The Health Consequences of Smoking THE CHANGING CIGARETTE a report of the Surgeon General U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Olfico WI Smoking and Health The Honorable Thomas P. O'Neill, Jr. Speaker of the House of Representatives Waahingto". D. C. 20515 Dear Wr. Speaker: I hereby submit to YOU the Health Conmequencee of Smoking- The Changing cigarette. lhia report ie in re*pon.e to two Co"gre8eio"al requirements. The Public Health Cigarette Smoking Act of 1969 call8 upon thin Department to iaaue annual reports on the health consequence. of smoking and to submit legislative ret-ndatione. Section 403 of the Health Service8 and Canter8 Amendment, of 1978 asks for a 'ntudv or etudiee of (11 the relative health risks aeeociated with lrmoking cigarettea of varying level, of tar, nicotine, and carbon monoxide: and (2) the health rinka aaeociated with mmoking cigarette8 containing any substances ccuumonly added to c-rcially manufactured cigarettem. * . In preparing this report, the ecientiets and scientific agencies of thin Department have reviewed all current scientific evidence and have concluded that the search for leea hazardous cigarette8 hoe not yielded a product which CL" be considered "mafe." The per.0" who changes to a cigarette with lower maaaured yielda may reduce certain hazards of smoking, but the benefits will be small coapared to the benefita of quitting entirely. The noat important conclusion of thin report is that government and the private comuunity alike muat intensify their effort8 to remind the public of the hazarda of emoking and to ameiet thoee who do smoke to quit. we mullt step up our programa to pareuade young people not to take up the habit in the firat place. This report also notes that we must continue to monitor the changing cigarette to insure that when new cigarette products appear they do not bring with them new hazard0 to health. Throughout this report the need to knew about substances added to cigarettem ia stated repeatedly. At present. there is no nschanian by which government or the scientific comrmnity can require diacloeure of these additive*, which must obviously be a firet step in aaaeeaing their health effects. 'his needs to be corrected by voluntary action or, if "ece*~ary, by legislation. 0" a "umber Of occasions previoue Secretaries of this Department have called for new and stronger health warnings, the eetablishment of maximum level6 of "tar" and nicotine and the dimcloeure of more information about cigarette products. ltlie 1981 report eatabliahea the need to move forward on these ret-ndationa. I" particular, I believe the manufacturere should list yields of "tar". nicotine and other harardoua colPpo"e"ta on their packagee and in their advertising with appropriate explanatory information on the health significance of theee meamuremente. Thin would be a minimum first 8tep in giving cigarette coneumera full and adequate information about the products they are buying. Patricia Roberts Harrim Enclosure PREFACE This is the fourteenth report on the health consequences of smoking which the Public Health Service has issued since 1964 and the third to be issued during my term as Surgeon General. By Congressional directive it considers the relative health effects of cigarettes with varying levels of "tar" and nicotine and the relative health effects of cigarette additives. At the present time, a third of all smokers, some 18 million persons, are smoking cigarettes with measured yields of less than 15 mg "tar," and this number is increasing by approximately 5 percent per year. Most of these persons have changed to lower yield cigarettes in the expectation that this will somehow reduce the hazards of their smoking. It is in the interest of these persons, and in the public interest, to know to what extent these expectations are justified. In 1966, the Public Health Service held that "The preponderance of scientific evidence strongly suggests that the lower the tar and nicotine content of cigarette smoke, the less harmful would be the effect." In 19'79, the Public Health Service confirmed this statement, citing new evidence, but was more cautious. "In presenting information to the public," I wrote in the Preface to the 1979 Report, "three caveats are in order: consumers should be advised to consider not only levels of tar and nicotine but also (when the evidence becomes available) levels of other tobacco smoke constituents, including carbon monoxide, They should be warned that, in shifting to a less hazardous cigarette, they may in fact increase their hazard if they begin smoking more cigarettes or inhaling more deeply. And, most of all, they should be cautioned that even the lowest yield of cigarettes presents health hazards very much higher than would be encountered if they smoked no cigarettes at all, and that the single most effective way to reduce the hazards associated with smoking is to quit." In this 1981 Report, the Public Health Service has reviewed the question again and in far greater depth than before. Overall, our judgment is unchanged from that of 1966 and 1979: smokers who are unwilling or as yet unable to quit are well advised to switch to cigarettes yielding less "tar" and nicotine, provided they do not increase their smoking or change their smoking in other ways. But our V new review raises new questions and suggests an even more cautious approach to the issue. Here are the basic findings of this Report: 1. There is no safe cigarette and no safe level of consumption. 2. Smoking cigarettes with lower yields of "tar" and nicotine reduces the risk of lung cancer and, to some extent, improves the smoker's chance for longer life, provided there is no compensatory increase in the amount smoked. However, the benefits are minimal in comparison with giving up cigarettes entirely. The single most effective way to reduce hazards of smoking continues to be that of quitting entirely. 3. It is not clear what reductions in risk may occur in the case of diseases other than lung cancer. The evidence in the case of cardiovascular disease is too limited to warrant a conclusion, nor is there enough information on which to base a judgment in the case of chronic obstructive lung disease. In the case of smoking's effects on the fetus and newborn, there is no evidence that changing to a lower "tar" and nicotine cigarette has any effect at all on reducing risk. 4. Carbon monoxide has been impugned as a harmful constituent of cigarette smoke. There is no evidence available, however, that permits a determination of changes in the risk of diseases due to variations in carbon monoxide levels. 5. Smokers may increase the number of cigarettes they smoke and inhale more deeply when they switch to lower yield cigarettes. Compensatory behavior may negate any advantage of the lower yield product or even increase the health risk. 6. The "tar" and nicotine yields obtained by present testing methods do not correspond to the dosages that the individual smokers receive: in some cases they may seriously underestimate these dosages. 7. A final question is unresolved, whether the new cigarettes being produced today introduce new risks through their design, filtering mechanisms, tobacco ingredients, or additives. The chief concern is additives. The Public Health Service has been unable to assess the relative risks of cigarette additives because information was not available from manufacturers as to what these additives are. In evaluating the public health significance of the finding of reduced risk of lung cancer, it is important to recognize that the largest component of excess mortality caused by smoking is cardiovascular disease deaths. There is not sufficient evidence to conclude that use of lower "tar" and nicotine cigarettes causes any reduction in this burden. The same is true of the other major diseases caused by cigarette smoking, most notably chronic obstructive lung disease and adverse effects on pregnancy. vi These findings raise important questions of public policy. Some appear to be easily resolved. It should be possible to work out procedures so that cigarette manufacturers can disclose the additives they use while still protecting their legitimate interest in trade secrets; an effort to accomplish this is now underway. It should also be possible to develop better methodologies to measure smoke constituents, although no machine will ever be able to duplicate human smoking behavior exactly. And longitudinal surveys are now being carried on in an effort to monitor smoking behavior, and to help answer some of the behavioral questions raised in this Report. Other questions pose greater difficulty. A common thread running through the sections of the Report is that too much reliance in the past has been placed on the nonselective measure of "tar" as a measure of risk to the neglect of other constituents and approaches to risk assessment. Additional epidemiologic and bioassay work is required, as is a better definition of the fundamental mechanisms of smoking- related disease. Further study is necessary to examine the addictive nature of smoking and its impact on initiation, maintenance, and ozssation, especially in light of the recent statement of the National DrugAbuse AdvisoryCouncil that cigarette smoking is addictive.These questions cannot be answered quickly or without expenditure of scientific resources. The questions raised by this Report suggest action in both the public and private sector. In the research community, a research plan is needed to enable us to monitor the changing cigarette and to answer the many research questions put forth in this Report, with special emphasis on the issues of initiation and cessation. New measures and markers of relative toxicity are needed to supplement "tar" and nicotine. As stated, a voluntary disclosure and testing program needs to be developed with cigarette manufacturers to assess the relative health risks of cigarette additives and to protect against new hazards. In the regulatory area, this Report suggests the need to increase the public's access to information about the product it buys. Advertise- ments and packages alike should display yield figures more prominent+ ly, including measures of carbon monoxide and possibly other hazard- ous ingredients. Marketing terms such as "low-low" and "ultra-low' need to be standardized. In the area of public information and education, much more needs to be done both by the Government and by private health and educational agencies. The overriding objective must be to persuade young people not to take up smoking and to encourage present smokers to quit. Smokers of the lower yield cigarettes should be warned not to begin smoking more cigarettes or inhaling more deeply. Pregnant women should be cautioned that lower yield cigarettes are not an alternative to quitting. vii Since 1964, when the first Public Health Service Report was issued, smoking has declined in the United States from 40.3 percent of the population to 33.5 percent. Per capita consumption of cigarettes is now at the lowest level since 1957. There is less smoking by boys than in many years, and smoking by girls has declined from the higher levels of the mid-1970s. This is a tribute to the educational efforts of our teachers, of our health professionals, and of our educational and health agencies. There is every reason to hope and believe these trends will continue. Yet 54 million Americans continue to smoke, unwilling or unable to quit. This population is at extra risk of lung cancer, heart disease, chronic lung disease, and other diseases; it is a population with a life expectancy months and years less than the population of nonsmokers. The evidence presented in this Report shows that there is no "safe" cigarette available to these smokers, but that some cigarettes may be less hazardous than others, reducing the risks of smoking in a limited and selective fashion. January 12, 1931 Julius B. Richmond, M.D. Assistant Secretary for Health and Surgeon General . . . VI11 ACKNOWLEDGEMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, John M. Pin'ney, Director. Medical Staff Director for the Report was Joanne Luoto, M.D., M.P.H. Managing Editor was Donald R. Shopland. Consulting scientific editors were David M. Burns, M.D., Ellen R Grits, Ph.D., Jeffrey E. Harris, M.D., Ph.D., and John H. Holbrook, M.D. The following individuals participated in working