) 1 smoker Natural 24 hr samples 37 f 15 21 f 12 butdooln) W&r and 44 officea Varied Natural and 429 x 2 min Fischer (1981) 133 f 130' 962' @?ak) mechanical fk3tUpleS Quad et al. OfTice No. 1 0.62 a Mechanical Five 10 hr workday 45 3954 (2932l 5-15 O&e No. 2 0.66' Mechanical averages; wntiiruoua 45 3740 l&m OfTice No. 3 1.46' Mechanical monitoring 68 42439 15-20 Brunekreef and 26 houaes 1-3 smokers Natural 2 mo averages 153" 60-340 55 Boleij (198zl 20-90 I Values above baclground. `Habitual amokem per 100 III*, ' Wciahti mean % TABLE ah.-Residuals measured under realistic conditions Study k of premieee Ventilation Monitoring conditions Nonsmoking Levels contmle MeaIl Ranse Mean Bange Badre et al. (1978r Gcafea Room Hospital lobby 2 train wmpartmenta car car Dockery and Spengler m91) Residences Not given Varied 24 hr samples 4.81 Fischer et al. (1978) Beataurant 5O-SOl470 ma Mechanical Restaurant 60-lW440 m' Natural Bar 30-40/50 mr Natural, open Cafeteria 80-W/574 ma 11 ch/hr Juet et al. (1972) 4 coffee houses Not given Not given 6 hr continuous 12.0-15.3 Varied 18 smokers 12 to 30 smokers 2 or 3 smokers 3 smokere 2 smokers Not given 100 mL samples Not given 100 mL eamplea Not given 100 mL samples Not given loo mL samples Natural, open 100 mL samples Natural, cloeed 100 mL samples 27 X 30 min samples 29 X 30 min samples 26 x 30 mill samples 24 X 30 min samples Other nonsmokers' rwm Acetone bng/m") 0.91-5.88 0.51 1.16 Ox-O.75 0.32 1.20 Sulfur dioxide (ppb) xl 9-32 12 Ppb 13 5-18 6 30 13-75 8 15 l-27 12 7 3-13 is also readily available. CO reflects the gas phase components of smoke and thus may not reflect the levels of particulate phase constituents. There are also a number of other CO sources in addition to cigarettes, both in the external environment (e.g., automobiles) and in the indoor environment (e.g., gas stoves). As a result, even the subtraction of external atmospheric levels may not entirely eliminate the contribution of other sources of CO to the indoor environment. Given these problems, use of several of these measures, or the tailoring of the measurement to the phenomenon being measured, seems appropriate. The measurement of total particulate matter may be a reasonable indicator of exposure to the particulate phase of smoke, once the measurement is limited to respirable particulates and once background levels with the same level of activity, but without smoke, are subtracted. Relatively precise methods have been developed to predict the levels of exposure to carbon monoxide (Jones and Fagan 1975; Coburn et al. 1965) and total particulate matter (Repace and Lowrey 1980) that would be expected in rooms of different size and ventilation with different rates of smoking. Stewart et al. (19741, using blood donors, found the median blood carboxyhemoglobin level for smokers and nonsmokers in selected populations to be 5.0 and 1.2 percent, respectively. This corresponds to a steady state ambient CO level of 7 ppm, which represents a combination of atmospheric pollution from cigarette smoke and the background level of urban pollution and is consistent with the levels described in Table 2. Exposure levels to carbon monoxide are highly dependent on ventilation, occupancy, smoking rates, and background levels in the ambient air. The half life of carboxyhemoglobin is approximately 4 hours, making blood carboxyhemoglobin a useful biologic monitor of acute exposure to passive smoking, but one that does not provide useful data for chronic exposure. Assessment of chronic exposure with a biologic marker requires the ability to measure some accumulating product of smoke. To date, substances such as cotinine (Matsukura et al. 1979; Langone et al. 1973; Williams et al. 1979; Feyerabend and Russell 1980; Russell et al. 19821, thiocyanate (Bottoms et al. 1982; Cohen and Bartsch 19801, and polonium-210 (Radford and Hunt 1964; Little and McGendy 1966) have been measured in active smokers. Plasma and urinary nicotine, plasma and urinary cotinine, and salivary nicotine and cotinine have been reported in nonsmokers exposed to tobacco smoke (Jarvis and Russell 1984; Russell and Feyerabend 1975; Feyerbend et al. 1982). Of these measures, it would appear that urinary cotinine offers the most promise as an index of exposure. However, there are no published data using these measures as biologic markers of chronic involuntary smoke exposure. In contrast to physiologic investigations, epidemiologic studies have used the number of smokers in the home or in the working environment as the principal exposure variable. These relatively crude indices, in general, ignore time spent with the smoker and the environmental factors known to influence ambient smoke concentra- tion noted above. In summary, involuntary smoking research deals with an expo- sure that is qualitatively and quantitatively different from that of active smoking. Adequate characterization of passive exposure in both epidemiologic and physiologic studies is substantially more difficult for involuntary exposure than for active smoking exposure. While the active smoker's total current cigarette consumption is relatively easily quantitated, the lower dose and greater influence of ventilation and ambient environment for involuntary smoke expo- sure makes assessment of exposure one of the most important methodologic issues of this research. Clearly, a biologic marker of chronic exposure that reflects the amount of tobacco smoke to which nonsmoking persons are exposed would be a useful tool. In addition, carefully formulated questionnaires quantifying passive smoking are also necessary, and may prove equally valid for assessing exposure. No single index has yet been accepted by all investigators, and comparison between studies remains difficult. However, Repace and Lowrey (1983) have estimated that the nonsmoking population may be exposed to from 0 to 14 mg of tar per day, with an average expo- sure of 1.43 mg per day. Acute Physiologic Response of the Airway to Smoke in the Environment Relatively little acute exposure data exist concerning the effects of passive inhalation of cigarette smoke on pulmonary function (Table 3). The data that are available 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 parts per million) were achieved in the chamber during involuntary smoking. Peak blood carboxyhemoglo- bin levels were always less than 1 percent in subjects before smoke exposure, but were significantly greater during the study exposure. Lung volumes, flow volume curves, and heart rate were measured for all subjects. Measurements were made at rest and following exercise under control conditions and smoke-exposure conditions. Flow at 25 percent of the vital capacity decreased significantly with smoke exposure at rest in men and with exercise in women. The magnitude of the change was small: a 7 percent decrease in flow in 384 TABLE 3.-Acute effects on pulmonary function of pas&e exposure to cigarette smoke Study Type of exposure Magnitude of exposure Effect0 Comments Pimm et al. u9m Chamber 14.6 m' with sparse furniture; smoking machine in room Peak [co] - 24 ppm; particulate8 >4 mg/m' Men: 5% increase FRC, 11% increase RV, 4% decrease v-as during exerciee Nonsmokers; average age of men = 22.7, women = 21.9; sham expoeure aa control Women: 7% decrease ON post exercise; no effect4 on vc. TLC. Fvc. lmv,. Shepard et al. (1979) As above Low erpoeurz peak (Co] - 20 ppm, particulate8 - mg/m'; high erpoeure: [Co] - 31 ppm Jhhma et al. (19Rl) Chamber 30 m I; climate controlled Room leveb not measured; estimated at penk [Co] - 20 PFm Low exposure: 3% decrease FEV,, 4% decrease VU 5% decrease 0-z~ with ererciee; no increaned effect with high exposure 0.9% increnee in FVC. 5.2% increase in FEY,, 2.2% increase in FJIFs,a at 1 hour Nonsmokers; average age of men = 23, women = 25, sham exposure as control; subjects estimated to have inhaled - l/2 cigarette/2 hours 10 nonsmokers; age range 2453 years; not blinded; no sham exposure men and 14 percent in women. No other consistent changes in lung function were observed. Shepard and coworkers (1979) utilized a similar crossover design in a chamber of exactly the same size as Pimm's. Their results were almost identical, with a small (3 to 4 percent) decrease in FVC, FEVl, VmaJr50, and Vrnax~. They concluded that these changes were of the magnitude anticipated from an exposure of less than I/2 cigarette in 2 hours (the exposure anticipated for a passive smoker). Dahms et al. (1981) used a slightly larger chamber with an estimated peak CO level of approximately 20 parts per million. They found no change in FVC, FEVI, or FEFw75 after 1 hour of exposure in normal subjects. This experiment was not blinded and had no sham exposure. The data from these studies suggest that involuntary smoke exposure can probably produce measurable, albeit small, changes in the airways of normal individuals. This response is consistent with the acute response to the inhalation of cigarette smoke by the active smoker, and it is not surprising that high dose involuntary exposure to tobacco smoke might produce similar results. The magnitude of these changes is small, even at moderate to high exposure levels, and it is unlikely that this change in airflow per se results in symptoms; however, it may be only one manifestation of a broader irritant response to smoke in nonsmokers. Symptomatic Responses to Chronic Passive Cigarette Smoke Exposure in Healthy Subjects Eye irritation is the most common complaint experienced by normal people acutely exposed to cigarette smoke. In one study, 69 percent of subjects reported ever experiencing this symptom @peer 1968). Headache, nasal irritation, and cough were reported by approximately one-third of the subjects in this and other investiga- tions (Weber and Hertz 1976; Slavin and Hertz 1975). Several factors may alter the prevalence of irritant symptoms, including the amount of smoking, the size of the area involved, the humidity and temperature of ambient air, and the extent of ventilation (Johansson 1976). No longitudinal studies of these irritant effects (e.g., develop- ment of increased sensitivity or tolerance) have been reported. Weber (1984) has examined the effect of dose and duration of exposure to environmental tobacco smoke on subjective reporting of eye irritation and objective measurement of eye blink rate. Figure 1 reveals that both eye irritation and blink rate increase with increasing dose of smoke exposure, and that substantial subjective irritation and objective increase in blink rate occur at levels of smoke exposure (CO levels of 20 to 24 ppm) equivalent to those used to evaluate pulmonary function changes in response to environmen- 386 eye lrritatlon vary strong 5 l- strong medium weak none co NO HCHO ecroloin ~ . . . . . . . . 4 3 /' .--.... --- . . . . . _...... *.*' ..a' *:. *:. ,:. .f ..: .:* .:' ,:* - 60 - 40 j/y I I I I 1 1 1: 0 10 2c mln 1 1 I I I 1 1 11 22 32 42 43 pm I I I I I 1 0.08 0.42 0.77 1.11 1.45 1.50 ppm f I I I I 1 0.03 0.16 0.32 0.47 0.62 0.64 ppm I I I I I 1 eye blink rstdmin c 60 number of cig. 0 10 20 FIGURE l.-Mean subjective eye irritation, mean eye blink rate, and concentrations of some pollutants during continuous smoke production in an unventilated climatic chamber NOTE- Thirty-three subjects. ventdatmn rate 0 01 h 1, eye ~rritatmn Index calculated from the answers ?A four questions concerning eye ~mtatmn: 0 mm = measurement before smoke production SOURCE. Weber (1984) tal tobacco smoke exposure. Both irritation and blink rate increase with duration of exposure to environmental tobacco smoke (Figures 2 and 3). After 60 minutes of exposure, distinct changes are evident in level of irritation with a smoke exposure of 1.3 ppm CO, and the blink rate increased with smoke exposures as low as 2.5 ppm CO. These levels of smoke exposure (1.3 to 2.5 ppm CO) are well within those measured under realistic conditions (see Table 1). Therefore, it is possible to demonstrate an objective irritant response in normal subjects at levels of smoke exposure substantially lower than the levels where an airway response (also presumably an irritant response) has been demonstrated. Whether this difference represents a difference in threshold for irritation in the eye and airway or a limitation in the ability to measure subtle changes in the airway is uncertain. eye irritation index -r-- - 10ppm 5 pm 2.5 ppm 1.3 ppm control 0 20 40 60 exposure min FIGURE S.-Subjective eye irritation due to environmenta tobacco smoke, related to smoke concentratio and duration of exposure NOTE: 0 values M levels dwing smoke pmduction minus backgnund level before smoke prcduction; 32 t subjects; 0 min = measurements before tunoke production. SOURCE: Weber W841. Chronic respiratory symptoms have been reported most common in children. Studies from several different countries (Table 4) ha shown a positive relationship between parental cigarette smoke; and the reporting of the symptoms of chronic cough, chronic phlegm and persistent wheeze (Colley et al. 1974; Bland et al. 1978; L&ow- and Burrows 1976; Weiss et al. 1980; Ware et al. 1984; Schilling et. 1977; Kasuga et al. 1979; Schenker et al. 1983). Some of these studi may be confounded by an increased reporting of symptoms in t child by parents who smoke and have symptoms (Colley et al. 19'. Bland et al. 1978; Kasuga et al. 1979) or by the child's own smoki habits (Colley et al. 1974; Bland et al. 1978; Kasuga et al. 1979). 