groups at the June 1980 conference on Research Needs on Low-Yield Cigarettes. Except where otherwise indicated, the working group chairperson also au- thored the corresponding working group report and was responsible for incorporating comments from other members of the group. phamnacologyand Toxicology Fred G. Bock, Ph.D. (Chairman), Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, New York S. P. Battista, Ph.D., Senior Staff Pharmacologist, Arthur D. Little, Inc., Cambridge, Massachusetts James F. Chaplin, Ph.D., Director, Oxford Tobacco Research Laborato- ry, Oxford, North Carolina 0. T. Chortyk, Ph.D., Chief, Tobacco and Health Laboratory, Richard Russell Research Center, Athens, Georgia Louis Diamond, Ph.D., Professor and Director of the Pharmacodynam- its and Toxicology Division, College of Pharmacy, University of Kentucky, Lexington, Kentucky M. R. Guerin, Ph.D., Section Head, Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Dietrich Hoffmann, Ph.D., Chief, Division of Environmental Carcino- genesis and Associate Director of Naylor-Dana Institute, American Health Foundation, Valhalla, New York Harold C. Pillsbury, B.S., Technical Director, Federal Trade Commis- sion, Tobacco Research Laboratory, Washington, D.C. ix W. S. Rickert, Ph.D., Department of Statistics, University of Waterloo, Waterloo, Ontario, Canada T. C. Tso, Ph.D., Chief, Tobacco Laboratory, U.S. Department of Agriculture, Beltsville, Maryland Cancer Jesse L. Steinfeld, M.D. (Chairman), Dean of the School of Medicine, Medical College of Virginia, Richmond, Virginia Lawrence Garfinkel, M.A., Vice President for Epidemiology and Statistics, American Cancer Society, Inc., New York, New York Michael Kunze, M.D., Professor of Social Medicine, Institute of Hygiene, University of Vienna, Vienna, Austria William Lijinsky, Ph.D., Director, Chemical Carcinogenesis Program, Litton Bionetics, Frederick Cancer Research Center, Frederick, Maryland Donald H. Luecke, M.D., Chief of Special Programs Branch, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Maryland Marvin A. Schneiderman, Ph.D., Bethesda, Maryland William D. Terry, M.D., Acting Director, Division of Cancer Control and Rehabilitation, National Cancer Institute, Bethesda, Maryland Elizabeth Weisburger, Ph.D., Chief of Laboratory for Carcinogenesis Metabolism Branch, Carcinogenesis Intramural Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Maryland Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York Dietrich Hoffmann, Ph.D. (Special Consultant), Chief, Division of Environmental Carcinogenesis and Associate Director of Naylor- Dana Institute, American Health Foundation, Valhalla, New York William P. Castelli, M.D. (Chairman), Medical Director, Framingham Heart Study, Framingham, Massachusetts Poul Astrup, M.D., Professor of Clinical Chemistry, University of Copenhagen, Copenhagen, Denmark Manning Feinleib, M.D., Dr.P.H., Associate Director for Epidemiology and Biometry, National Heart, Lung, and Blood Institute, Bethesda, Maryland William Friedewald, M.D., Associate Director, Clinical Applications and Prevention Program, National Heart, Lung, and Blood Institute, Bethesda, Maryland Robert S. Gordon, Jr., M.D., Special Assistant to the Director, National Institutes of Health, Bethesda, Maryland William R. Harlan, M.D., Professor and Chairman, Department of Postgraduate Medicine, University of Michigan, Ann Arbor, Michi- gan X Richard J. Havlik, M.D., M.P.H., Chief, Clinical and Genetics Epide- miology Section, National Heart, Lung, and Blood Institute, Bethes- da, Maryland John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah, Salt Lake City, Utah Stephen B. Hulley, M.D., M.P.H., University of California, School of Medicine, San Francisco, California Henry C. McGill, M.D., Professor, Department of Pathology, Universi- ty of Texas Health Science Center, San Antonio, Texas Gardner C. McMillan, M.D., Associate Director for Etiology, Arterio- sclerosis and Hypertension, Division of Heart and Vascular Disease, National Heart, Lung, and Blood Institute, Bethesda, Maryland Douglas R. Rosing, M.D., Senior Investigator, Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland Nicholas J. Wald, M.D., I.C.R.S., Cancer Epidemiology and Clinical Trials Unit, Radcliffe Infirmary, Oxford, England William J. Zukel, M.D., Associate Director for Program Coordination and Planning, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland Chronic Obstructive Lung Disease Philip Kimbel, M.D. (Chairman), Chairman, Department of Medicine, The Graduate Hospital, Philadelphia, Pennsylvania A. Sonia Buist, M.D., Associate Professor, Department of Physiology, School of Medicine, University of Oregon, Portland, Oregon David M. Burns, M.D., Pulmonary Division, University Hospital, San Diego, California Jeffrey M. Drazen, M.D., Assistant Professor of Medicine, Harvard Medical School, Peter Bent Brigham Hospital, Boston, Massachu- setts Eric R. Jurrus, Ph.D., Health Scientist Administrator, Airways Dis- eases Branch, Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland James F. Morris, M.D., Chief, Pulmonary Disease Section, Veterans Administration Medical Center, Portland, Oregon Clifford H. Patrick, Ph.D., Chief, Prevention, Education, and Manpow- er Branch, Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland Diana Petitti, M.D., Department of Medical Methods Research, Kaiser Permanente Medical Care Program, Oakland, California Pregnancy and Infant Health Lawrence D. Longo, M.D. (Chairman), Professor of Physiology and Perinatal Biology, Professor of Obstetrics and Gynecology, School of Medicine, Loma Linda University, Loma Linda, California Heinz W. Berendes, M.D., M.H.S., Director, Epidemiology and Biome- try Research Program, National Institute of Child Health and Human Development, Bethesda, Maryland xi William A. Blanc, M.D., Professor of Pathology, Head, Division of Developmental Pathology, College of Physicians and Surgeons, Columbia University, New York, New York Alfred W. Brann, M.D., Professor, Department of Pediatrics, Director, Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Atlanta, Georgia Charlotte S. Catz, M.D., Head, Pregnancy and Perinatology Section, Clinical Nutrition and Early Development Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, Bethesda, Maryland Eileen G. Hasselmeyer, Ph.D., Associate Director for Scientific Review, National Institute of Child Health and Human Development, Bethesda, Maryland Mary B. Meyer, Sc.M., Associate Professor, Department of Epidemiolo gy, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland David Rush, M.D., Ph.D., Associate Professor of Public Health (Epidemiology) and Pediatrics, Faculty of Medicine, School of Public Health, Columbia University, New York, New York Zena Stein, M.D., Professor of Public Health (Epidemiology), Sergiev- ski Center at Columbia University, New York, New York Behawiwal Aspects Charles R. Schuster, Ph.D. (Chairman), Departments of Psychiatry and Pharmacological and Physiological Sciences, Pritzker School of Medicine, University of Chicago, Chicago, Illinois Lynn T. Kozlowski, Ph.D. (Author), Scientist, Clinical Institute of the Addiction Research Foundation, Toronto, Ontario, Canada Roland R. Griffiths, Ph.D., Associate Professor of Behavioral Biology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland Ellen R. Gritz, Ph.D., Associate Research Psychologist, Department of Psychiatry and Pharmacology, University of California at Los Angeles; Research Psychologist, Veterans Administration Medical Center, Brentwood, Los Angeles, California Murray E. Jarvik, M.D., Ph.D., Professor of Psychiatry and Pharmacol- ogy, University of California at Los Angeles; Chief, Psychopharma- cology Unit, Veterans Administration Medical Center, Brentwood, Los Angeles, California Chris-Ellyn Johanson, Ph.D., Research Associate (Associate Professor), Department of Psychiatry, University of Chicago, Chicago, Illinois Sandra Levy, Ph.D., Acting Chief, Behavioral Medicine Branch, Division of Resources, Centers, and Community Activities, National Cancer Institute, Bethesda, Maryland Margaret E. Mattson, Ph.D., Program Scientist, Behavioral Medicine Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland xii David M. Monsees, -Ph.D., Program Director for State and Evaluation Projects, Behavioral Medicine Branch, Division of Resources, Cen- ters, and Community Activities, National Cancer Institute, Silver Spring, Maryland Edward J. Roccella, Ph.D., Deputy Branch Chief, Health Education Branch, Office of Prevention, Education and Control, National Heart, Lung, and Blood Institute, Bethesda, Maryland Michael Russell, M.D., Institute of Psychiatry, Maudsley Hospital, London, England The editors acknowledge with gratitude the many distinguished scientists, physicians, and others who lent their support in the preparation of this Report by coordinating manuscript preparation, contributing critical reviews of the manuscript, or assisting in other ways. Henry Blackburn, M.D., Professor and Director, Laboratory of Physic logical Hygiene, School of Public Health, University .of Minnesota, Minneapolis, Minnesota Lester Breslow, M.D., M.P.H., Dean, School of Public Health, Center for the Health Sciences, University of California, Los Angeles, California Benjamin Burrows, M.D., Director, Division of Respiratory Sciences, Arizona Health Sciences Center, Tucson, Arizona Vincent T. .DeVita, M.D., Director, National Cancer Institute, Bethes- da, Maryland Donald S. Fredrickson, M.D., Director, National Institutes of Health, Bethesda, Maryland Maureen Henderson, M.D., Associate Vice President for Health Sciences, University of Washington, Seattle, Washington Norman Kretchmer, M.D., Ph.D., Director, National Institute of Child Health and Human Development, Bethesda, Maryland Robert I. Levy, M.D., Director, National Heart, Lung, and Blood Institute, Bethesda, Maryland Abraham Lillienfeld, M.D., M.P.H., D.S.C., University Distinguished Service Professor, Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Kenneth Moser, M.D., Director, Pulmonary Division, University Hospi- tal, San Diego, California R. L. Naeye, M.D., Professor and Chairman, Department of Pathology, M.S. Hershey Medical Center, Hershey, Pennsylvania Richard Peto, M.A., M.S.C., I.C.R.S., Regius Assessor of Medicine, Radcliffe Infirmary, Oxford, England William Pollin, M.D., Director, National Institute on Drug Abuse, Rockville, Maryland . . . Xl11 Richard D. Remington, Ph.D., Dean, School of Public Health, Universi- ty of Michigan, Ann Arbor, Michigan Robert Resnick, M.D., Associate Professor, Department of Reproduc- tive Medicine, Medical Center, University of California, San Diego, California Dorothy P. Rice, Director, National Center for Health Statistics, Hyattsville, Maryland Marvin A. Sackner, M.D., Chairman, Department of Medicine, Mt. Sinai Medical Center, Miami Beach, Florida Irving J. Selikoff, M.D., Professor of Community Medicine, Professor of Medicine, Mt. Sinai School of Medicine, City University of New York, New York, New York Jeremiah Stamler, M.D., Chairman, Department of Community Health and Preventive Medicine, Northwestern University Medical School, Chicago, Illinois Ronald W. Wilson, M.A., Chief, Health Status and Demographic Analysis Branch, Division of Analysis, National Center for Health Statistics, Hyattsville, Maryland The editors also acknowledge the contributions of the following staff and others who assisted in the preparation of the Report. Erica W. Adams, Copy Editor, Informatics Incorporated, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Jacqueline 0. Blandford, Secretary, Office on Smoking and Health, Rockville, Maryland Tina K. Brubaker, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Betty Budd, Administrative Clerk, Office on Smoking and Health, Rockville, Maryland Marsha Clay, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Martha E. Davis, Technical Illustrator, Informatics Incorporated, Rockville, Maryland Wesley Dean, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Stephanie D. DeVoe, Data Entry Operator, Informatics Incorporated, Rockville, Maryland Steve A. Fairbairn, Applications Manager, Information Processing Services Division, Informatics Incorporated, Rockville, Maryland Rose M. Gerondakis, Secretary, Office on Smoking and Health, Rockville, Maryland xiv John F. Hardesty, Jr., Public Information Officer, Office on Smoking and Health, Rockville, Maryland