5 all studies show statistical significance for all symptoms @bow and Burrows 1976; Schilling et al. 1977; Schenker et al. 198 However, a consistent finding in all reported data is an increase symptoms with an increased number of smoking parents in t 388 eye blink ratelmin 40- 35- 25- 20- 15- OJ 5 ppm 5 rwm _-- 1.3 ppm control 2.5 ppm 2.5 ppm 1.3 ppm control I I I I I I 1 0 20 40 60 exposure min FIGURE 3.-Effects of environmental tobacco smoke on eye blink rate home. This effect persists after controlling for parental cough and is most marked in the first year of life. British researchers, studying a birth cohort, demonstrated an increased incidence of wheezing over a 5-year period among nonasth- matic children who had two parents who smoked. However, when examined by logistic regression, parental smoking was not a significant predictor of occurrence of wheeze or the future occur- rence of asthma (Bland et al. 1978). In a subgroup of the cohort-861 children of asymptomatic parents, Leeder and colleagues (1976al found no significant trend in asthma-wheeze symptoms with in- creasing levels of parental smoking over a 5-year period. 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 1.85 percent, 6.85 percent, and 11.8 percent for zero, one smoking parent, and two smoking parents, respectively. Although the data given are for all 389 TABLE 4.--Respiratory symptoms in children in relation to invohntary smoke exposure Study Subjecta Respiratory symptoms or illness Rates pm 100 by number of smoking parents 0 1 2 Comment Colley et al. 2,426 children, aged 6-14, (1974 England Chronic cough assessed by questionnaire completed by P==t 15.6 17.7 22.2 Trend significant; possible that 8ymptoms in parent8 could result in reporting biae; active amok& in children could aleo bias resulta; bias unlikely to explain full effect of trend Bland et al. (1978) Weiss et al. (19Bo) Ware et al. u984 3,105 children, aged 12-13. who did not admit to ever smoking cigarettea, England 650 children, aged 5-9, united States 6,628 children, aged 5-9. with two parents of known smoking atatua, air U.S. cities Cough during day or at night 16.4 19.0 23.5 Morning cough 1.5 2.6 2.9 Chronic cough and phlegm 1.7 2.7 3.4 Self-reported symptoms and smokiug history collected aimultaneoualy from children; difference between morniug and daytime cough suggested ae different dkaees, but could be difference in exposure, in that exposure more likely in daytime than when asleep Trend not aiguiticant Persistent wheeze Chronic cough Per&tent wheeze 1.6 6.6 11.8 Trend &u&ant 7.7 6.4 10.6 Adjusted for age, sex, and city cohort effects, significant trends 9.9 11.0 13.1 TABLE 4.-Continued Study Subjecta Respiratory nymptomn or iunem Bates per 196 hy number of amokin parents 0 1 2 Comment Dodge W8fT) 626 children, graden 3-4, in tweparent householde; questionnaire renponee of parenta, United Statee Schenker et al. U983) 4.971 chikhan, aged 614. in weatern Pennsylvania cough Chronic cough Chronic phlegm Pereistent wheem 21.6 27.9 40.0 All trends significant; some of effect might relate to parental 6.4 10.9 12.0 symptoms, but not likely to influence trends 14.6 23.0 27.8 6.3 7.0 6.3 None of these rates significant; data not adjusted for parental 4.1 4.6 4.0 Bymptom 7.2 7.7 5.4 Lebowitz and Burrows (1976) SchiUing et al. (1977) 1,252 children, (16 years old. United States 816 children, age 7 t. United smea Persiatent cough Persistent phlegm whew? Cough, phlegm, wheeze Never Parent smoking smoking 3.7 7.2 Higher rates in symptomatic households with trends persisting, 10 12.6 but not significant for asymptomatic households 23.4 24.1 No significant Specific data not provided effect Knsuga et al. (1979) 1.937 children, aged 6-11. Japan wheeze, asthma Increased prevalence in families with a heavy smoker (2 21 ciglday); km clear effwt in family with a light smoker ((21 ciglday) Data adjusted for distance of home fmm main traftic, highway households, when the analysis was restricted to those households where neither parent reported symptoms, the results were identical, suggesting that in this population, significant reporting bias was not responsible for the observed results. Lebowitz and Burrows (1976), in a group of 463 current-smoking and never-smoking households with children below age 15, found trends-but no statistically significant differences-for a variety of symptoms, including wheeze most days, in households with smokers. In the same study, among 849 house- holds with older children and adults, there were no significant differences for any symptom prevalence between current-smoking and never-smoking household members. In a general population study, Schilling et al. (1977) reported no association between wheeze and involuntary smoking. A preliminary report from one of the largest studies currently under way (Speizer et al. 1980) indicated no association of persistent wheeze with the presence of smoking in the household for approxi- mately 8,000 children aged 6 to 11 in six communities. However, subsequent analyses of these same cohorts with the addition of approximately 2,000 more children and a more detailed assessment of the smoking behavior of each parent revealed a positive relation- ship that increased with the amount of maternal smoking and was only modestly affected by taking into account the parents' own symptoms (Ware et al. 1984). Dodge (1982), studying third and fourth grade children, found that symptoms, including wheeze, were related to both the presence of symptoms in the parents and the number of smokers in the household. The gradient of the wheeze effect persisted even after excluding the potential effect of reporting bias by symptomatic parents. Few data are available on the level of exposure necessary to produce symptoms or on the implication of these symptoms for future lung growth and development. No data are currently available on the relationship of passive smoking to other putative risk factors for wheezing such as atopy, respiratory infection, and increased levels of airways responsiveness, nor are sufficient data available to estimate whether these early exposures affect the occurrence of respiratory disease later in life. The characteristics of the child who may be susceptible to this type of exposure are unknown. However, the data are sufficiently consistent to suggest that pediatricians should routinely inquire about smoking habits of parents when caring for children with chronic or recurrent respiratory symptoms and illnesses. It would also be prudent to advise parents of children who are suffering from recurrent respira- tory illnesses or persistent wheeze or asthma not to smoke. 392 Respiratory Infections in Children of Smoking Parents Bronchitis and pneumonia and other lower respiratory illnesses are significantly more common in the first year of life in children who have one or two smoking parents (Table 5). Bonham and Wilson (1981) showed that in 1970 the majority of homes with children under 17 years of age had at least one smoker. Thus, passive smoking by children, even in early childhood, is widespread. Harlap and Davies (1974) studied 10,672 births in Israel between 1965 and 1968 and observed that infants whose mothers said they smoked (as determined at a prenatal visit) experienced a 27.5 percent greater hospital admission rate for pneumonia and bronchitis than children 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. It should be noted that the mothers were reporting prenatal smoking and not postnatal smoking for the first year of life. British investigators studying live births between 1963 and 1965 in London also observed an increased frequency of bronchitis and pneumonia in the first year of life associated with involuntary smoking that did not carry over to years 2 to 5 (Colley et al. 1974). This effect was independent of parents' own symptoms and increased with the amount of smoking by parents. Bronchitis and pneumonia also increased with an increased number of siblings, and this was not controlled in the analysis. Fergusson et al. (19811, studied 1,265 New Zealand children from birth to age 3. They demonstrated an increase in both bronchitis and pneumonia and lower respiratory illness during the first 2 years of life in children whose mothers smoked. Corrections for maternal age, family size, and socioeconomic status did not affect the linear relationship between the degree of maternal smoking and the rate of respiratory illness. This effect declined with the increasing age of the child. Leeder and colleagues (1976b) studied a British cohort of children born between 1963 and 1965 and demonstrated that parental cigarette smoking was associated significantly with bronchitis and pneumonia during the first year of life. A dose-response association persisted after correction for parental respiratory symptoms, sex of the child, number of siblings, and a history of respiratory illness in the siblings. Pullan and Hey (1982) studied children who were hospitalized with documented respiratory syncytial virus (RSV) infection in infancy. They found a significant difference in the smoking habits of mothers at the time of the infection, compared with children hospitalized for other illnesses-including respiratory diseases for which RSV infec- tion was not documented. These children reported an excess occurrence of wheeze and asthma and had lower levels of pulmonary 393 ART)-144 0 - Rk14 % TABLE Z-Early childhood respiratory illness and involuntary cigarette smoking Study Subjecta Findings lllneea rates per 100 Commenta Harlap and Davies (1974 10,672 births, 1965-1966. Weat Jeruealem, Israel Hospitalized for bronchitis/pneumonia in first year of life RB'=1.38 By cigarettee per day 0 l-10 11-20 20+ 9.5 10.8 16.2 31.7 Smoking history obtained antenatally; maternal smoking OdY Collev s (1974) 2,205 births. 1963-1965. Questionnaire on 7.6 10.4 11.1 15.2 = Asymptomatic parents London, England bmnchitislpneumonia in first year of lie RlL1.73 for one parent smoker RR=260 for two parent smokers 10.3 15.1 14.6 23.2 = SyLptomatic p&W8 Neither mntmlled for number of siblings or sex of smokers Fergwwn et al. (1981) 1@5 births, 4 months, 1977, Christchurch. New Zealand Queationnairea on doctor or hospital visita for bmnchitis/pneumonia; check by hospital records Aaemement at 4 months, 1, 2. and3yearm RR=2.04 if mother smoked 7.0 12.8 7.0 4.6 13.4 Maternal Combined effect Significant for OdY maternal smoking in first year 6.6 Paternal of life only OdY By number of smoking parents 0 1 2 Ware et al. wJ4l 8,528 children, aged 5-9, with two pnrenta of known smoking ntatun. six U.S. cities lIeapiratory illness in last year 12.9 13.7 14.8 Adjusted for age, eex:, and city cohort effect; significant trends TABLE 5.-Continued Study Subjecta Findinga nlnees rates per 1M) commente Said et al. (1978) 3.920 cbildm. agfd lcF20, France Toneillectomy and/or adenoid&my. generally before age 5, 88 indicator of frequent rcapiratory tract infection 28.2 41.4 50.9 Self-reporting by children; not clear that smoking habite of pm-de at time of reporting directly related to erpoeure appmximately lO+ years earlier Schenker et al. 4,071 children, aged 614, &St illrem before age 2 6.1 7.9 11.5 Trends for both &nificant UW wfmtern Pennsylvania chmtinn~ >3dayainpaet 8.8 11.8 13.6 Year Cameron et al. W%.!3 158 chikiren, aged 6% parents completed telephone questionnaim, United Statm Respiratory illness with restricted activity and/or medical consultation in last Y- 1.33 1.4 nh38 reporting 00t verified; not clear how reporting adult was related to child Leeder et al. (1976a, b) 2,149 infants. horn 1963- 1965, Harmw, England RR - 2.0 for infants with two smoking parente Not provided Parents answered for children, but response bii eeeme unlikely hesaw effect.3 were obeerved for infants of aaymptomatic parents; effects of maternal w. paternal smoking not inveetigated Sim et al. (1978) 35 children hoepitnlized with RSV bmnchiolitie, 35 controla, England Borderline significant inc- in maternal smoking during fti year of life RR=2.65 Not provided No significant effect for paternal smoking. average amount smoked greater for parents of caeea than for controls TABLE %-Continued Illness rate3 per loo commenta Rantakallio (1978) 1,821 children of smoking mothers. 1,823 children of nonsmoking mothers significant increase in hospitalization for respiratory illness during first 5 yeare of life RR=1.74 Not provided F'mepective followup of doctor visits. hospitalizations, deaths up to age 5; only maternal smoking evaluated Pullan and Hey (19LVl 130 children admitted to hospital during finrt year of life with RSV infection. 111 nonhoepitalized controls Signiticant effect of maternal (RR=l.W and paternal CRR=1.53) smoking at time of study; significant maternal effect of smoking during fust year of life CRR=1.55) Not provided ' Relative risk for children of smoking mothers vernu~ children of nonsmoking mothers calculated from published data provided by J M. &met. M.D `These data are considered in B more expanded analyaia provided by Leder et al (1976). function that persisted to age 10. The authors could not distinguish between the possibilities that infection caused damage that persisted and affected the maturation of the lung or that these children were already more susceptible to severe RSV infection. Greenberg et al. (1984) examined the tobacco smoke exposure of infants in the first year of life by measuring urinary cotinine-to-creatinine ratios. They found that infants of mothers who smoked had a ratio of 351 ng per mg, as contrasted with a ratio of 4 ng per mg in infants of mothers who did not smoke. Breast-fed infants were excluded because of the presence of nicotine in the breast milk of mothers who smoke. A dose-response relationship was present between the cotinine-to- creatinine ratio and the reported level of maternal smoking in the previous 24 hours. This study suggests that infants of mothers who smoke absorb measurable amounts of the smoke from this environ- mental exposure. Rantakallio (1978) studied over 3,600 children for 5 years, half of whom had mothers who smoked and half of whom did not. Children of mothers who smoked had a 70 percent greater chance of being hospitalized for a respiratory illness than children of nonsmoking mothers. Some of these studies may be confounded by the increased reporting of symptoms in the child by parents who smoke and have symptoms (Cameron et al. 1969; Said et al. 1978; Leeder et al. 1976b), but in those studies in which parental symptoms were controlled, the effects persisted. Other studies may be influenced by the child's own smoking habits (Said et al. 1978), although the majority of research examined children in an age range in which smoking would be unlikely. In summary, several studies suggest important increases in severe respiratory illnesses, particularly in the very young (less than 2 years old) children of smoking parents. Young children may repre- sent a more susceptible population for adverse effects of involuntary smoking than older children and adults. The amount of time spent with active smokers, particularly by children under 2 years of age with smoking mothers, may be an important factor. How in utero exposure influences this risk is unknown. Pulmonary Function in Children of Smoking Parents In recent years, a number of studies have examined the relation- ship of parental cigarette smoking to pulmonary function in children (Table 6). The majority of these studies have been cross sectional (Tager et al. 1979; Weiss et al. 1980; Vedal et al., in press; Burchfiel et al., 1983; Tashkin et al. 1983; Hasselblad et al. 1981; Ware et al. 1984) and have demonstrated decreases in level of pulmonary function (FEVo75, FEV1, FEFz75, and flows at low lung volumes) in 397 children of smoking mothers compared with children of nonsmoking mothers. In some studies, there seems to be a dose-response relationship (Tager et al. 1979; Weiss et al. 1960); i.e., the greater the number of smokers in the home, the lower the level of function. When analyzed by multiple regression techniques, maternal smoking has the greatest impact (as would be expected from the greater contact time with the child), and a d-response relationship with the amount smoked seems to exist (Weiss et al. 1980; Tager et al. 1979; Ware et al. 1964; Vedal et al., in press). Younger children seem to be more adversely affected than older children (Tager et al. 1979, Weiss et al. 19601, and clearly there is an added effect in older children if they themselves smoke (Tager et al. 19791. Tager and colleagues (1963) followed 1,156 children for 7 years to determine the effect of maternal smoking on growth of pulmonary function in children. After correcting for previous level of FEVi, age, height, personal cigarette smoking, and correlation between moth- er's and child's pulmonary function, maternal smoking was associ- ated with a reduced rate of annual increase in F'EVl and FEF267s. The magnitude of the effect was consistent with a 3 to 5 percent decrease in expected lung growth due to the maternal smoking effect, constant over the time period of the study. Because so few mothers changed their smoking habits, the study did not attempt to differen- tiate between postnatal and in utero effects of involuntary smoke exposure. Ware et al. (1964) followed 10,106 white children for two successive annual examinations. The FEV, was 0.6 percent lower in the children of smoking mothers at the first examination and 0.9 percent lower at the second examination. These differences were statistically significant, but represent very small absolute differences. In this study, and in the other studies that show small changes in pulmonary function, it is not clear whether these changes represent small changes occurring uniformly among the children of smoking mothers or somewhat larger changes occurring in a small subpopula- tion of susceptible children. The available data demonstrate that maternal smoking affects lung function in young children. However, the absolute magnitude of the difference in lung function is small; it is unlikely that this small difference, per se, is of functional significance. The concern generat- ed by the demonstration of even small differences is directed at the future lung function of those children, particularly if they become active cigarette smokers as adults. The possibility that this differ- ence in lung function may result from pathophysiologic mechanisms similar to those present in active smokers raises the concern that these children may be "sensitized" to smoke at an early age, and that this "sensitization" may result in a more rapid decline in lung TABLE 6.-Pulmonary function in children exposed to involuntary smoking Study Subjecta Pulmonary function measure Outcome Comment24 Schilling et al. (1977) 816 children, aged 7-17, Connecticut and South Carolina FFW, a8 percent predicted No effect of parental smoking No control for sib&p size or correlation of siblings pulmonary function; when analysis restricted to children who never amoked, 0~ .9igniflcant1y less in children with smok& mothers Teger et al. UmQ 444 children. eg4 6-19. East Boston, Massachusetts MMEF in standard deviation units Significant effect of parental smoking Analysis wntrolld for sit&p size end mrreletion of siblinga pulmonary function Weim et al. (15180) 650 children, aged 6-9, EM Boston, Maxachueetta MMJZF in etandard deviation unite Significant effect of parental smoking Analyeie controlled for aibehip size and correlation of siblings' dmonaw function Vedal et al. (in prem) Lebowitz end BumW8 (1976) 4.000 children, eged Cl3 271 households with complete hietoriea of parents' smoking and of pulmonary function of children 2 age 6. Tucson, Arimna FEV7a Fvc, vcMlm vkwa v- FEV,, Fvc. vmum vmds derived from MEF, 0 CUTV~LI, expreaed aa etandard deviation units FVC positively associated, flow8 negatively aeaocieted No effect of parental smoking Flows doee-response with amount smoked by mother Suggestion that real differences in indoor levels of erpmure compared with more northerly cliitfs may be occurring TABLE 6.--Continued Study Subjectn Pulmonary function measure Outcome Comments 558 children, aged 8-10, ArizolUI FEV, by age change FEV,/H' per year No effect of parental smoking Potential bias in participation rates; crwseectional data not controlled for children's height; annual change in FEV,/H' at ages 8, 9, and 11 consistently greater in nonsmoking households than in tweparent smoking households; statistical test not significant, however Tager et al. (1981) 1,156 children, aged 5-19 at initial survey, Eaet Boston, Massachusetts Significant decreased rate of growth in FJW, and FEFzws for children of smoking mothers `I-year followup; no effect of paternal smoling; maximum effect of maternal smoking on fully developed lung not more than 4 or 5 percent Burchfiel et al. (198.3 4,378 children. aged O-19, Tecumeeh. Michigan Fvc, FEV,, v- Decreased FEV, and FVC for boys and 0-m for girls with increased number of smoking paren@ Abetract, no distinction between effects of maternal and patemal smoking; effects most prominent for boys and youngest age groups T&kin et al. U983l Hasselblad et al. m!?Z) 1.070 nonsmoking, nonasthmatic children, Lea Angeles 16,669 children, aged 5-17, seven geographic regions, united states v,, vm& Vmuzh FEFabrs FEY78 88 percent predicted Decreased v,, vmu26 for boyE and FEFzM~ V-X for girls with at leaat a smoking mother Siiificant effect of maternal smoking. but not paternal smoking No effect of paternal smoking Large number of children excluded became of invalid pulmonary function data or missing parental smoking data TABLE 6.-Continued Study Subjecta Pulmonary function measure Outcome Comments Speizer et al. W?UJ 8,120 children, aged 6-10, in six U.S. cities FVC and FEV, as percent predicted No eNect for F'EV, or FVC Recent analysis of this cohort demonstrated an effect for FVC and FEV, Ware et al. 10,COO children, aged 611, (ZW in six US. cities FEX,andFVC FVC positively associated with smoking, FEV, negatively associated FEW, dose-response with amount smoked by mother function as adults, particularly if they become smoking adUS. no data are currently available to establish the role, if any, of the small physiologic changes in children on the development of adult obstruc- tive lung disease. Pulmonary Function in Adults Exposed to Involuntary Cigarette Smoke White and Froeb (1980) reported on 2,100 asymptomatic adults drawn from a population about to enter a physical fitness program. They demonstrated statistically significant decreases in FEVI and MMEF as a percent of predicted in nonsmokers exposed to tobacco smoke in the work environment compared with nonexposed workers. The decrement was comparable to that seen in smokers inhaling 1 to 10 cigarettes per day. However, the absolute magnitude of the difference in mean levels of function in the smoke-exposed and unexposed groups was quite small: 160 ml (5.5 percent) for FEVl and 465 ml/set (13.5 percent) for MMEF. Carbon monoxide levels were measured in the workplace and ranged from 3.1 to 25.8 ppm. The population was self-selected, response was related to current work- place exposure and did not account for people who changed jobs, and it is unclear how the ex-smokers in the population were handled in the analysis. Comstock et al. (1981) examined 1,724 subjects drawn from two separate studies in Washington County, Maryland. They found no statistically significant greater risk of having an FEVl less than 80 percent of predicted in male nonsmokers exposed to wives' cigarette smoke at home. &hilling et al. (1977) did not find an effect of passive smoking exposure in adults. Both of these studies included adults in their samples who were relatively young and generally would not have had a long-term passive exposure in adult life. This point was brought out by a recently reported large study from France. Kauffmann et al. (1983) reported on a seven-city investigation in which a total of 7,818 adults were studied. In a subsample of 1,985 nonsmoking women aged 25 to 29, in which 58 percent were exposed to smoking husbands, there was a significant difference in level of MMEF between truly nonsmoking women and women of comparable ages exposed to passive smoking. This effect did not become apparent until age 40. These changes were small, and although not adjusted for differences in body size, may suggest a possible effect of long-term exposure in adult life. The physiologic and clinical significance of these small changes in pulmonary function in adults remains to be determined. In addition, variables such as ventilation, room size, number of rooms in the home, duration of contact with the active smoker, and number of cigarettes smoked could significantly influence total exposure and 402 need to be explored more fully. Differences in these exposure variables and the characterization of exposure may explain some of the differences in these study results (Table 7). The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD There are very limited data on the effects of passive smoke exposure in patients with preexisting pulmonary disease, and the available data are conflicting. Clinical studies have suggested a relationship between respiratory symptoms in asthmatics and expo- sure to parental cigarette smoke, but methodologic problems compli- cate the interpretation of the limited available data. O'Connell and Logan (1974) identified 37 asthmatic children who were "bothered" by parental cigarette smoke. Parents of 20 of the children stopped smoking and 18 (90 percent) of the 20 children had an improvement in symptoms. The control group consisted of 15 children (2 were not followed up) whose parents did not stop smoking. Only 4 (27 percent) of the children in the control group improved. The self-selection of those parents who quit, subjective criteria for improvement, and an unclear duration of followup limit the interpretation of this data. Gortmaker and coworkers (1982) studied two populations of children aged newborn to 17 years. They found a significant association between parental reporting of chil- dren's asthma and maternal smoking. Maternal smoking alone was associated with approximately 20 percent of all asthma. The effect persisted when age and sex of the child, allergies, and family income and education were controlled in the analysis. No control was attempted for the children's own smoking habits or for increased reporting of symptoms in children of symptomatic parents. Other population-based studies (Lebowitz and Burrows 1976; Speizer et al. 1980; Schilling et al. 1977) have not shown such results, Dahms et al. (1981) studied 10 patients with bronchial asthma and 10 normal subjects passively exposed to smoke in an environmental 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. Carboxyhemo- globin 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 (FVC), forced expiratory volume in 1 second (FEVl),and maximum mid expiratory flow rate (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 403 IP p TABLE `I.