Rebecca C. Harmon, Manager, Graphics Unit, Informatics Incorporat- ed, Rockville, Maryland Reginald V. Hawkins, M.P.H., Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Linda Herold, Information Specialist, Clearinghouse Projects Depart- ment, Informatics Incorporated, Rockville, Maryland Shirley K. Hickman, Lead Data Entry Operator, Informatics Incorpo- rated, Rockville, Maryland Cindi M. Holgash, Secretary, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Robert S. Hutchings, Associate Director for Information and Program Development, Office on Smoking and Health, Rockville, Maryland Barbara Hyde, Editor, Biospherics, Incorporated, Rockville, Maryland Lisa A. Katz, Graphic Artist, Informatics Incorporated, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Assis- tant, Office on Smoking and Health, Rockville, Maryland Julie Kurz, Graphic Artist, Informatics Incorporated, Rockville, Mary- land C. Yvonne Lee, Statistician, Informatics Incorporated, Rockville, Maryland William R. Lynn, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Jacquelene Mudrock, Technical Illustrator, Informatics Incorporated, Rockville, Maryland Judith L. Mullaney, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Marjorie L. Olson, Secretary, Office on Smoking and Health, Rockville, Maryland Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Karen Robinson, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Roberta A. Roeder, Secretary, Informatics Incorporated, Rockville, Maryland Matthew J. Schudel, Editor, Biospherics, Incorporated, Rockville, Maryland Valsala Sekhar, Data Entry Operator, Informatics Incorporated, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Scott Smith, Editor, Biospherics, Incorporated, Rockville, Maryland xv Linda Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Sol Su, Sc.D., Statistician, Office on Smoking and Health, Rockville, Maryland Carol M. Sussman, Writer-Editor, Office on Smoking and Health, Rockville, Maryland Selwyn Waingrow, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Melissa L. Yorks, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Xvi TABLE OF CONTENTS Preface.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Acknowledgements . . . . ..*............................................. ix 1. Introduction, Summary, and Research Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Pharmacology and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 4. Cardiovascular Diseases ........................................ 111 5. Chronic Obstructive Lung Disease .......................... 131 6. Pregnancy and Infant Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 7. Behavioral Aspects ............................................... 173 8. Lower "Tar" and Nicotine Cigarettes: Product Choice and Use .............................................................. 193 Index .................................................................... 239 xvii Section 1. INTRODUCTION, SUMMARY, AND RESEARCH RECOMMENDATIONS CONTENTS Introduction Dose-Response Relationship Relative Risks of Lower "Tar" Cigarettes for Specific Disease8 Methodologies for Assessing Relative Risk Conclusion Summariefs Pharmacology and Toxicology Cancer Cardiovascular Diseases Chronic Obstructive Lung Disease Pregnancy and Infant Health Behavioral Aspects Lower "Tar" and Nicotine Cigarettes: Product Choice and Use Reaearch Recommendations From the Working Meeting "Research Needs on Low-Yield Cigarettea" Introduction Great changes have taken place in the cigarette product in recent decades. In 1954, the average "tar" yield of the sales-weighted average cigarette was 37 mg and average nicotine yield was 2 mg. In 1930, the comparable figures are expected to be less than 14 mg of "tar" and leas than 1 mg of nicotine. No cigarette marketed in the United States in 1979 yielded more than 30 mg of "tar."l Smokers have turned to these new products because of health concerns. In the 19509, cigarette manufacturers introduced cigarette filters as "health protection" and advertised them widely. The 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health did not discuss cigarette smoke filtration, but in 1966 the Public Health Service reviewed the issue of smoke constituents. That report stated, "The preponderance of scientific evidence strongly suggests that the lower the `tar' and nicotine content of cigarette smoke, the less harmful would be the effect." Thereafter, Government and tobacco industry scientists conducted studies of cigarette engineering and tobacco cultivation that could lead to lower "tar" and nicotine yields. Later, when new products appeared, cigarette manufacturers aggressively promoted them through advertising. The request by Congress for an assessment of the "relative health risks associated with smoking cigarettes of varying levels of `tar,' nicotine, and carbon monoxide," and "the health risks associated with smoking cigarettes containing any substances commonly added to commercially manufactured cigarettes" has come at an appropriate time. In the 2 years since Congress called for the present study, manufacturers have marketed cigarettes that yield as little as 0.01 mg of "tar" when measured by present Federal Trade Commission technology. The technology of producing lower "tar" cigarettes has progressed well beyond a simple reduction in the amount of tobacco in the cigarette or the removal of a portion of the "tar" by filtration. Present technology has achieved "tar" reduction by alterations in plant genetics, changes in the cultivation and processing of the tobacco leaf, and changes in cigarette paper and filtration of the cigarette. The methods used in testing cigarettes by machine may not correspond to the way persons actually smoke. There is evidence to suggest that the cigarette yields measured by machine are very different from the yields that the consumer actually obtains by smoking the cigarette, due in part to the difference in patterns of smoking between testing machines and individual smokers. Therefore, "tar" measurements of current cigarettes may not reflect the same 5 estimate of risk provided by the "tar" measurement of cigarettes manufactured at the time of the 1966 Public Health Service Review. Another closely related concern about lower "tar" and nicotine cigarettes is the use of flavorings and other chemical additives. In order to enhance consumer acceptability, flavoring substances are added to cigarettes; it may be that the lower the "tar" yield, the more flavoring additives are used. It is impossible to make an assessment of the risks of these additives, as cigarette manufacturers are not required to reveal what additives they use. No agency of the Federal Government currently exercises oversight or regulatory authority in the manufacture of cigarette products. Further, no agency is empow- ered to require public or confidential disclosure of the additives actually in use by the cigarette manufacturers. At the same time that changes have occurred in the cigarette, marked changes have occurred in the smoking patterns of the U.S. population that may have substantially altered the risk of smoking lower "tar" cigarettes. Over recent years, smokers have been taking up regular smoking at younger ages, and the number of women who smoke currently far exceeds the number from several decades previously. The multiplicative risks of smoking and oral contraceptive use is an example of how changes in the population of smokers can make both quantitative and qualitative changes in the nature of the risk. The proportion of the population that smokes has declined, but the average number of cigarettes smoked by each smoker appears to have increased over several decades. Changes have occurred in the environ- ment, dietary habits, and behavioral patterns of the population, which may alter the interaction between cigarette smoking and other risk factors for disease. Thus, we have a continually changing population of smokers who smoke a continually changing cigarette in a continually changing manner. DoeResponse Relationship A clear dose-response relationship has been established between cigarette smoking and a number of disease states; this constitutes a major part of the evidence suggesting that lower "tar" cigarettes may be less hazardous. It is important to understand this dose-response relationship and the limits of the data. The major prospective studies on smoking and disease show that the risk of coronary heart disease and lung cancer increases in a roughly linear manner with increasing numbers of cigarettes smoked per day. There is also a marked increase in the risk of death from chronic lung disease with the number of cigarettes smoked per day, but problems in classification of this disease make it unclear whether the relationship is linear. There is no clear evidence of a threshold effect in any of these studies. The relationship between number of cigarettes and disease is strengthened by showing that the risk increases with longer duration 6 of the smoking habit and with younger age at initiation of regular smoking. Risk is thus closely related to smoke dose as measured by number of cigarettes consumed. The relationship may result from the effect either of repetitive doses or of cumulative smoke dosage. The effect on risk of the time interval between cigarettes has not been thoroughly examined, but there is evidence to suggest that risk is related to the total dose of smoke delivered to the smoker, regardless of the time pattern of exposure. Overall, disease risk clearly increases with increasing depth of cigarette smoke inhalation. Pipe and cigar smokers who do not inhale have a lower risk of tobacco-related diseases. Thus, it is logical to hypothesize that a reduction in the actual dose of cigarette smoke to the smoker would be accompanied by a reduction in the risk of developing heart and lung disease. "Tar" is a major portion of the total particulate matter of cigarette smoke. To the extent that the machine measurements of `Yar" yield of cigarettes reflect the actual smoke exposure resulting from use of that cigarette, a lower "tar" cigarette should be less hazardous. In order for the measured "tar" yield of a cigarette to reflect smoke exposure, a number of conditions would have to be met. First, changing the "tar" yield should not change the pattern, or style, of cigarette use. If the smoker compensates for reduced yield by increasing the number of cigarettes, the depth of inhalation, or the volume or frequency of puffs, a reduction in "tar" might not result in a reduced smoke exposure. The possible increase in the average number of cigarettes smoked by each smoker and the possibility that the depth of inhalation and puff volume may also have increased as the average "tar" yield of the cigarette has declined raise a real concern that the shift to the use of lower "tar" cigarettes may not have resulted in a proportionate drop in smoker exposure. A second assumption in equating lower "tar" yield per cigarette with lower smoke exposure, and therefore lower risks of disease, is that the reduction in "tar" is accompanied by a similar reduction in all of the constituents of smoke, or at least all of those constituents related to disease. As long as the lowering of the "tar" yield was largely secondary to a reduced amount of tobacco in the cigarette or a filtration of the smoke, a reduced "tar" yield could be assumed to represent a lower smoke exposure. Prior to 1971, the reduction in "tar" yield was very similar to the reduction in weight of tobacco per cigarette (see Figure 8, Section 8), but since that time the reduction in "tar" has been proportionately somewhat greater than the reduction in weight of tobacco per cigarette, and this difference appears to have increased since 1975. As discussed in this Report, the recent reductions in "tar" yield have been accomplished by altering tobacco growth and processing and by changes in cigarette manufacture. These changes may have produced a "tar" with a different composition from that of 7 old higher "tar" cigarettes, and may have changed the concentrations of some of the constituents contained in the gas phase of the smoke. An additional concern L that the production of cigarettes with lower "tar" and nicotine yields may involve the increasing use of additives for tobacco processing or flavoring. Some additives available for use are either known