-Pulmonary function in adults exposed to involuntary smoking Study Subject8 Pulmonary function meaeupe Outcome Comments White and Froeb 2,100 adult.9, San k430, U980) California PVC, FEV,, and Mh@ aa percent predicted Siiticant effect of office eqxmm to involuntary smoke Cometock et al. 11981) 1,724 adults, waehington County, Maryland FEV, an percent predicted No effect of wives' smoking on huebands' pulmonary function Knuffma~~ et al. (198.3 7.818 ad&e, eeven French cities, eelected subgroupE FE!`,, FVC, and MMEF Significant effect in wives of smoking husbands in all measures; significant Only for hMEF in husbands of smoking wives Potential bti in selection; d only current cimrette smoke exposure Includes adults aged zOt Not adjusted for height; doee-reepoose to amount of hu&mda' smoking for MMEF in wivf!e; no effect below age 40 the preexposure values. Normal subjects had no change in pulmo- nary function 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 et al. (1979), in a very similar experiment, subjected 14 asthmatic subjects to a 2-hour cigarette smoke exposure in a closed room (14.6 ma). The carbon monoxide levels (24 ppm) were similar to those predicted in the study of Dahms and coworkers. No blood carboxyhemoglobin levels were measured. Subjects were randomized and blinded to sham (no smoke) and smoke exposure and tested on two separate occasions. Data were expressed as a percentage change from the sham exposure. No significant changes in FVC or FEVI were observed between sham and smoke exposure periods, although 5 of 12 subjects did report wheezing or tightness in the chest on the day of smoke exposure. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and symptoms in patients with known pulmonary disease. Further study of this important question is warranted. Summary and Conclusions 1. Cigarette smoke can make a significant, measurable contribu- tion to the level of indoor air pollution at levels of smoking and ventilation that are common in the indoor environment. 2. Nonsmokers who report exposure to environmental tobacco smoke have higher levels of urinary cotinine, a metabolite of nicotine, than those who do not report such exposure. 3. Cigarette smoke in the air can produce an increase in both subjective and objective measures of eye irritation. Further, some studies suggest that high levels of involuntary smoke exposure might produce small changes in pulmonary function in normal subjects. 4. The children of smoking parents have an increased prevalence of reported respiratory symptoms, and have an increased frequency of bronchitis and pneumonia early in life. 5. The children of smoking parents appear to have measurable but small differences in tests of pulmonary function when compared with children of nonsmoking parents. The signifi- cance of this finding to the future development of lung disease is unknown. 6. TWO studies have reported differences in measures of lung function in older populations between subjects chronically exposed to involuntary smoking and those who were not. This difference was not found in a younger and possibly less exposed population. 405 7. 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DEPOSITION AND TOXICITY OF TOBACCO SMOKE IN THE LUNG 413 CONTENTS CIGARETTE SMOKE DEPOSITION IN THE LUNG Introduction Characterization of an Aerosol Characterization of Cigarette Smoke Aerosols Factors That Affect Particulate Deposition Deposition of Cigarette Smoke Particulates Particulate Retention in the Lung Passive Smoking Conclusions CIGARETTE SMOKE TOXICOLOGY Introduction Preliminary Considerations Effects on Airway Function and Ventilation Human Studies Animal Studies Effects on Permeability of the Pulmonary Epithelium Human Studies Animal Studies Effects on Mucociliary Structure and Function Effects on Cells Human Studies Animal Studies Effects on Protease Inhibitors Human Studies Animal Studies Effects on Lung Tissue Repair Mechanisms Human Studies Animal Studies Summary and Conclusions References 415 CIGARETTE SMOKE DEPOSITION IN THE LUNG Introduction Previous Reports of the Surgeon General on the health conse- quences of smoking have focused on characterizing and quantifying responses to the inhalation of cigarette smoke. Typically, dose is given in terms of packs per day or cumulative pack years. However, a more accurate description of dose would include how much smoke is inspired into the respiratory tract, how much is deposited and fails to exit with the expired air, and the fate of the deposited smoke. A commonly held fallacy is that "living in New York is like smoking two packs per day." Is the amount of particles produced by smoking comparable to that encountered in urban air pollution? A person who smokes two packs of cigarettes per day with an average tar rating of 20 mg per cigarette would breathe in 800 mg of material per day, or 292 g of tar per year. A reasonable value for urban air would be 100 pg, OF 0.1 mg per cubic meter. The average person breathes approximately 20,000 liters, OF 20 cubic meters, of air per day. Thus, 2 mg of material per day, or 0.73 g of particulate per year, would be inspired. At the outset, it is evident that the amount of smoke entering the lungs is considerably greater than the amount of particulates from air pollution. This chapter emphasizes the size and aerodynamic properties of smoke and relates them to the fraction of the inspired smoke that deposits in the lungs. Also considered is where the smoke deposits, and its possible fate is described. The particulate phase of cigarette smoke, commonly known as tar, is inhaled as an aerosol into a smoker's respiratory tract. An aerosol is defined as a suspension of solid or liquid particles in a gas (Hinds 1982). In the case of cigarette smoke, the aerosol contains ambient air as well as the gases, liquids, and solids produced during tobacco combustion. The particulates include a wide variety of organic and metallic compounds, many of which are toxic to lung tissues. Hydrocarbons, aldehydes, ketones, organic acids, alcohols, nicotine, md phenols are among them. Metallic compounds such as radioac- ive lead and polonium are also present. The gas phase is also :omplex; in addition to the nitrogen and oxygen in the air, ,onsiderable amounts of carbon dioxide and carbon monoxide are jresent, and also significant amounts of cyanides, acrolein, nitrogen xides, and ammonia. The precise quantitative composition of the obacco smoke varies with many different factors, including the type f tobacco plant grown, the soil used to grow the plant, the method of tiring the leaves, the temperature of combustion during smoking, nd the composition and physical properties of the cigarette paper 417 and other additives. As the cigarette butt length decreases, many substances that have previously condensed on the remaining tobacco are revaporized. Generally, as butt length shortens, the smoke from the cigarette contains an increasing concentration of these sub- stances. Most of these constituents in smoke are toxic to lung tissues. Their toxicity extends from impairment of mucociliary transport, critical for clearing particles from the lungs, to carcinogenic and cocarcinogenic activities (Wynder and Hoffmann 1979; Battista 1976). To understand where the numerous particulates in cigarette smoke deposit in the lungs and how they are removed is important for determining the pathologic effects of chronic cigarette smoking. Characterization of an Aerosol To predict the deposition patterns of any aerosol, such as cigarette smoke, it is necessary to know the size, shape, and density of the individual particles or droplets. Describing the distribution of particle diameters is essential. It is convenient to describe particle size as an aerodynamic diameter rather than as an actual particle size based on optical measurements, because the former is a better predictor of aerodynamic behavior (Hinds 1982). Aerodynamic diameter is defined as the diameter of a sphere of unit density that has the same settling velocity as the particle being measured. This may be expressed as a count median aerodynamic diameter (CMAD) and a mass median aerodynamic diameter (MMAD). These are, respectively, the diameters for which half of the number or mass of the particles are less than that diameter and half are more. Characterization of Cigarette Smoke Aerosols The particulates in cigarette smoke `have been measured by several investigators using a variety of analytical devices. Because of different apparatus and different methods of smoke generation and dilution, results vary but are reasonably consistent. McCusker et al. (1983) used a device called the single particle aerodynamic relaxa- tion time @PART) analyzer to determine the size of particulates from several brands of cigarettes, with and without filters. The mass median aerodynamic diameter (MMAD) for all brands averaged approximately 0.46 urn; it was not markedly different when the filters were removed. These measurements showed that, even with a filter, billions of particles are present in an average 35 ml puff of cigarette smoke generated by an automatic smoking-machine. Par- ticulate concentrations per ml ranged from 0.3 x 109 to 3.3 x log, depending on whether the cigarettes were rated ultra-low, low, or medium in tar content. The reduced particulate concentration reported for low tar cigarettes results principally from filter 418 efficiency and air dilution of the smoke. When the specially designed filters were removed or the vent holes were covered, as could be accomplished by the smoker's fingers, particulate concentrations per milliliter increased to levels comparable to that for higher tar content cigarettes. Hinds (1978) compared the particulate size distribution in ciga- rette smoke using an aerosol centrifuge and a cascade impactor. Although these devices are based upon different physical principles, Hinds found that the results were comparable. The MMAD values ranged from 0.37 to 0.52 urn. Variations depended primarily upon the dilution of the smoke. The MMAD and concentration values reported by Hinds and coworkers (1983) were similar to those reported by Keith and Derrick (19601, who used a specially modified centrifuge, called a conifuge, to analyze cigarette smoke. Particulate analysis by a light scattering photometer yielded an MMAD of 0.29 pm and particulate concentrations of 3 x lOlo per ml (Okada and Matsunuma 1974). Carter and Hasegawa (1975) "fixed" cigarette particulates with methyl cyanoacrylate, a method that may produce artifacts, and measured a mean diameter of 0.48 urn from electron micrographs of the particulates. Earlier methods of measurement were based upon the collection of smoke particulates on various surfaces. Harris (1960) reported a range of 0.16 to 0.54 urn from a replica of cigarette smoke particulates that included a correction for droplet-spreading during sample preparation. Langer and Fisher (1956) found a median range of 0.6 pm, but made no correction for droplet-spreading during sample collection. Time and concentration are important modifiers of tobacco smoke. Cigarette smoke aerosols contain volatile components, and evapora- tion gradually reduces particle diameters. It is also true that with the extremely high particle concentrations encountered in main- stream smoke, the aerosol can agglomerate rapidly because nearby particles collide with each other and coalesce. If smoke is cooled (reducing the vapor pressure of the volatile components) and diluted (reducing the probability of particle collisions) the particle size will be more stable. Thus, it is difficult to reliably measure the size and concentration of particles in cigarette smoke produced under realis- tic experimental conditions. The size and concentration of the particulates are also affected by the decreasing length of a cigarette as it is smoked. McCusker et al. (1983) found the particulate concentration to be 67 percent greater in the last three puffs of a filtered cigarette than in the first three. Ishizu et al. (1978) also reported that particulate concentrations in unfiltered cigarettes increased and that the mean geometric diame- ter of the particles decreased with decreasing cigarette length. They attributed the former effect to the decreased filtration by the tobacco column and the latter effect to the shorter length traveled by the 419 particles to reach the butt end and, hence, the decreased time for particulate coagulation. In addition, their results illustrate that filters may trap the larger particles and generate more uniform aerosols; McCusker et al. (1983) noted no change in MMAD between the first and last three puffs of filtered cigarettes. Ishizu et al. (1978) also reported that larger puff volumes decreased the average particulate diameters. This can affect interpretation of experimental data in that standard cigarette smoking-machines draw 35 ml puff volumes, whereas Hinds et al. (1983) reported that 54 ml was the average puff volume measured in smoking subjects. Particle size is a critical factor in determining what fraction of the particles that enter the respiratory tract will deposit there and fail to exit with the expired air, as well as where they will deposit. Submicrometric particles will deposit not only in small and large airways, but also in alveoli. Breathing pattern is also important (see review by Brain and Valberg 1979). Large tidal volumes will favor alveolar deposition. Higher inspiratory flows will promote deposition at bifurcations. Breath-holding is important, because the greater the elapsed time before the next expiration, the higher the fraction deposited (collection efficiency). Individual anatomic differences may influence the amount and distribution of deposited particles. The cross-section of airways will influence the linear velocity of the inspired air. Increasing alveolar size decreases alveolar deposition. Factors That Affect Particulate Deposition A typical puff volume is approximately 30 to 70 ml. It is usually inspired with a volume of ambient air that is one to two times the normal tidal volume. Particle size not only can change in experimen- tal equipment as described above, but also may change within the human respiratory tract. After a volume of smoke is drawn into the mouth and upper respiratory tract of a smoker, it may be retained in that humidified air before deep inhalation. Here too, the particulates can change in size through coagulation or evaporation. They can also grow because of the particulates' affinity for water, termed hygroscopicity (Davies 1974; Hiller 1982b3. Other aspects of each smoker's behavior may also influence dose. Most manufacturers achieve low tar yields by the use of ventilated cigarette holders; this causes the inhaled smoke to be diluted with air. However, 32 to 69 percent of interviewed smokers of "low" tar cigarettes reported that they blocked these filter preparations with their fingers or lips. This causes dramatic increases in the amount of tar and nicotine in a way not predicted by studies using smoking-machines (Kozlowski et al. 1980). 420 Such individual differences in cigarette use as well as other strategies designed to increase the inhalation of tar and nicotine probably account for the poor correlation between the machine- determined nicotine yield of a cigarette and the concentration of nicotine or its metabolites in blood or urine (Russell et al. 1975, 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). For example, Herning and coworkers (1981) demonstrated that when low nicotine cigarettes are used, most smokers compensate by increasing the puff volume. In addition, Tobin and Sackner (19821 reported that some subjects increase their puff volume by up to 70 percent after switching to low tar cigarettes. In some instances, this compensatory increase occurred during a single experimental session. In contrast, a few smokers may reduce smoke deposition in their lungs by retaining the smoke in their mouth for several seconds before inhaling it. Stupfel and Mordelet-Dambrine (1974) showed that if a smoker holds the smoke in his mouth for 2 seconds, 16 percent of the particulate matter is removed. Also, 60 percent of the water-soluble components of the gas phase are absorbed by the upper airways. Chronic smoking also causes alterations in lung structure that affect deposition patterns. Sanchis et al. (1971) studied the deposition of an aerosol of radioactively labeled albumin inhaled by smokers and nonsmokers. They found less aerosol deposition in the alveolar region of smokers than of nonsmokers and suggested that the difference may be the result of alterations in the small airways produced by chronic smoking. Similar results were reported for hamsters exposed to cigarette smoke for 3 weeks prior to a single exposure of radioactively labeled cigarette smoke (Reznik and Samek 19801. More labeled smoke concentrate was found in the lungs of hamsters not previously exposed to cigarette smoke. The rate and pattern of breathing can also affect the total dose of cigarette particulates deposited in the lungs. Dennis (19711 reported that exercise increased the percent deposition of two experimentally generated aerosols in human subjects. Increased deposition was also measured in exercising hamsters that inhaled a radiolabeled aerosol (Harbison and Brain 1983). These results are most relevant to those who smoke when ventilation is increased while working or shortly after a period of exercise. Deposition of Cigarette Smoke Particulates The factors discussed in the previous section illustrate that experimental measurements of the size and concentration of ciga- rette aerosols are insufficient for the prediction of deposition patterns. Cigarette smoke is a mutable aerosol, which complicates the collection of accurate and reproducible data regarding its particulate composition. In addition, alterations in respiratory 421 structure and respiratory rate can affect the deposition of particu- lates. These complexities stress the importance of actual measure- ment of the regional deposition of cigarette smoke particulates in human lungs. However, few data have been published on this important area, despite the prevalence of smoking and its impact on human health. Most of the available information on the deposition of cigarette smoke particulates is based upon theoretical or physical models of the lungs and measurements of differences in the concentration of aerosol between inhaled air and exhaled air. A model to predict the percent deposition of particles based upon MMAD was presented by the Task Group on Lung Dynamics of the International Commission on Radiological Protection (1966). The respiratory tract was divided into three main regions: nasopharynx, trachea and bronchi, and alveoli. In conjunction with estimates of particulate clearance, deposition calculations were made for these regions at three different inhalation volumes. This model suggests that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in the alveolar region and 5 to 10 percent will deposit in the tracheobronchial region. This model also emphasizes the impact of particle solubility on the total integrated dose over time. Brain and Valberg (19741 developed convenient nomograms and a computer program to demonstrate how particle solubility and particle size significantly affect the net amount of particulates retained in the lungs. Aerosol deposition has also been studied in airway casts. Physical models of the upper airways of human lungs have been made by a double casting technique in order to study particulate deposition at several airway generations (Schlesinger and Lippmann 1972). Lungs obtained at autopsy were filled with wax or alloy. When these materials became solid, the tissue was removed and the casts were coated with silicon rubber or latex. The wax or alloy was then melted and removed, leaving a cast of the original airways. Different flow rates and particulate sizes were used to study deposition patterns. Schlesinger and Lippman (1978) reported a correlation between the deposition sites of test aerosols in the lung casts and the most common sites of origin of bronchogenic carcinoma in humans. Both occurred preferentially at bifurcations. Martonen and Lowe (1983) added an oropharyngeal compartment and a replica cast of the larynx to the tracheobronchial casts in order to better simulate air flow patterns in the upper respiratory tract. They used these models to evaluate the amount of cigarette smoke condensate deposited in the airways at different flow rates. More condensate was present at branching regions, especially at carinal ridges. Aerosol was also deposited preferentially along posterior airway walls. Most experiments designed to determine aerosol deposition in human subjects measure differences in aerosol concentration before 422 and after inhalation. Hinds and associates (1983) measured the percent mass of inhaled tobacco smoke particulates that deposited in male and female smokers. A transducer placed in the filter of a smoked cigarette relayed information to an automatic smoking- machine to duplicate inhaled puff volume. This method was used to produce a more natural smoking pattern. Comparisons were then made between particulate mass concentrations in the machine- generated smoke and the amount of smoke actually exhaled by the smoker. With these measurements, a 57 percent deposition of particulate mass was seen in men. This was greater than the significant 40 percent collection efficiency measured in women (p < 0.01). No data regarding particulate size or deposition sites were reported. Hiller and coworkers (198213) also measured the deposition fraction of an aerosol containing three different sizes of polystyrene latex spheres in nonsmoking humans. They measured a 10 percent deposition for 0.6 pm (MMAD) spheres, which is similar to the results of Davies et al. (1972) and Muir and Davies (1967) using 0.5 pm aerosols and of Heyder et al. (1973) using aerosols with a 0.2 to 1.0 pm range. The size ranges of these aerosols are comparable to those experimentally measured in cigarette smoke, as previously discussed. These percentages are lower than those observed by Hinds et al. (1983), probably reflecting differences in breathing patterns. The measurements of Hinds et al. (1983) were made with realistic breathing patterns used during smoking; the other investigators had used normal breathing patterns. Increased breath-holding following inspiration probably accounts for the enhanced collection efficien- cies. Particulate Retention in the Lung The amount of particulates retained in the lung at different times following the inhalation of an aerosol such as cigarette smoke depends upon the balance between the amount that deposits in the respiratory tract and the efficiency of the lung clearance mecha- nisms in the airways and alveoli. Particles depositing in the airways are entrained in the mucus layer lining these passages. This layer is swept toward the mouth by the action of ciliated cells and eventually swallowed. Macrophages present in the airways may also phagocy- tose deposited particulates and are also carried toward the mouth by the mucociliary transport system. Particulates reaching the alveolar region-those that are usually smaller than several micrometers in size-are soon engulfed by alveolar macrophages. These cells gradu- ally migrate toward the airways and exit the lung via the mucocili- ary escalator. Dissolution is also an important clearance mechanism for soluble particles. Clearance mechanisms are a dynamic compo- nent of normal lung function and operate to keep the lung sterile. 423 Lung disease and cigarette smoking itself can affect particulate clearance and retention in smokers' lungs. Previous studies have shown that smokers have different aerosol deposition patterns and slower clearance rates than nonsmokers (Albert et al. 1969; Cohen et al. 1979; Sanchis et al. 1971). These alterations in clearance are, in part, caused by components in cigarette smoke that are ciliotoxic (Battista 1976) and impair phagocytosis by alveolar macrophages (Ferin et al. 1965). Clearance mechanisms in smokers may be further compromised by lung diseases, such as emphysema and fibrosis, and by exposure to air pollutants, Oxidants in photochemical smog, such as ozone and nitrogen oxides, are toxic to ciliated cells and macrophages (Bils and Christie 1980). Measurements of retention of cigarette particulates in the lungs over time are difficult to estimate from data obtained with airway casts or from differences in the aerosol concentration of inhaled and exhaled smoke because these methods do not take clearance mechanisms into account. Unfortunately, few data are available regarding the actual retention and sites of deposition of cigarette smoke particulates in either humans or animals. The most accurate method is quantification of particulate deposits in individual pieces of tissue dissected from the lung. Impossible in living animals, this is a tedious procedure with animal lungs or human material obtained at surgery or autopsy and is especially difficult with large lungs. Little et al. (1965) examined lungs from humans at autopsy and suggested a correlation between the sites of bronchogenic carcinoma in the lungs of smokers with the deposition of polonium21o, a radioactive component of cigarette smoke. Resnik and Samek (1980) used a radioactive marker to study the retention of smoke in hamster lungs. They exposed hamsters to the smoke from cigarettes containing a labeled component in the tobacco and then measured the amount of radioactivity present in different lobes. They found that more radioactivity was present in the lung tissue of hamsters not previously exposed to unlabeled cigarette smoke. However, the clearance of the labeled component from the lungs was slower in the group