or suspect carcinogens or give rise to carcinogenic substances when burned. The use of these additives may negate beneficial effects of the reduction of "tar" yield, or might pose increased or new and different disease risks. Therefore, the "tar" yield of cigarettes currently being manufactured probably cannot be used as a precise measure of current smoke exposure risk, nor be compared quantitatively with the smoke exposure risk of the older higher "tar" cigarettes. The major prospective studies that provide the data for our assessment of smoking-related health risks examined persons who smoked these older, higher "tar" cigarettes. A third assumption in equating "tar" yield with smoke exposure is that the "tar" yield of a machine-smoked cigarette be equal to or at least proportional to the yield of the same cigarette when it is consumed by the smoker. Later sections of this Report clearly establish that the "tar" yield of the current cigarette may vary markedly with style of smoking, with much higher yields being produced by higher puff volumes or occlusion of the perforations in the cigarette wrapper. Thus, the manufacturing changes that have resulted in low "tar" yield measurements may not have resulted in a comparable reduction in the exposure of the individual cigarette smoker. Relative Risks of Lower `Tar" Cigarettes for Specific Diseases Having examined the nature of the dose-response relationship and some of the limitations of using "tar" measurements as the measure of dosage, we can now examine the evidence available that aases~~ the relative risk of lower "tar" cigarettes for specific disease processes. An understanding that the different health consequences of smoking may be caused by different smoke constituents is pivotal to these assess- ments of relative risk. Our understanding of the specific etiologic mechanisms by which cigarette smoke constituents cause different diseases remains incomplete at this time. The individual sections of this Report review in detail evidence on the relative health hazards of lower "tar" and nicotine cigarettes. Assessment of the relative risk of these cigarettes requires the integration of this information; final assessment of the overall relative health hazard of these cigarettes has not been reached. The major issue is the potential and actual health impact of the introduction of these cigarettes into the marketplace. Assessment of thii requires under- standing of the changes that have taken place in the cigarette product, the effects of those changes on smoking initiation, cessation, and patterns of cigarette use, and the probable health effects of the net change in cigarette smoke dose. It also requires an understanding of the changes in risk that occur secondary to switching to lower "tar" cigarettes distinct from the risks of lifelong use of these products. Lung cancer is the disease process in which the relative risk of lower "tar" and nicotine cigarettes has been most clearly evaluated. Approxi- mately 85 percent of the incidence of lung cancer can be directly attributed to cigarette smoking; there are relatively few problems with changing criteria for classification of cause of death, and there is a clear, linear dose-response relationship. Moreover, the "tar" portion of the smoke probably contains most of the carcinogenic activity of the whole smoke. If the reduction in machine-measured "tar" yield is accompanied by an actual reduction in smoker exposure dose, then there should be a relatively proportionate reduction in lung cancer risk. Lower "tar" cigarettes are associated with a reduction in the risk of developing lung cancer, although the proportionate reduction in risk is substantially less than that of "tar" yield. A smaller percent reduction in lung cancer risk versus that of measured cigarette "tar" yield could result from several factors, including compensation (such as an increased depth of inhalation or a greater number of cigarettes smoked per day), or from a lack of comparable reductions in other carcinogens. For several reasons, it is difficult to extrapolate these risk reduction data to the current very low "tar" cigarettes. Because the lower "tar" yield of the cigarettes evaluated in the published studies probably was accomplished predominantly by reducing the weight of tobacco in the cigarette and by removing "tar" through filtration, use of these cigarettes might reasonably be expected to result in a lower smoke exposure if compensation did not occur. It is not clear, however, that the alterations in the techniques of tobacco processing and cigarette manufacture that have produced the very low ma&me-measured "tar" yields can be expected to result in similar reductions in actual smoker exposure to toxic smoke constituents. In addition, the ptential carcinogenic effect of the substances added to these cigarettes has not been evaluated The demonstrated reduction in mouse skin tumorigen- icity of "tar" has not, however, been accompanied by a reduction in the incidence of or mortality rates due to lung cancer among humans. Cigarette smoking is an independent risk factor for coronary heart disease, one that interacts synergistically with other risk factors such as hypertension and hypercholesterolemia. The effect of cigarette smoking in coronary heart disease risk is clearly dose related, and cessation of smoking reduces the risk. Estimation of the impact of varying cigarettes on coronary heart disease risk is difficult, because the exact etiologic agent(s) have not been identified. A number of agents have been suggested to be active in the development of coronary heart disease, including nicotine and carbon monoxide. Any change in risk that might occur because of switching to lower "tar" 9 and nicotine cigarettes might be expected to become evident more rapidly for coronary heart disease risk than for cancer risk, due to the acute effects of cigarette smoke in causing adverse coronary heart disease events such as sudden death. As in the ease of cancer, the expectation that a risk reduction for coronary heart disease would accompany the use of lower "tar" and nicotine cigarettes is baaed on the premise that the use of lower %r" cigarettes results in a reduction of exposure to the responsible smoke constituents. This assumption is reasonable if nicotine is a major etiologic agent, because there is a close relationship between the "tar" and nicotine yields for individual cigarettes. That is, among the cigarettes currently available in the United States, a lower "tar" cigarette is also a lower nicotine cigarette. The variations of the other constituents in the particulate phase of the smoke in relation to "tar" yield is largely unknown, especially in those cigarettes specially formulated to produce very low machine measurements of "tar" yields. Carbon monoxide is one gas in cigarette smoke that may be closely associated with coronary heart disease risk, perhaps through interfer- ence with myocardial oxygenation, enhancement of platelet adhesive ness, or promotion of atherosclerosis. The relationship between carbon monoxide yield and "tar" yield, however, has not been as thoroughly examined as that between "tar" and nicotine. The factors that influence the carbon monoxide yield are closely related to the manufacturing process (e.g., porosity of the paper, filter ventilation, etc.), and therefore may vary somewhat independently of "tar" yield. In addition, the absorption of carbon monoxide is more dependent on depth of inhalation than is the absorption of nicotine and, if the use of lower "tar" products results in a compensatory increase in depth of inhalation, smoker exposure to carbon monoxide may remain un- changed or actually increase. The reality of this concern is home out by those studies that show no lowering of carboxyhemoglobin levels in smokers who switch to lower "tar" cigarettes. If carbon monoxide is an active etiologic agent for cigarette-related coronary heart disease, and if significant compensatory changes in the style of smoking occur with use of lower "tar" cigarettes, then the risk of coronary heart d&ease with lower "tar" cigarettes may be similar to, or possibly greater than, the risk of smoking higher "tar" cigarettes. Some other agents in the gas phase of cigarette smoke have also been suggested as possible contributors to the development of coronary heart disease. Little is known about the relationship between the yield of the gas phase of the smoke and the "tar" yield The change in formulation that allows the reduction in "tar" yield of the new lower "tar" cigarettes has not been examined for its effect on the yield of individual gas phase constituents. The potential for creating new substances and for increasing the yields of existing gas phase 10 constituents by changes in formulation cannot be assessed from existing data, but may well impact on the risk of coronary heart disease produced by smoking lower "tar" cigarettes. It is not surprising that the studies looking at the relative risk of lower "tar" cigarettes reviewed in the cardiovascular section have not produced a clear estimate of relative risk, given the difficulty in relating a difference in "tar" yield to a difference in coronary heart disease risk and the existence of gaps in our understanding of the etiologic agents in smoke that cause coronary heart disease. Thus, the impact of a reduction in the "tar" yield of cigarettes on the coronary heart disease risk produced by smoking cannot be estimated at this time. Approximately 70 percent of chronic obstructive lung disease deaths are attributable to cigarette smoking. The number of deaths attributed to chronic obstructive lung disease is much smaller than the number of lung cancer deaths. This fact, and the relatively long interval of time between the onset of symptomatic chronic airflow limitation and death from respiratory failure, reduce the usefulness of mortality data from chronic lung disease in assessing the relative risks of lower "tar" cigarettes. Therefore, attention has focused on the level of symptoms and measured reductions in air flow for evaluating relative risk of chronic obstructive lung disease. As reviewed in the section on chronic obstructive lung disease, there are three major aspects of cigarette-induced lung injury: chronic mucous hypersecretion, airway inflammation and narrowing, and alveolar septal destruction. The causal agents for each type of lung injury may be different, and therefore each type may be affected quite differently by a reduction in the "tar" yield of the cigarette. The mucous hypersecretion and cough are a response of the lung to the chronic irritant effects of cigarette smoke. To the extent that a reduction in "tar" yield reflects a reduction in smoke exposure, smoking lower "tar" cigarettes should result in reduced cough and sputum production. In the studies that have looked at this question, the expected decrease in cough and sputum production has indeed accompanied the use of lower "tar" cigarettes. Airflow limitation is not produced by mucous hypersecretion per se but rather by airway narrowing and loss of parenchymal lung units. The same studies that showed a reduction in symptoms with the use of lower "tar" cigarettes failed to show a similarly reduced effect on air flow limitation. This finding may indicate that tests of air flow limitation are not sufficiently sensitive to measure the differences in extent of disease. It could also result from a failure to produce lower exposure to the causative agent(s) with the use of lower "tar" cigarettes, either due to a lack of reduction in concentration of the agent(s) or to compensatory changes in smoking behavior. 11 The loss of parenchymal lung units that is the hallmark of emphysema is extremely difficult to measure during life, but there has been substantial progress toward an understanding of how this disease is produced by cigarette smoking. This work is reviewed in detail in the section on chronic obstructive lung disease; it is suggested that alveolar walls are destroyed by excess proteolytic activity. Cigarette smoke may promote this excess activity through a combination of an increased cellular release of proteolytic enzymes and the oxidative inactivation of the inhibitor of these proteolytic enzymes. Since the airways filter out most of the particulate matter in the smoke, it is felt that the gas phase may be the component of smoke responsible for the changes in enzymatic activity. The gas phase contains a number of agents capable of oxidative inhibition of the enzyme inhibitor alphal- antitrypsin. Therefore, the risk of developing emphysema may not be related to the "tar" yield of the cigarette smoked. Even if the reduction in "tar" yield results in a reduction in smoker exposure to "tar," a pattern of compensation that produces a deeper inhalation may deliver a greater dose of the gas phase of that smoke to the alveoli where it produces a pathologic effect. In addition, the techniques used in formulation of the newer very low "tar" cigarettes may result in an increase in the concentrations of etiologic agents in the smoke. Therefore, the relative risk for lower "tar" cigarette usage in the development of chronic obstructive lung disease is highly problemati- cal. The lower "tar" and nicotine cigarettes may well produce less of the symptomatic component of this disease, but even if they do result in a reduction of total smoke exposure, the pattern of that smoke exposure may negate any reduction in risk. The relative risks for both the mother and the fetus of smoking lower "tar" and nicotine cigarettes during pregnancy are of great concern, both because of the numbers of young women who smoke and because of younger women's more frequent use of lower "tar" cigarettes. The increased use of cigarettes with lower "tar" yields has not been investigated for its effect on changes in risk of adverse effects of smoking on pregnancy. Accordingly, no reduction in risk relative to higher "tar" and nicotine cigarettes has been demonstrated. Of particular concern is the potential teratogenic effect of additives and their combustion products. Thus, it is not possible to assume that switching to a lower "tar" cigarette would have an effect in reducing risk during or after pregnancy. It is clear that the only recommenda- tion that can be made to reduce risk in the smoking mother is for her to quit smoking. The ultimate assessment of risk is, of course, overall mortality. One study examined the effect of smoking lower "tar" and nicotine cigarettes on overall mortality. Persons smoking cigarettes with lower "tar" and nicotine yield exhibited a decline in mortality rate from any cause of approximately 15 percent in comparison with that of smokers I.2 of higher "tar" cigarettes. Direct extrapolation of these overall mortality results to current smoking exposure is not possible. The lowest "tar" categories in that study included cigarettes that would be considered higher "tar" products today; the mechanisms by which subsequent reductions have been achieved may differ from earlier techniques. There was no evidence available on the duration of use of lower "tar" products in this population. Methodologies for Ames&g Relative Risk The task of monitoring the relative risks of lower "tar" cigarettes is complex, but it is not impossible. Four approaches can be used: constituent toxicology, bioassay systems, observational epidemiology, and the study of fundamental mechanisms of disease production. Each approach makes a unique contribution to our understanding of relative risk. Each approach also has significant limitations to its contribution to a complete assessment of risk. It is necessary to combine the information gathered by each of these methods in order to understand the risk. The final assessment of relative risk requires data from each of these four methodologies. To the extent that information from any one area is lacking, the estimation of relative risk is incomplete. The first approach is that of constituent toxicology. A tremendous amount of time and effort has been spent to characterize cigarette smoke and to identify disease-producing smoke constituents. Several thousand individual constituents have been identified. Much has been learned about the effects of cigarette reformulation on the pyrolytic process. Studies have led to a better understanding of human absorption of these substances and how this is influenced by differing patterns of puffing and inhalation. The identification of carcinogens, oxidants, and ciliatoxic compounds represents an important advance in understanding the risks of cigarette smoking. The fundamental strength of this approach is that it might ultimately allow risk to be measured by examining the chemical composition of the smoke and its absorption. Thus, assessment of risk might be made prior to allowing human exposure to the smoke. It could lead to the selective removal of toxic substances from smoke. The major limitation of this approach is the sheer magnitude of the task. It would be necessary to identify each of the several thousand substances, the site and amount of absorption with different patterns of smoking, and the toxicity for each organ system. It would also be necessary to address the more complicated question of the potential interactions between smoke constituents, environmental and occupa- tional exposures, and other exposures, such as medications. The monumental nature of this task does not mean that constituent toxicology is unable to contribute to our assessment of relative risk. It simply means that it alone cannot solve the problem. The choice of what substances to measure in order to assess risk must be guided by 13 an understanding of the basic mechanisms of disease production and must be correlated with changes in disease occurrence in human populations. In this way the search can be, and is being, focused on those areas and substances that may provide the best measure of risk. A second method of assessing risk is through the use of bioassay systems. The term "bioassay" is used broadly to include animal models as well as cellular or organ responses. This approach can also rapidly provide information on risk without human exposure and has the additional advantage that whole smoke or major fractions of smoke can be tested rather than individual constituents. The limitation of this method is that the estimate of risk is only as go& as the bioassay system. Unless the system truly approximates the disease process of concern, changes in that system may not reflect risk of disease. A number of bioassay systems exist for the study of cigarette risk. Unfortunately, none of them can be said to exactly duplicate human disease. At the present time, estimates derived from these systems cannot stand alone, but must be interpreted in the light of information derived from other methods. The ultimate "bioassay" is, of course, human exposure. The oeeur- rence of disease in human populations would provide the most accurate estimate of the relative risk of lower "tar" cigarette smoking. An important drawback to this approach is that it permits the develop ment of that disease in the population prior to measuring risk and taking appropriate public health action. An additional limitation of the observational epidemiology is that the risk being measured is caused by a product and a pattern of use that occurred in the past. Because of the long time lag between regular exposure to smoke and the development of most cigarette-related diseases, and the time lag between develop ment of disease and diagnosis of that disease, the relative risk determined by observational epidemiologic methods may lag many years behind the current risk. It may take 20 to 30 years before smoking-related disease is observed. With a rapidly changing cigarette product, it is necessary to estimate the risks of current exposures rather than those of past exposures. This assessment is complicated by the difficulty of defining and measuring any differences in individual smoker exposure resulting from changes or individual variations in styles of smoking. Nonetheless, despite these difficulties, the epidemio- logic method remains the major tool in assessing the relative health risks of differing cigarettes. Some of the limitations of the observational epidemiologic method can be overcome by incorporating information from the other ap proaches to risk assessment. Information on the toxicology of cigarette smoke might allow epidemiologists to sharpen their measurement of actual smoker dosage, and might identify earlier tests of toxicity than the traditional end points of disease occurrence or death. Information on the basic mechanisms of disease production could improve the 14 estimation of relative risk by directed measurement of the basic pathophysiologic processes or their biochemical or metabolic sequelae. An excellent example of this kind of potential interaction is the testing of populations of smokers for the byproducts of elastin degradation suggested in the section on chronic obstructive lung disease. The fourth method of assessing relative risk is the definition of the fundamental mechanisms of disease production. An obvious attraction of this approach is its potential to provide information that would permit the prevention or cure of the disease process. The difficulty with this method of risk assessment is our limited understanding of these fundamental mechanisms. It is important to incorporate what understanding we do have into the risk assessment produced by other methods, and equally important to incorporate information from other methods into the search for disease mecha- nisms. As an example, it would be fruitless to examine the effect of a given substance on the cell function in alveoli if it has been learned from absorption studies that the substance is absorbed in the upper airway and never reaches the alveoli. Once the mechanism of disease is understood, however, an estimate of relative risk might be made, not only by measuring the dose of etiologic agents in smoke, but also those determinants of the disease process preexisting in a given individual. Conclusion In summary, the final estimation of the relative risk of smoking lower "tar" and nicotine cigarettes must be based on a synthesis of the information derived from several methodologies. Despite the lack of comprehensive and conclusive evidence currently available, the Public Health Service policy on lower "tar" and nicotine cigarettes must remain unchanged. The health risks of cigarette smoking can only be eliminated by quitting. For those who continue to smoke, some risk reduction may result from a switch to lower "tar" and nicotine cigarettes, provided that no compensatory changes in style of smoking occur. This F&port of the relative risks of lower yields of "tar," nicotine, and carbon monoxide has defined the following more clearly: the conclusions warranted by present evidence; the difficulties and importance of defining and monitoring changes in cigarette yields and actual smoker exposure; and the major questions remaining unan- swered, which constitute the major areas for future researc h efforts. Summaries of the available data on the relative risks of cigarette- related diseases among smokers of differing cigarettes follow. They are grouped by topic. Following these summaries are the research recommendations from the Working Meeting, "Research Needs on Low-Yield Cigarettes." 15 These recommendations are combined, reflecting the common underly- ing concerns among disciplines. Summaries Pharmacology and Toxicology l! Several thousand constituents have been identified in tobacco and tobacco smoke. Of these, nicotine appears to be the most important acute-acting pharmacologic agent. Nicotine's physio- logic effects include increased heart rate and blood pressure. Nicotine also can permit the formation of tobacco-specific nitrosamines, which are potent carcinogens, and nicotine itself may be a significant cocarcinogen. The carcinogenic potency of cigarette smoke condensates appears to depend on the nicotine content of the "tar." This relationship may be due in part to the conversion of nicotine to tobacco-specific nitrosamines or to the coexistence of nicotine and some other unidentified carcinogen. Whether the carcinogenic effects of nicotine as determined in animal studies are directly applicable to humans is not known at present. 2. In an important study to predict the carcinogenic activity of cigarette smoke condensate, the amount of available nicotine delivered to the mice was found to be a factor in every term but one of the predictive model. 