previously exposed to smoke. There are problems with using animal models for smoke uptake. Most rodents are obligatory nose breathers, and significant fractions of the smoke may be taken up as it passes through the upper airways. Page et al. (1973) studied mice using radiolabeled cigarettes. They found that 50 percent of the deposited smoke was recovered from the nasal passages. About 30 percent was recovered from the esophagus, stomach, and other organs, and only 20 percent was present in the lungs. Exposing animals via a tracheostomy avoids this excessive and unnatural deposition in the nose, but it bypasses the mouth and larynx, which may remove some particles during smoking in man. 424 Passive Smoking Recently concern has increased regarding the health effects of cigarette smoke inhaled by nonsmokers, a phenomenon called passive smoking. The smoke is composed of that exhaled by the smoker and the sidestream smoke produced by the burning cigarette between inhalations. The concentration of respirable particulates in areas where there are smokers can range from 100 to 700 pg/m3. This is up to 25 times higher than that found in nonsmoking areas (Repace and Lowrey 1980). Using mean deposition values of 11 and 70 percent for the passive smoker and the active smoker, respective- ly, from the data presented by Hiller et al. (1982), the deposition would be approximately 0.55 mg for a nonsmoker over an 8-hour day in a room with 500 pg/m3 of smoke. In comparison, a smoker would deposit approximately 400 mg of tar in his or her lungs if he or she smoked two packs of cigarettes with an average tar rating of 20 mg per cigarette during the same time period. As has been discussed earlier, the rate and pattern of breathing can also affect the total dose of cigarette particulates deposited in the lungs. Although the amount of smoke depositing in the lungs of nonsmokers during passive smoking is small compared to that encountered by the active smoker, large numbers of people are involved. In the United States in 1979, 36.9 percent of men and 28.2 percent of women were current smokers (USDHEW 1980). Conclusions Cigarette smoke is the most important cause of chronic obstructive lung disease. This significant response is matched by the significant dose of toxic particulates received by the respiratory tract of smokers. The particle size of cigarette smoke is so small that little protection is offered by the filtering capacity of the upper airways. Cigarette smoke penetrates deep into the lungs and reaches the small airways and alveoli. The fraction of the smoke deposited is high because most smokers employ some breath-holding following inhalation of a puff. Their attempt to enhance deposition of smoke is successful, resulting in increased lung burdens of toxic smoke products. 425 450-144 0 - 85 - 15 CIGARETTE SMOKE TOXICOLOGY Introduction The inhalation toxicity of tobacco smoke has become one of the major public health problems of the 20th century. The chemical complexity of tobacco smoke confounds the task of identifying its toxic constituents. Tobacco smoke is comprised of thousands of chemical components arising primarily from volatilization and pyrolysis of the tobacco leaf (Stedman 1968; Green 1977). The chemical gamut runs from traces of elemental metals, such as cadmium, to nonvolatile whole tobacco leaf components that have escaped degradation during the burning process (USDHHS 1981). Approximately 90 percent of the individual constitutents are organic compounds associated with both the particulate phase and the gas phase (Guerin 1980). It is not surprising that chronic inhalational exposure to this diverse mixture of potentially bioactive compounds can evoke a wide variety of toxicologic responses. Over the years, scientific and public concern has centered primarily on the carcino- genic and atherogenic effects of tobacco smoke. In contrast, relative- ly little is known about the involvement of tobacco smoke constitu- ents in the pathogenesis of chronic obstructive lung disease (COLD) (USDHHS 1981). For the most part, smoke constituent toxicity studies, both epidemiologic (Dean et al. 1977; Higenbottam et al. 1980) and toxicologic (Walker et al. 1978; Lewis et al. 1979; Coggins et al. 19801, have been confined to a comparison of the varying amounts of particulate matter or tar delivered by smoke. In studies of this nature, attempts have been made to distinguish between the relative toxicities of the vapor phase and the particulate phase of tobacco smoke. The general conclusion reached is that gas phase components that penetrate to the small airways and alveoli may play a significant role in the production of peripheral airway and parenchy- ma1 diseases such as emphysema, whereas particulate phase compo- nents that deposit in larger airways may play a role in the development of disorders of the more proximal airways such as chronic bronchitis (USDHHS 1981). This generalization may not always hold, however. For example, in a review of the effects of smoking on mucociliary clearance, Newhouse (1977) noted consider- able disagreement among investigators with regard to whether the vapor phase or the particulate phase was the major factor in smoke- induced dysfunction of the mucociliary transport system. Also, Coggins and associates (1980) observed an increase in both peripher- al and central airway goblet cell number in rats after exposure to tobacco smoke from which most of the vapor phase had been removed. Cohen and James (1982) found that the level of oxidants in tobacco smoke (oxidants have been implicated in the pathogenesis of 426 emphysema) correlated with the amount of particulate matter in smoke from various brands of cigarettes. At present, therefore, attempts to associate a specific toxicologic response solely with either the vapor phase or the particulate phase of tobacco smoke are not recommended. Because so little is known regal-ding the role of specific constitu- ents or phases of tobacco smoke in the pathogenesis of COLD, this section of the Report is organized on the basis of specific insults to the respiratory system that may be brought on by exposure to whole tobacco smoke and that may lead to structural and functional changes within the lung. Included, as available information permits, are data on the known contribution of individual smoke constituents or phases to a specific insult. Human and animal studies are described separately to provide a perspective on the extent to which animal research has verified or extended clinical research and vice versa. Preliminary Considerations Tobacco smoking is generally accepted as the major cause of COLD (USDHEW 1979; USDHHS 1981). COLD is often subdivided into three categories: (1) uncomplicated bronchitis, characterized by mucus hypersecretion and cough, (2) chronic bronchitis with bronchi- olar inflammation and obstruction of distal airways, and (3) pulmo- nary emphysema, characterized by distal air space enlargement with loss of alveolar interstitium. These three pathologic condit.ions are often considered collectively within the context of COLD because they can coexist in the lungs of smokers and because signs and symptoms associated with one condition may presage the develop- ment of another. Effects on Airway Function and Ventilation Human Studies Cigarette smoke appears to have both chronic and acute effects on airway function. In adults, smoking over a period of years leads to narrowing of and histopathologic abnormalities in small airways (Ingram and O'Cain 1971; C osio et al. 1980; Suzuki et al. 1983). Even in teenagers, regular smoking for 1 to 5 years is sufficient to cause demonstrable changes in tests of small airway function in some smokers (Seely et al. 1971); the lungs of young cigarette smokers who die suddenly show definite pathologic changes in the peripheral airways (Niewoehner et al. 1974). The acute response to cigarette smoke has been reported to involve large airways, small airways, or both. Costello and associates (1975), in a study of asymptomatic smokers and nonsmokers, found that 427 tests of small airway function (maximum expiratory flow volume curves, closing volume, and frequency dependence of compliance) were unaltered after smoking one cigarette; however, specific airways conductance, a measure of large airway function, fell significantly in both groups. Essentially the same results were obtained by Gelb and associates (1979), who reported a decrease in airways conductance but little or no change in volume of isoflow (another test of small airway function) in healthy nonsmokers after smoking one cigarette. Likewise, McCarthy and colleagues (1976), using several different tests, found no evidence for an acute effect pf intensive cigarette smoking on small airways, but did demonstrate increased large airways resistance. The decrease in conductance caused by cigarette smoke has been shown to occur within 7 or 8 seconds of a single inhalation (Rees et al. 1982), and filtration seems to reduce the degree of bronchoconstriction (Da Silva and Hamosh 1980). Irritant effects of tobacco smoke are not limited to the particulate phase, because exposure to oxides of nitrogen at levels present in cigarette smoke also can precipitate acute bronchospasm (Tate 1977). Nicotine does not appear to be responsible for the acute bronchoconstriction that accompanies cigarette smoking (Nadel and Comroe 1961). Zuskin and coworkers (1974) showed that in healthy human subjects, smoking one or two cigarettes decreased flow rates on maximum and partial flow-volume curves, and concluded that smoking causes acute narrowing of small airways. Da Silva and Hamosh (1973) and Sobol and colleagues (1977) measured airways conductance, as well as maximum mid-expiratory flow rates, and concluded that both large and small airways are probably affected by the acute inhalation of cigarette smoke. Though the bronchoconstrictive response to cigarette smoke has most often been attributed to a cholinergic reflex originating with stimulation of irritant receptors in the airways, there are data suggesting that histamine may also be involved. Walter and Walter (1982b) found a significant increase in the number of degranulated basophils in the blood of smokers 10 minutes after smoking compared with just before smoking. There is also some evidence to indicate that smokers may differ from nonsmokers in their respon- siveness to inhaled histamine (Brown et al. 1977; Gerrard et al. 1980) as well as methacholine (Malo et al. 1982; Kabiraj et al. 1982; Buczko et al. 1984), but smoking immediately prior to an inhalation test does not appear to affect bronchial responsiveness to either histamine or methacholine (McIntyre et al. 1982). Asthmatic subjects have a greater than normal susceptibility to the bronchoconstrictive effects of cigarette smoke when the smoke is actively inhaled. The question whether tobacco smoke plays a role in 428 allergic asthma has yet to be resolved completely I USDHEW 1979; Shephard 1982; Burrows et al. 1984). Animal Studies Binns and Wilton (1978) studied the acute ventilatory response to cigarette smoke in rats. They found that within the first 3 minutes after initiation of smoke exposure, tidal volume fell to 80 percent of the preexposure level, then rose to 160 percent after 9 minutes of exposure; respiratory rate dropped to 40 percent of the preexposure level within 1 minute and remained there for the duration of the exposure period. There was no adaptation of the acute ventilatory response after 4 weeks of daily smoke exposures. In a similar study, Coggins and associates (1982) found that rats exposed to a relatively low dose of cigarette smoke demonstrated a persistent depression in tidal volume and breathing frequency, whereas animals exposed to a relatively high dose exhibited an increase in tidal volume with no change in frequency. Acute airway responses to cigarette smoke have not been studied as extensively in animals as they have been in man. Experiments in anesthetized dogs (Aviado and Palecek 1967), rabbits (Sellick and Widdicombe 1971), and cats (Boushey et al. 1972) indicate that acute smoke exposure elicits reflex bronchoconstriction. There also is evidence from experiments with isolated monkey lungs that smoke exposures stimulate histamine release (Walter and Walter 1982a). Histamine appears to be responsible, at least in part, for mediating .he increase in collateral resistance in dogs following administration If cigarette smoke (Gertner et al. 1982). The chronic effects of cigarette smoking on pulmonary function in logs were studied by Park and coworkers (1977). Active inhalation of 100 and 200 puffs of diluted (1:4) smoke 5 days per week for periods jf 6 months and 1 year, respectively, did not produce any noteworthy :hanges in pulmonary function. The effects of chronic cigarette ,moke exposure on ventilation in rats were studied by Loscutoff and *oworkers (1982). Animals exposed for up to 24 months to cigarette urcficd tr,Pi, nnJ bronchopu!:::cJ- n:;irv lavage fluids on both pctrcir~:~ :I::d ELI.:::!:; ;lastase. The suppression of human serum e::istxtacl I,;ilib!tc>r>, r;,pa::ity 51; s:moke condensate solutions in vitro has aisu been den-,-.:Ltl,;ltt-d bp others ~Ohlsson et al. 1980,. Comparison of the protease inhibitory