3. Polycyclic aromatic hydrocarbons and tobacco-specific nitrosa- mines are two prominent classes of tumor initiators found in the smoke condensates of commercial cigarettes. Of the polycyclic aromatic hydrocarbons formed during combustion, ben- zo[a]pyrene (BaP) may be the most important and has been studied the most extensively. A correlation has been found between benzo[a]pyrene levels and the carcinogenic activity of smoke condensates from several types of cigarettes, but other studies have failed to show that carcinogenic potential is significantly dependent on benzo[a]pyrene content. However, the interaction of BaP with nicotine does appear important in carcinogenesis. 4. The tobacco-specific nitrosamines (TSNA) are formed during curing and fermentation of tobacco leaves and combustion of cigarettes. TSNAs induce cancer in the lungs and trachea of hamsters and may be of particular importance in the induction of human laryngeal cancer. They may be active as contact carcino- gens, or their metabolism at distant sites may produce carcino- gens that are then transported to a target site. 5. It is not known whether the unidentified mutagens in cigarette smoke are an important cause of lung cancer in humans, but 16 added exposure to any tumor initiators probably carries an increased risk of cancer. 6. Cigarette smoke contains oxidants that have been shown to reduce the activity of alphal-antitrypsin in animals and man. This inhibitory function is distinct from the effect whole smoke has on increasing levels of elastolytic enzymes released by neutrophils and macrophages. 7. The great variety of tobacco types makes it possible to manipu- late the plant genetically to change the content of the constitu- ents of the leaf. The chemical content of the leaf is also affected by agricultural practices and curing methods. The nicotine content of tobacco, for example, is related to the amount of nitrate fertilizer used in cultivation. Modification of tobacco as reconstituted sheet incorporates substantial amounts of tobacco stems that contain less nicotine than the leaf. The physical nature of reconstituted sheets can be controlled to change their burning characteristics and smoke composition. 3. Vapor-phase constituents of cigarette smoke inhibit ciliary motility and mucous flow in experimental animals. 9. Cigarette smokers metabolize several compounds more rapidly than do nonsmokers. This effect is believed to be caused by the induction of microsomal oxidases, which include aryl hydrocarbon hydroxylase (AHH). Induction of AHH activity appears to be caused by systemic exposure to the smoke compounds themselves or to the metabolites of those compounds. The AHH system may be involved in the metabolic formation of ultimate carcinogens from procarcinogen precursors. 10. In recent years, a number of flavoring additives or cellulose- based tobacco substitutes may have been included in manufac- tured cigarettes. The nature and amounts of such additives as actually used are not known, nor is it known what influence these additives may have on the chemical composition or subsequent biological activity of cigarette smoke. 11. Cigarette design has a major effect on smoke composition. The filter is the design characteristic that has the most impact on "tar" yield; it can also selectively remove nitrosamines and semivolatile phenols from smoke. The porosity of cigarette paper and the presence of holes in the mouthpiece influence smoke composition because ventilation reduces the quantity of "tar" and dilutes the gas phase of smoke. 12. Because of the complexity of cigarette smoke, the total impact of any cigarette modification on smoke composition will probably never be fully known. 13. Many laboratory studies of the effects of smoke constituents have been carried out using smoking machines that control puff volume, frequency and duration, butt length, and other factors 17 according to standardized parameters. However, the most widely used parameters were established in 1967, and the type of cigarettes generally smoked today are substantially different with respect to length, paper porosity, "tar" and nicotine content, and concentration of gas phase constituents. Evaluation of the toxicological and pharmacological properties of smoke from new types of cigarettes requires detailed knowledge of the manner in which those cigarettes are smoked, as well as of how smoking patterns affect smoke composition. Cancer -1. Today's filter-tipped, lower "tar" and nicotine cigarettes produce lower rates of lung cancer than do their higher "tar" and nicotine predecessors. Nonetheless, smokers of lower "tar" and nicotine cigarettes have much higher lung cancer incidence and mortality than do nonsmokers. 2. Smokers of lower "tar" and nicotine cigarettes may tend to smoke larger numbers of cigarettes, to inhale more deeply, to have relatively higher amounts of carboxyhemoglobin than predicted from machine measurements of carbon monoxide yield, and to have higher than predicted carbon monoxide in exhaled air. 3. In attempting to develop a "less hazardous" cigarette, singular emphasis has been placed on reducing the "tar" yield of cigarette smoke because of the early demonstration of a causal relationship between "tar" and lung cancer. Comparable data on changes in yield of constituents in the gas phase of smoke are not publicly available. 4. The occurrence of laryngeal cancer has. been reported to be reduced among smokers who use filtered cigarettes, compared with those who use nonfiltered cigarettes. d There is no epidemiologic evidence to prove or to di?yrove a decreased occurrence of cancers of other sites in humans who smoke lower "tar" and nicotine cigarettes. 6. In evaluating the effect of smoking lower "tar" and nicotine cigarettes on histologic changes in the bronchial epithelium, it was determined in one autopsy study that male smokers who died between 1970 and 1977 had fewer histological changes than those smokers who died between 1950 and 1955. `7. Even among those who do not develop cancer, histologic changes in the tracheobronchial tree are more advanced at autopsy in smokers of cigarettes with higher "tar" and nicotine than among smokers of cigarettes with lower yields. 8. The "tar" content of smoke condensate of today's cigarettes is less tumorigenic to mouse skin than that of cigarettes of 30 years ago. Levels of the known carcinogen benzo[akyrene are lower in 18 the smoke of today's cigarettes than in that of cigarettes of 30 years ago. Flavor additives used in lower "tar" and nicotine cigarettes produce traces of mutagenic compounds. 9. Although studies point to polycyclic aromatic hydrocarbons in the "tar" of inhaled cigarette smoke as potential carcinogens for humans, additional work is needed to determine whether nicotine plays a major role as a carcinogen. Definition of the role of nicotine in carcinogenesis is necessary prior to advocacy of cigarettes yielding less "tar" but more nicotine. 10. Animal studies have shown that a significant reduction of "tar" and a selective reduction of tumor initiators and cocarcinogens can markedly reduce the tumorigenic potency of cigarette smoke. Cardiovascular' Dieeases P&pidemiological studies show that the incidence of coronary heart disease (CHD) increases as the daily number of cigarettes smoked increases and that the incidence of CHD decreases among those who quit smoking. These dose-related effects suggest that lower "tar" and nicotine cigarettes might be associated with lower risks of CHD. However, the overall changes in the composition of cigarettes that have occurred during the last 10 to 15 years have not produced a clearly demonstrated effect on cardiovascular disease, and some studies suggest that a decreased risk of CHD may not have occurred. 2. Of the several thousand substances found in cigarette smoke, only a few have been implicated in cardiovascular risk. A number of substances have not yet been adequately assessed. Further, the changes in smoke constituents that have resulted from changes in the cigarette product have not been documented. 3. Linking cigarette smoke yields to cardiovascular disease is complicated by the evidence that smokers of lower "tar" and nicotine cigarettes may smoke more "intensively," although they may not smoke a substantially greater number of cigarettes daily than do smokers of higher "tar" and nicotine cigarettes. The net result could be to decrease the actual intake of "tar," nicotine, and carbon monoxide less than that expected on the basis of machine measurements. &Nicotine stimulates the sympathetic nervous system, producing a rise in catecholamines that in turn increases heart rate, elevates systolic blood pressure, constricts cutaneous blood vessels, and increases levels of free fatty acids. The nicotine-stimulated release of catecholamines has been suggested as the cause of increased platelet stickiness and aggregation, pointing to a potential role in coronary disease. There is some evidence that these physiological effects may be dose related and somewhat diminished with lower nicotine varieties of cigarettes. 19 5. Carbon monoxide has a negative inotropic effect on the myocar- dium of patients with angina pectoris. When combined with hemoglobin in the form of carboxyhemoglobin, carbon monoxide may increase the permeability of the blood vessel walls to lipids, thereby promoting atherosclerosis. 6. Cigarettes with unperforated filters yield lower "tar" and nicotine levels than unfiltered cigarettes, but they yield more carbon monoxide than do unfiltered cigarettes at the same "tar" yield. Carbon monoxide yields are lower in cigarettes with perforated filters, but as the composition of cigarettes has changed, carbon monoxide yields have decreased much less in proportion to the decrease in "tar" and nicotine yields. 7. In studies of patients with angina pectoris, increased carboxy- hemoglobin levels significantly shorten exercise time until the onset of angina pectoris. 8. Myocardial ultrastructural changes have been found in rabbits exposed to carbon monoxide. 9. Most cardiovascular studies have focused on nicotine and carbon monoxide rather than on "tar," which has not been shown to have a major acute role in cardiovascular disease. Even less is known about other constituents of cigarette smoke. 10. Not all cigarettes that produce a lower yield of one substance necessarily provide a lower yield of other substances. 11. Evidence on the association between CHD and filter cigarettes is somewhat conflicting. One major study showed a reduction of 10 to 20 percent in coronary deaths among persons smoking lower "tar" and nicotine cigarettes as compared with those who smoked higher yield cigarettes, but other surveys have shown a slightly increased risk of coronary mortality in people who smoked filter cigarettes relative to those who smoked nonfiltered cigarettes. Recent unpublished data from the Framingham Study do not show a lower CHD risk among smokers of filter cigarettes. Chronic Obstructive Lung Disease 1. The relationship between cigarette smoking and chronic obstruc- tive lung disease (COLD) is well documented. The constituents of cigarette smoke that are responsible are currently not known. Whether a difference in risk of COLD has occurred with lower "tar" and nicotine cigarettes as compared with higher "tar" and nicotine cigarettes is currently unknown. 2. Cigarette smoking is associated with the release by alveolar macrophages of an increased amount of the elastolytic enzymes, which degrade alveolar tissue, and with reduced activity of alphal-antitrypsin, the primary elastase inhibitor. This mecha- nism has not yet been directly related to the development of human emphysema. To date there are no published studies that 20 compare the effects of higher versus lower "tar" and nicotine cigarettes on elastolytic enzymes and inhibitor activity. 3. Cigarette smoke also contains relatively high levels of oxides of nitrogen. The nitrogen oxides produce lung damage in animals that is similar to that induced in humans by cigarette smoke. The oxides of nitrogen may be responsible for the early lesions of human emphysema. 4. An individual's smoking pattern is one of the most important determinants of the relative concentration of smoke constituents that reach the lungs and of the subsequent response of the airways to smoke inhalation. Holding smoke in the mouth before inhaling it into the lungs produces less response of the airways than direct inhalation, which causes spirometric changes indica- tive of bronchoconstriction. This effect is independent of the "tar" content of the cigarette. 5. Pulmonary mucous hypersecretion and symptoms of cough and phlegm appear to be affected by the "tar" content of cigarette smoke. The development of airway obstruction is closely related to the number of cigarettes smoked. Smokers of lower `Yar" and nicotine cigarettes who compensate by smoking more or inhaling more deeply might thereby increase their risk of developing obstructive airway disease. 6. Population studies that have examined the rate of decline of lung function in relation to the number of cigarettes smoked have shown variable results, and most of the available data do not relate lung function to cigarette yield. Overall, the mean difference between the rate of decline of FEVl in asymptomatic smokers and nonsmokers is very small, but there is a subgroup of the smoking population that shows more rapid decline and is apparently more likely to develop significant pulmonary disease. Pregnancy and Infant Health 1. Cigarette smoking during pregnancy has been shown to have adverse effects on the mother, the fetus, the placenta, the newborn infant, and the child in later years. There is no evidence available that lower "tar" and nicotine cigarettes decrease or increase these health risks, relative to those posed by higher "tar" and nicotine cigarettes. 2. Problems that have been linked to smoking during pregnancy include placenta previa, abruptio placentae, vaginal bleeding, and reduced average birthweight of newborn infants. 3. Smoking by pregnant women increases the risk of spontaneous abortion, premature delivery, fetal death, and perinatal death. Parental smoking is associated with the sudden infant death syndrome. 21 4. The fetuses of smoking mothers have higher blood carboxyhemo- globin levels and lower fetal arterial oxygen levels than do the mothers. 5. Children of smoking mothers appear to show a greater suscepti- bility to some adverse health effects, such as bronchitis, pneumo- nia, and respiratory disease, during early childhood. Slight differences in physical growth and other forms of behavioral and intellectual development may be found in children as old as 11 years of age. 6. Although "tar," nicotine, carbon monoxide, and some other constituents of cigarette smoke produce deleterious effeeta, the specific etiologic agents and their mechanisms of action for adverse effects on pregnancy are not clearly determined. Thus, the relative importance of "tar" and nicotine, or carbon monoxide and other constituents of tobacco smoke in the etiology of adverse gestational and fetal events is not known. Behavioral Aqtects 1. Nicotine appears to be the primary pharmacological reinforcer in tobacco, but other pharmacological and psychosocial factors may also contribute a reinforcing effect. 2. It appears that some smokers make compensatory adjustments in their smoking behavior with cigarettes of different yields that might increase the amounts of harmful substances entering the body. The frequency and amount of spontaneous compensatory changes in smoking style with different cigarettes require further investigation. 3. Additional information is needed on the role of lower "tar" and nicotine cigarettes in the initiation, maintenance, and cessation of smoking. 4. Rigorous comparative behavioral studies involving animals are needed to provide comprehensive, experimentally valid results on behavioral aspects of smoking. 5. Laboratory techniques developed for study of opioids and alcohol should be adapted for studies of tolerance and dependence on nicotine. 6. Improved laboratory facilities are necessary for more tightly controlled behavioral research. A particular need exists for clinically acceptable cigarettes with standardii ingredients. 7. Smoking-machine measurements that more closely simulate the practices of human smokers must be developed. Lower `Tar" and Nicotine Cigarettes: Product Choice and Use 1. Public awareness of the dangers of smoking has steadily increased since 1965. In 1978, more than 99 percent of all Americans believed cigarette smoking to be hazardous to health. 22 2. Cigarette product choice has shifted dramatically since the 1950s. In 1979, 91.7 percent of U.S. smokers used filter-tipped ciga- rettes, compared with 1.4 percent in the early 1950s. 3. Lower "tar" cigarettes conventionally have been defined as yielding 15 mg of "tar" or less per cigarette. The proportion of all cigarettes consumed in the United States that are lower "tar" has increased from 3.6 percent in 1970 to almost 50 percent in 1979. In 1979,58.5 percent of all cigarette brands marketed in the United States yielded 15 or fewer mg of "tar." 4. Since 1968, the "tar" content of the "average cigarette" in the United States has declined by 32.2 percent, and nicotine content has fallen by 25.6 percent. These declines may be partially amunted for by lower tobacco weight per cigarette-down 23.8 percent from 1968 to 1978-and by the greater length of the filter and overwrap of the average cigarette, which could result in a declining number of machine puffs per cigarette. 5. The prevalence of smoking in the U.S. adult and adolescent populations has continued to decline. In 19'79,32.5 percent of the adult population smoked cigarettes (36.1 percent of men and 29.4 percent of women). However, evidence suggests that the average daily number of cigarettes consumed by those adults who continue to smoke has increased over several decades. The availability and use of lower "tar" cigarettes have increased over recent years. 6. In 1979, 33.3 percent of adult regular smokers used cigarettes yielding 15 mg "tar" or less. Studies show that women smokers are more likely to use lower yield cigarettes than men are, and white smokers use lower yield cigarettes in greater proportions than do blacks. Smokers of higher income and education also select lower yield cigarettes in a higher percent of cases. 7. A large national survey found that smokers in older aged cohorts choose both the lowest and highest yield cigarettes in higher proportions than do younger cohorts. 8. Although black smokers choose cigarettes of higher "tar" and nicotine in greater proportions than do whites, the lower daily number of cigarettes smoked by blacks suggests that their average daily intake of "tar" and nicotine may be lower than that of white smokers. 9. In 1979, 33.5 percent of adolescent smokers (age I2 to 18) used lower "tar" cigarettes, compared with 6.7 percent in 1974. Boys and girls smoke cigarettes of about the same level of "tar" content. 10. Adult smokers started smoking regularly at the average age of 18 years. One survey showed that the higher the "tar" level of the cigarette currently smoked, the younger the reported age of beginning smoking. 23 11. Evidence from a large national survey does not support a correlation between a greater mean number of cigarettes smoked per day by users of lower "tar" and nicotine cigarettes than by higher "tar" users, 12. In a national survey, smokers of lower "tar" and nicotine cigarettes more frequently reported having attempted to quit at least once, and among these smokers, a higher proportion report having attempted unsuccessfully to quit multiple times. The applicability of these data to defining the role of "tar" or nicotine yields of cigarettes in quitting behavior is not clear in the absence of more detailed longitudinal data. 13. Although a greater proportion of unsuccessful quitters reported smoking the lowest "tar" and nicotine products than did recent successful quitters in one large survey, interpretation of these data is made difficult by the noncomparability of brand reported (i.e., unsuccessful quitters reported the brand smoked after an attempt, successful quitters reported the brand smoked prior to the attempt). 14. In a large national survey, the mean duration of the latest unsuccessful attempt to quit shows no clear relationship to "tar" or nicotine yields. Research Recommendations From the Working Meeting "Research Needs on Low-Yield Cigarettes" The following list is an overview of research recommendations submitted as a result of the working group reports from the June 1930 conference "Working Meeting: Research Needs on Low-Yield Ciga- rettes." No attempt has been made to place them in order of priority. o It must be determined whether lower "tar" and nicotine cigarettes change smoking behavior. For instance, compensatory adjustment, such as deeper, longer, and more frequent puffs, may turn a nominally lower yield cigarette into a higher yield cigarette. Studies am needed to determine whether adjustments made by smokers of lower "tar" and nicotine cigarettes may inadvertently increase their exposure to "tar" and carbon monoxide beyond that expected from a less intensively smoked higher yield cigarette. o Because of changes in cigarette composition, further retrospec- tive and prospective epidemiologic studies are needed to assess the health effects of these changes. A primary need is to establish whether there are measurable differences in morbidity between smokers of higher "tar" and nicotine cigarettes and smokers of lower "tar" and nicotine cigarettes. Efforts should include ongoing long-term studies that are adaptable to such epidemiologic inquiry. 24 o The increased use of nonhuman primate models might permit comparison of the effects of lower "tar" and nicotine cigarettes with those of higher "tar" and nicotine cigarettes under controlled conditions. 0 More indepth studies on the mechanisms of cardiovascular and pulmonary disease are needed to assess new brands of lower "tar" and nicotine cigarettes. With improved noninvasive tech- niques, scientists will be better able to determine how a particular cigarette affects cardiac function and other physio- logical activities. Genetic markers should be explored as a possible method of identifying high-risk groups who are more likely to develop tobacco-related diseases if they smoke. 0 Additional emphasis should be given to both human and animal research models for the developmental mechanism of chronic obstructive pulmonary disease and its possible alteration by lower "tar" and nicotine cigarettes. The elastase-inhibitor imbalance hypothesis of emphysema pathogenesis needs confir- mation for human disease. Recently developed tests that measure lung elastin degradation products in plasma and urine need rapid clinical evaluation. 0 Emphasis should be placed on studies that determine the character and magnitude of the health hazards that lower "tar" and nicotine cigarettes pose for pregnant women and their offspring. Specifically, the smoking habits of pregnant women should be analyzed in prospective epidemiologic studies to determine the effect of varying cigarettes on the course and outcome of pregnancy. Careful laboratory measurements of various physical capacities and functions of newborn infants and pregnant women should be performed in case-control and prospective studies to determine the influence of smoking on pregnancy outcome. Clinical and experimental studies using animals should be conducted to evaluate the effect of individual constituents of cigarette smoke on tissues and physical re- sponses. Direct intervention strategies should be aimed at pregnant adolescents who smoke. 0 Another research need is routine, frequent surveillance of current and future lower "tar" and nicotine cigarettes for specific chemical constituents and biological activity. In addition to "tar," nicotine, and carbon monoxide yield, new types of cigarettes should be monitored regularly for delivery of other potentially harmful constituents, such as benzda]pyrene, phe- nols, catechols, nitrosamines, nitrogen oxides, volatile aldehydes, and radionuclides. More frequently updated ratings of "tar," nicotine, and carbon monoxide content would permit more accurate studies on the potential impact of cigarette components on health. 