capacity ,)t` serum sarnples from smokers and nonsmokers has revealed a significant depression in smokers that is correlated with smoking history (Chowdhury 1981: Chowdhury et al. 1982). The latter st.udies also reported that the depression of serum prot,ease inhibitor; was reiated to an effect of smoke on the inhibitors per se. and not to a decrease in serum antiprotease concentration. Still, the effect of tobacco smoke on serum and lung lavage fluid antiprotease concenrr:~tion and activitj- remains controversial. Several investigators have reported that smokers have elevated serum protease inhibitor le\pels (Rees et al. 1975; Ashley et al. 1980); others (Olsen et al. 197.5: Warr et al. 19771, like Chowdhury and colleagues, have shown no difference in serum or lavage fluid protease inhibitor concentrations between smokers and nonsmokers. Gadek and associates (1979) compared cr,Pi activity of lung lavage fluids taken from smokers and nonsmokers and found that smokers had a twofold depression of functional a,Pi activity. The activity of a,Pi in this study was tested against porcine pancreatic elastase. In a similar study (Carp et al. 19821, in which human neutrophil elastase was used, bronchoalveolar lavage fluids obtained from smokers had 40 percent less a,Pi activity than fluids from nonsmokers. However, Stone and colleagues 11983) found that smokers' bronchoalveolar lavage fluids did not exhibit decreased functional cr,Pi activity when tested against either porcine pancreatic elastase or human neutro- phi1 elastase, and suggested that increased elastaae derived from neutrophils may be the main factor in the genesis of emphysema in smokers. Smokers may have a functional deficiency in bronchial mucus protease inhibitor (BMPi) activity. A comparison of BMPi obtained from tracheal aspirates of smokers with BMPi from nonsmokers 435 revealed that smokers' BMPi was 20 percent less active against PMN elastase than nonsmokers' BMPi iCarp and Janoff 1980a). Specific cigarette smoke constituents that may be responsible for the inactivation of lung protease inhibitors have not been identified. Nicotine and acrolein were studied for their ability to suppress a,Pi activity and were found to be ineffective (Janoff and Carp 1977). Several studies have shown that oxidizing compounds such as chloramine-T and N-chlorosuccinimide can oxidize methionine groups on a,Pi and reduce its activity against porcine pancreatic and human PMN elastases (Cohen 1979; Johnson and Travis 1979; Satoh et al. 1979; Abrams et al. 1980; Beatty et al. 1980). This has led to the current belief that oxidants in cigarette smoke may be involved in the inactivation of protease inhibitors (Janoff et al. 1983). In addition to free radicals (Pryor 19801, cigarette smoke contains oxides of nitrogen possessing their own free radical properties and able to react with olefins in the gas phase or with peroxides to generate potent oxy-radicals (Dooley and Pryor 1982; Pryor et al. 1983). As mentioned previously, smoke condensate solution suppresses the elastase inhibitory capacity of serum a,Pi in vitro. This suppression can be prevented by the incorporation of phenolic antioxidants into the test media (Carp and Janoff 1978). Similarly, BMPi suppression by smoke condensate can be prevented by antioxidants (Carp and Janoff 1980a). Cohen and James (1982) used odianisidine oxidation to quantify the levels of oxidants in tobacco smoke condensates from various brands of cigarettes and found that oxidant levels correlated with capacity to suppress a,Pi deactivation of elastase. Further, this study provided evidence that peroxides and superoxide anions were responsible for the loss of a,Pi activity, because inclusion of catalase and superoxide dismutase in the test system reduced smoke condensate effects on a,Pi activity. Bron- choalveolar fluid from smokers contains some amount of oxidant- inactivated a,Pi, as evidenced by the presence of methionine sulfoxide residues (Carp et al. 1982). In addition to the numerous oxidizing agents present in cigarette smoke, byproducts of smoke-stimulated phagocyte metabolism repre- sent another potential source of oxidants capable of inactivating lung protease inhibitors. Carp and Janoff (1979) demonstrated that phagocytosing human PMNs produce activated oxygen species that diminish the elastase inhibitory capacity of human serum and pure a,Pi in vitro. These workers presented evidence to show that hydroxyl radicals resulting from the reaction between superoxide anions and H,O, were responsible for this effect. The inactivation of a,Pi by a myeloperoxidase-mediated reaction was also described in the study, which concurs with other studies demonstrating that purified myeloperoxidase, in conjunction with H,O, and a halide ion, can inactivate a,Pi in vitro (Matheson et al. 1979, 1981). Further 436 work has shown that activation of human blood monocytes, PMNs, and PAMs by use of a membrane-perturbing agent (as opposed to phagocytosis) results in the release of superoxide anions and H,O, and the suppression of serum elastase inhibitory capacity (Carp and Janoff 1980b). Clark and colleagues (1981) have demonstrated that the myeloperoxidase-H,02-halide system from chemically stimulated PMNs oxidizes a,Pi in vitro. Similar evidence ascribing inactivation of BMPi to the myeloperoxidase-H,O,-halide system has been reported (Carp and Janoff 1980a). In the studies noted above, phagocytederived oxidants were shown to be capable of inactivating a,Pi when porcine pancreatic elastase was used as the substrate. These findings were recently extended to include the more pathophys- iologically relevant protease, human neutrophil elastase (Zaslow et al. 1983). Little is known about in vivo inactivation of protease inhibitors by phagocyte-derived oxidants, other than that inactive a,Pi (in the oxidized state) has been found in the synovial fluid of patients with inflamed joints (Wong and Travis 1980). The extent to which oxidants from stimulated phagocytes play a role in the suppression of lung a,Pi activity in smokers is at present unknown. Animal Studies Although most of what is known about cigarette-smoke-induced oxidant injury to lung protease inhibitors has been derived from human studies, some work has gone into the effects of cigarette smoke on lung protease inhibitors in laboratory animals. It has been demonstrated that very brief exposure of rats to cigarette smoke can cause a significant reduction in the elastase inhibitory capacity of a,Pi obtained from lung lavage fluid (Janoff et al. 1979). Very likely this toxic effect of cigarette smoke is caused by oxidant damage to protease inhibitors, because treatment of the lavage fluid with a reducing agent partially restored normal elastase inhibitory capaci- ty and because animals rendered oxidant tolerant by preexposure to ozone did not exhibit a significant reduction in a,Pi activity following exposure to cigarette smoke. Effects on Lung Tissue Repair Mechanisms A preponderance of the research to elucidate mechanisms by which cigarette smoking induces emphysema has focused on the factors that initiate lung tissue degradation. Recent studies suggest, however, that the increased risk of emphysema associated with cigarette smoking may be due partially to the effects of smoke on lung repair mechanisms. 437 Human Studies For the most part, work concerning the effects of cigarette smoke on lung repair mechanisms has been conducted in experimental animals. It has been shown, however, that cigarette smoke contains an inhibitor that can prevent the cross-linking of human fibrin polymers and thereby impede normal tissue repair (Galanakis et al. 1982). Smoke and smoke constituents have also been shown to induce membrane damage in human lung fibroblasts (Thelestam et al. 1980). Of 464 smoke constituents tested, approximately 25 percent caused membrane damage. The most active constituents were amines, strong acids, and alkylated phenols; nitriles and polycyclic aromatic hydrocarbons were inactive. Animal Studies Cigarette smoke has been shown to affect elastin synthesis in vitro and elastin repair in vivo. Laurent and coworkers (1983) determined the effect of solutions of smoke condensate on elastogenesis in vitro by measuring the formation of desmosine (one of the major cross- linking amino acids of elastin) during conversion of tropoelastin to elastin. Using a cell-free system of purified tropoelastin from chick embryo aorta or porcine aorta and lysyl oxidase purified from chick embryo or bovine lung, these investigators found that desmosine synthesis was inhibited from 80 to 90 percent in the presence of an aqueous solution of the gas phase of cigarette smoke. Elastin repair in vivo has been reported to be retarded by tobacco smoke. Osman and colleagues (1982) showed that hamsters with elastase-induced lung injury resynthesized elastin at a reduced rate if they were exposed to six or seven puffs of whole cigarette smoke hourly for 8 hours per day during the repair period. Summary and Conclusions 1. The mass median aerodynamic diameter of the particles in cigarette smoke has been measured to average approximately 0.46 pm, and particulate concentrations have been shown to range from 0.3 x log to 3.3 x log per milliliter. 2. The particulate concentration of the smoke increases as the cigarette is more completely smoked. 3. Particles in the size range of cigarette smoke will deposit both in the airways and in alveoli; models predict that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in alveolar regions and 5 to 10 percent will deposit in the tracheobronchial region. 4. 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MITCHELL, C.A., BOUHUYS, A. Interaction between effects of beta blockage and cigarette smoke on airways. Journal of Applied Physiology 36: 449- 452,1974. 450 CHAPTER 9. ROLE OF THE PHYSICIAN IN SMOKING CESSATION 451 CONTENTS Introduction Patient Groups General Practice Patients Pregnant Patients Patients With Pulmonary Disease Patients With Cardiac Disease The Use of Nicotine Chewing Gum Discussion and Synthesis Methodological Considerations Trends in the Literature Patient Variables Related to Abstinence Physician Variables Related to Effectiveness Conclusions Recommendations for Physicians Future Research Summary and Conclusions References 453 Introduction Although a variety of health care providers have attempted to change the smoking behavior of the groups with whom they work (USDHEW 1979), most of the research in this area, and this review, is confined to patient populations or patient groups who provide opportunities for physician intervention. The nature and extent of the relationship between patient and physician enhances the oppor- tunity for long-term behavior change. Major international studies on utilization of health care reveal that 70 percent or more of North Americans see a physician at least once a year (Kahn and White 1976; National Center for Health Services Research 1983; Pacific Mutual 1978; National Center for Health Statistics 1982). Given this frequency of contact between smokers and their physicians, some 38 million of the 54 million adults in the United States who smoke could be reached annually with a smoking cessation message. Even if only 5 to 10 percent quit on a long-term basis, the potential impact of such contact is enormous. A recent study comparing free medical care to insurance plans requiring shared cost by participants did not show a beneficial impact on smoking (or other health habits associated with coronary heart disease and some types of cancer) from the average of one to two more encounters per year for several years (Brook et al. 1983). The authors comment that "these health habits, especially smoking, were at levels at which substantial health benefit from behavior change was possible" (p. 1432). Thus, physician contact alone does not increase smoking behavior change. Rather, a mix of physician, motivation, educational, and training efforts are doubtless called for. Many techniques have been described in the literature to assist physicians in treating cigarette smoking in their patients (Allaire 1983; Best 1978; Bohm and Powell 1982; Danaher et al. 1980; Fowler 1983; Hochbaum 1975; Hymowitz 1977; Indyke and Ellis 1980; Luban-Plozza 19'77; Pechacek and Grimm 1983; Pechacek and McAlister 1980; Pomerleau 1976; Rose 1975/76; Rosser 1977; Russell 1971; Seeker-Walker and Flynn 1983; Sherin 1982; Shipley and 3rleans 1982; Windsor et al. 1979). These range from supplying nformation about smoking and health with advice to quit smoking ;o implementing complex behavior modification techniques with -outine monitoring and long-term followups. Lichtenstein and Danaher (1978) have described a hypothetical node1 for the various roles that the physician can perform. iccording to their formulation, the physician can "(1) act as a model If a healthy lifestyle by not smoking, (2) provide information larifying the risks associated with smoking and the risk reduction if he patient stops, (3) encourage abstinence by direct advice and uggestions, (4) refer the patient to a smoking cessation program, nd (5) prescribe and follow up the use of specific cessation and 455 maintenance strategies in his or her own office management" (p. 233). This scheme is a hierarchical one, with each role subsuming the behavior of the ones that precede it. Other roles such as political lobbyist and researcher are related only indirectly to patient care (Rosen and Ashley 1978). In addition to advising their patients to quit, an overwhelming majority of physicians have quit smoking; the prevalence of smoking among physicians has most recently been estimated at 10 percent or less in the United States, considerably below that of the general population (Enstrom 1983; Fletcher and Doll 1969; Garfinkel 1976; USDHEW 1976; Sachs 1983). Physicians are, therefore, carrying out their role as exemplars. In a major national survey, over 90 percent agreed that it was their responsibility to set a good example for patients by not smoking cigarettes (USDHEW 1976). With regard to other roles, the majority of reports (both research and advisory) indicate that physicians usually function as information providers and advice givers. However, evaluations of treatment procedures that can be used for referral or in-depth treatment have also been carried out. It is expected that as results become known and more referral agencies are availa.ble, more physicians will be expanding their roles. The literature on rates at which physicians advise patients to quit smoking shows a disparity between physician estimates and patient reports. Over time, the proportion of physicians recommending cessation has increased dramatically. A mid-1960s survey revealed that 38 percent of physicians claimed that they advised "all" or "almost all" (95 to 100 percent) of their patients who did not have smoking-related disorders ,to quit or cut down (Green and Horn 1968). Eighty-eight percent of physicians claimed they gave this advice to patients with lung and pulmonary conditions. In 1979,85 to 92 percent of physicians participating in the evaluation of a quit smoking kit said they had spoken to smoking patients in the past few weeks, advising quitting t,o 6 to 7 out of the last 10 smoking patients seen (American Cancer Society 1981). In a 1981 survey of primary care practitioners in Massachusetts, 90 percent of all physicians who responded said they routinely asked about smoking; however, only 58 percent felt "very prepared" to counsel patients, and a mere 3 percent felt they were currently "very successful" in helping patients to change their smoking behavior (Wechsler et al. 1983). Ninety-eight percent of a Canadian sample of primary care physi- cians surveyed in late 1981-1982 reported advising patients who smoke to stop, with 45 percent claiming some success (Battista 1983; Battista and Spitzer 1983). There is evidence that smoking physi- cians feel less comfortable in dispensing advice to quit smoking and, therefore, do it less forcefully (American Cancer Society 1981). 456 The majority of persons who smoke feel that physician advice to quit or cut down on smoking would be influential (American Cancer Society 1977; Pacific Mutual 1978). In a 1978 survey of the public, doctor's advice was perceived to be the most effective means of prompting cessation or reduction among six alternatives considered, the other five being prohibition of smoking at work and in public places; urging by children, spouse, or relatives; higher taxes on tobacco; antismoking informational campaigns at work; and anti- smoking advertising on television (Pacific Mutual 1978). In this survey, 76 percent of smokers reported that doctor's advice would be "very" or "somewhat" effective in this regard. Given this general level of enthusiasm and confidence in physician-delivered messages, actual rates of reported advice are quite low. In the survey just reported, only 8 percent of former smokers spontaneously mentioned a doctor's recommendation as a cause of their cessation, although 51 percent cited health reasons (Pacific Mutual 1978). In the 1975 Adult Use of Tobacco survey, a full 64.6 percent of male and 60.8 percent of female current smokers claimed they had never received advice from any doctor about quitting, cutting down, or continuing smoking (USPHS 1976). About 20 percent of current smokers had been advised to quit. Combining advice to quit or cut down, the percentage rose to approximately 35 percent. A somewhat lower estimate of physician advice was obtained from a nationwide study of approxi- mately 8,000 people (Stewart et al. 1979). Advice to quit or cut down was reported by 22.4 percent, and lack of advice by 77.6 percent. However, patient recall for the details of a physician visit may be flawed. In one study, almost complete recall of cessation advice was reported 1 year later (Mausner 19701, but in a second study only 50 percent of patients recalled cessation advice 2 months after it was given (Rose and Udechuku 1971). It seems quite likely that physicians do offer varying degrees of advice and guidance to their patients (Fowler and Jamrozik 1983; Wechsler et al. 19831, and in view of the decrease in social acceptability given to the smoker, more physicians will be spending more of their time and energy in this way in the future. A growing number of editorials in medical journals have been devoted to the importance of primary prevention and to motivating physicians to this task (Check 1979; Yankauer 1983). This chapter reviews and summarizes studies of smoking cessation in various groups of patients, with a special focus on physician intervention. Four classes of patients are considered: general prac- tice, obstetric, pulmonary disease, and cardiovascular disease. Re- views of this literature show a positive relationship between severity of disease and the likelihood of quitting smoking (USDHEW 1979, 1980; Lichtenstein and Danaher 1978; Pederson 1982). However, Pederson cautions that a causal interpretation of this relationship 480-144 0 - 85 - 16 may not be warranted, as physician involvement may be greater and the effect of physician advice more salient or intense with sicker patients. In addition, a section on research using nicotine chewing gum as a treatment is included. Suggestions regarding future research and treatment are also presented. Patient Groups General Practice Patients Unlike the physician whose practice involves mainly patients with pulmonary or cardiac disease, a large proportion of the general practitioner's time may be spent in lifestyle modification of a preventive nature with patients who are not experiencing smoking- related problems. It may be that compliance among these patients is dependent upon diagnosis, but no available studies have related the reason for the office visit to success or failure in quitting, although most counseling is said to take place during regular checkups or during visits for respiratory problems, much less often than during visits for unrelated major medical problems or minor problems (Battista 1983). Nine studies have dealt specifically with general practice pa- tients. Mausner et al. (1968) followed 157 smoking patients of two physicians sharing an office. One physician advised all the smokers in his practice who came to his office over a 2-month period to quit (n=121). Patients were told that smoking was harmful, and were given written information on quitting techniques as well as lobeline, a nicotine substitute. The other physician made no special mention of smoking (n= 36 patients). At a 6-month followup, 33 percent of those who were told to quit had reduced the amount they smoked, compared with 9 percent in the group without such cessation advice. Reduction was defined as a decrease of at least 10 cigarettes per day. There was no validation of self-report. The factors found to be related to decrement in smoking were higher initial consumption and number of pack-years; a marginally significant relationship with being male was noted, and for both sexes it was the heavier smokers who changed. Porter and McCullough (1972) compared the smoking behavior of 101 randomly selected patients who were counseled by one general practitioner about their smoking with 90 patients who were not counseled. Counseling consisted of advice, discussion, and a leaflet. There was no significant difference in quit rate after 6 months between the two groups: 2.5 percent in the counseled group and 4.4 percent in the not counseled group quit. No validation was per- formed. Handel (1973) followed for 1 year a group of 100 patients whom she had advised in l- to 7-minute messages to quit smoking. The advice 458 was followed by 38 percent of the men and 11 percent of the women. Eighteen percent of the remaining male smokers and 22 percent of the female smokers reported reducing consumption by more than 50 percent. No control group was included in this study. Pincherle and Wright (1970) reported a smoking intervention in a clinic that provided health examinations of business executives on an annual or biannual basis. Physicians were encouraged to deliver a strong antismoking message, and a booklet was made available. Results varied among the 10 participating physicians; between 17 and 35 percent of the 1,493 smokers seen at a followup visit at approximately 18 months had stopped smoking cigarettes or had reduced their smoking more than 30 percent, There were no controls or validation of self-report. The doctor's own past or present smoking habits only partially accounted for the variation in success rates (cf. American Cancer Society 1981). The quit rate of 19 percent reported by Richmond (1977) in a similar setting is consistent with their findings. In preliminary findings, Rosser (1979) reported that 10 percent of smokers counseled by family physicians about cardiovas- cular risk reduction report smoking cessation 1 or 2 years later. In a large-scale study of 2,138 patients of 28 London physicians in five practices, Russell et al. (1979) assessed the effectiveness of physician smoking advice in comparison with no advice. Assignment to group was by day of attendance at practice. Four groups were used: a nonintervention control, a questionnaire-only control, an advice-only group, and an advice group receiving a two-page pamphlet and a warning of subsequent followup. Advice was delivered in the physician's own style in a l- or 2-minute message. At l-year followup, the overall quit rate was 14.4 percent-respectively for each group, 10.3, 14.0, 16.7, and 19.1 percent. The percentages of patients who stopped within 1 month of the initial visit and who were still abstinent at followup were 0.3, 1.6, 3.3, and 5.1 percent, respectively. These results were statistically significant, indicating that advice to quit was effective and enhanced by written material and information about a subsequent followup. The major effect was to increase motivation in terms of the percentage of patients in each group attempting to quit but not the success rate of quit attempts, and to reduce relapse at the l-year point compared with the initial l- month assessment. One can interpret this as due to the limited scope of advice, focused on health education, and not to quitting skills. Quit rates differed markedly among physicians and were inversely related to the patient's initial consumption. Validation of the verbal report of abstinence on a very small subsample of patients, using a measure of nicotine concentration in saliva, revealed a low deception rate (7 percent), which may have been unreliable, owing to patient selection methods. 459 In an attempt to replicate findings of Russell et al. (1979) in a Canadian sample, Stewart and Rosser (1982) randomly assigned 691 patients to one of three groups: control, advice, and advice plus pamphlet. There were no differences between the groups; only 3 to 4 percent of patients had stopped smoking at the 5-month followup and were still abstinent at 1 year. At that later followup, the overall success rate was 11.7 percent; no objective measure of smoking status was included. The researchers note that the control group had a higher rate of long-term quitting (3.1 percent) than in the Russell group's 1979 study (0.3 and 16 percent). A second study by Russell et al. (1983131 enrolled a sample of 1,938 cigarette smokers, aged 16 and older, who visited 34 general practitioners in six group pra.ctices in Kent and London in November 1980. All smokers were included and were assigned in balanced design by week of attendance to one of three groups; nonintervention controls, 1 to 2 minutes of advice in the physician's own style plus booklet and warning of followup, and similar advice plus booklet plus offer of a nicotine gum prescription. A questionnaire was mailed and a personal followup was performed after 4 months and 1 year. Patients who did not provide adequate data at both points were counted as smokers. Two-thirds of those who claimed to have quit at each time point were checked by measurement of expired air carbon monoxide. At 1 year, self-reported quit smoking rates in the three groups were 13.4, 10.8, and 16.2 percent (p ~0.021, respectively. For those patients not smoking at 4 months and at 1 year, the cessation rates were 6.0, 6.4, and 11.9 percent, respectively (p ~0.02). After correction for those who refused or failed chemical validation (22 percent) and for those who switched from cigarettes to pipes or cigars, the cessation rates were 3.9, 4.1, and 8.8 percent (p