25 o More data are also needed on cigarette flavor additives and their combustion products. Flavoring agents and additives should be studied by cigarette companies for carcinogenicity and toxicity before their commercial use is permitted, and the results of such studies should be made available. o Research should be done on the distribution, partitioning, and penetration of lower "tar" and nicotine cigarette smoke in the lung, with consideration of potential changes in smoking patterns by those who smoke lower "tar" and nicotine ciga- rettes. Cigarette smoking-machines currently in use and the techniques by which animals inhale cigarette smoke in research models may not be representative of the human situation because human smokers are able to take larger, more frequent, and higher velocity puffs. To conduct meaningful assays of cigarette yields and the biological activity of cigarette smoke, it must be determined how smokers actually smoke various types of commercial cigarettes. When this information is available, it will be possible to design smoking-machines that yield more accurate estimates of human risk. o Controlled studies are needed to determine the role of nicotine as a primary reinforcer in cigarette smoking and to determine whether there are other chemicals in addition to nicotine that may contribute to or reinforce the smoking habit. By analyzing the mechanisms whereby nicotine reinforces smoking behavior, it may be possible to design more efficacious methods of smoking cessation. o Research should be conducted to define what effects modifica- tions of the physical and chemical properties of leaf tobaccos have on the pharmacology of cigarette smoke. Since tobacco culturing and curing practices are continually changing, it is important to determine whether such changes as the use of new pesticides also alter the composition and biological activity of cigarette smoke. o Standardized experimental cigarettes have frequently proved unpalatable and unacceptable for behavioral research. Proto- type cigarettes should be especially designed to deliver a wide range of constituent concentrations, particularly those that approximate commercial cigarettes. This would allow research- ers to predict the behavior of smokers of new types of cigarettes more accurately. 26 Section 2. PHARMACOLOGY AND TOXICOLOGY CONTENTS Introduction Experimental Systems for Assay of Relative Risks of Cigarette Smoking Lung Cancer Animal Models Lung Carcinogens in Cigarette Smoke Polycyclic Aromatic Hydrocarbons Tobacco-Specific N-Nitrosamines Other Mutagenic or Co-mutagenic Agents Weak Acids Nicotine Polonium 210 Volatile N-Nitrosamines Bladder Cancer Laryngeal Cancer Other Cancers Early End Points Suggestive of Carcinogenic Potential Chronic Obstructive Lung Disease Sudden Death Due to Cardiovascular Disease Animal Models Nicotine Carbon Monoxide Other Agents Complications of Pregnancy and Early Childhood Nonspecific End Points of Toxicologic Significance Reduction of Lung Defense Mechanisms Induction of Microsomal Oxidase Changes in Genetic Status Changes in Immune Status composition of Smokes From Various Types of Cigarettes Smoking-Machine Design Dependence of Smoke Composition on Cigarette Design Filters Ventilation Tobacco Variety Agricultural Practice Reconstituted Sheet and Modified Tobaccos 29 Additives Variations in Human Smoking Behavior Research Needs Surveillance of New Cigarettes Determination of Parameters of Human Cigarette Smoking Evaluation of Health Effects of Nicotine The Effects of Smoking-Machine Parameters on Relative and Absolute Yields of Smoke Components From Various Types of Cigarettes Influence of Raw Product Modification on Pharmacology of Cigarette Smoke Physical and Chemical Properties of Smoke From Cigarettes Delivering Less Than 10 mg of "Tar" Development and Validation of Analytical Methods Other Research Needs Summary References LIST OF FIGURES Figure l.-Effect of cigarette smoke differing in selected chemical components on pancreatic elastase levels in beagle dogs after a f5OO-day exposure protocol of 12 cigarettes per day, 7 days per week LIST OF TABLES Table I.-Major toxic agents in the gas phase of cigarette smoke (unaged) Table 2.-Major toxic agents in the particulate matter of cigarette smoke (unaged) Table 3.Ahefficient.a and standard deviations of coefficients for Prediction Model 10 Table 4.-Comparison of mutagenic and tumor-promoting activity of fractions of cigarette smoke condensate 31 lntroductlon Tobacco and tobacco smoke are very complex mixtures. In 1968, Stedman (155) reported that they contained more than 1,200 clearly identified substances in addition to a number of polymer classes, such as pigments, resins, and proteins, that were not resolved into specific compounds. Since that time, many additional compounds have been isolated; at least a thousand additional constituents were found in tobacco and tobacco smoke in the following 10 years (67). Cigarette smoke components arise through distillation of volatile and semivola- tile materials from the leaf and from the pyrolytic decomposition of leaf constituents. In addition, nonvolatile components of tobacco leaf can be transferred to the smoke without degradation. Thus, the components of smoke are very diverse. Many suspected or proved toxic agents have been identified in the gas phase (Table 1) or in the particulate matter (Table 2) of smoke (290). It is not surprising that chronic exposure to such a complex mixture will lead to a variety of pharmacologic and toxicologic responses. TABLE l.-Major toxic agents in the gas pham of cigarette smoke (unaged)* Di~thylnitmaamine EthYlmethytnitroMmine Diethylnitmsandne Nitnxopyrrdidine other nitmoaminen (4 compotmde) Hydrrdw Vinyl chloride urethane Folldd&@ Hydmseneyanide Aaolein Aeetaldehyde Nitrogen oxides (NO& Ammonia Pyridii Carton monoxide C C TI CT Qc `X T Ei T T?d TM T TABLE 2.-Major toxic agents in the particulate matter of cigarette smoke (unaged)* B-+h~ bbiethmne Ber&jjuonulthene Bellr+~thInceDe other polymlclear erometic hydm carbons (>26 compound@ JXben&jJecridhe Diben&h~dine Dibe.nz&gJcuhemie m= Fl~OthlX B-ofaimw other polymldsv -tic by&o- carbons (>lO compounds) NapMtmlenea l-Methylindokd MbhthylarbsFales Other neutrel compoundn catechol b & CMethyka~ 0th c&e&oh (>4 mmpounde) U&OtWlphC3ldSIWldhd6 N'-Nitmmnombtine other nonvoletik nitmeeminea &N~htbyluniM OthW-tiCMUilE8 Unknown nitro compound8 Polonium-210 Niid mmpour& Cedmium compounds Aneaic Nkotine Mioor t4baan 8lkabida I%mol Crcaols (3 eompouoda) TI TI TI TI TI TI TI TI ac cot ccc cd: cot COG cd2 cot cd2 ccc cot cd2 C C Bc Bc Bc C C C C T T CT CT ? l-10 M 0.349 H o.m.2 pg ? u)-r16ocB 80-4oM ? ? loo-250 !q ? o-26 w ? ? 0.62-1.2 pci 1@600 w 9-70 ng l-26 M 0.1-20 mg 0.01-02 mg l&206 #tg 10-166 R ? 6 M 0s P2 0.1 pg Experimental Systems for Assay of Relative Risks of Cigarette Smoklng Lung Cancer Animul Models The mouse skin carcinogenesis assay is thus far the most fruitful method of evaluating smoke condensates from different types of cigarettes for carcinogenic potency for the human lung (46,51,89,106). 34 This model for the development of cancer dates back to 1915 (191). A large body of laboratory experience has provided consistent evidence for the quantitative validity of this relationship. Procedures providing good dose-response relationships are in use in many laboratories. Assays can be standardized to give relatively consistent results within a laboratory, and probably among laboratories (62, 63,64, 65). The assay depends on a number of similarities between the laboratory model and human experience. The epithelium of both the skin and lung is directly exposed to the presumptive carcinogenic agent-in this case, cigarette smoke or cigarette smoke condensate. Babbit and mouse skin develop tumors after exposure to coal tar, a known occupational carcinogen. Mouse skin assays have predicted occupational induction of human lung cancer by bis-chloromethyl ether w, 170. It is conceivable that the mouse skin carcinogenesis assay may give a misleading measure of the relative risk of various types of cigarettes. Skin is covered with a lipid film, and the pilo-sebaceous apparatus is particularly suited for penetration of lipid materials into the skin. In contrast, the airway surface is covered by an aqueous film and might be less readily penetrated by fat-soluble materials. There is no evidence, however, that such a difference is important. Indeed, the response of mouse skin to different types of experimental cigarettes is roughly parallel to the response of hamster larynx to the same materials (49,50,189). The hamster larynx has been used for comparative studies of different types of cigarettes (17, 50, 52). Invasive carcinomas of the larynx were induced in 37 percent of inbred hamsters exposed to cigarette smoke for 59 to 30 weeks. Both the cancer incidence and the incidence of other epithelial changes were dose related. Exposure of rats and mice to cigarette smoke for up to 21/2 years resulted in a small incidence of respiratory tract tumors, primarily pulmonary adenomas (44, 68, 72). Cigarette smoke `produced changes in cultured human gastric epithelial cells suggestive of malignancy (158). Experience in man and with the mouse skin system indicates that two or more distinct classes of carcinogenic stimuli lead to the occurrence of tumors (16, 26, 48). Tumor initiators appear to alter the genetic constitution of the cell; tumor promoters accelerate and enhance the neoplastic expression of previously initiated cells. Both may play a role in the induction of tumors. Other types of coca&n+ gens may also play a role in the induction of mouse skin tumors by cigarette smoke condensate (16, 74,89,176). If similar mechanisms act in man, it may not be possible to differentiate between a human carcinogen in the conventional sense and a cocarcinogen or tumor 35 promoter acting on a diverse population already exposed to low levels of a variety of tumor initiators. Two prominent classes of tumor initiators are found in smoke condensates of commercial cigarettes-polycyclic aromatic hydrocar- bons (PAH) and tobacco-specific nitrosamines (TSNA), Other car&+ gens or tumor initiators are present in cigarette smoke as well; however, they appear to be less significant because they either are less potent or are present at lower concentrations than are PAH or TSNA. Polycyclic Aromatic Hydrocarbons A large variety of PAH molecules are formed by the pyrolytic process during combustion of the cigarette (87, 105). Of the PAHs, be&a&rene (BaP) is the most prominent and has been studied most intensively. Chemical assays for BaP in smoke condensates are well established, and it has been suggested that such assays can serve as indicators of production of all of the PAHs. This appears to be generally true. Among smoke condensates from 98 experimental cigarettes, the correlation coefficient between BaP and bem$a]anthracene content was 0.78 (15). Although highly signiicant, the value is sufficiently low to indicate that real differences do exist in the ratios of these cyclic molecules in the various cigarette smokes. Nevertheless, BaP appears to be the most important single member of this class of compounds, taking into consideration both its concentra- tion and its relative carcinogenic potency. The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully mea- sured at this time. Wynder and Hoffmann (188) found a correlation between BaP levels and carcinogenic activity of smoke condensates from several types of cigarettes. A much larger series of experimental cigarettes was studied in the smoking and health program of the National Cancer Institute. No significant dependence of carcinogenic potency on BaP content was observed (6&63,64,65). The relationship between chemical composition of the experimental smoke condensates and the biological activity of this series was examined extensively by Bayne (15). He employed the linear terms, squared terms, and all interaction terms between any 2 of 10 independent variables. Starting with a 66-&m regression equation, he searched for simpler prediction models that would provide useful estimates of carcinogenic activity. The simplest model (Table 3) that retained good predictability contained nine terms. The interaction of BaP with the nicotine term was one that appeared important. BaP and other tumor initiators are particularly important because humans are already exposed to a number of initiators in the environment. The effect of initiators is cumulative and irreversible. Hence, any additional exposure to initiators such as the PAH might be expected to increase tumor incidence in smokers. 36 TABLE 3.-Coeffkienta and standard deviations of coefficients for Prediction Model 10 t3taDdIud deviatioo Terms. Coefficienta of aleffiientd 1 Intercept 2.667 0292 2C 4.792 E-2 0.234 Is2 2cI 4.66s E-4 0.406 El 1 PH 4.464 E-l OMO El-1 5vwA 1.242 E-l 0.555 Fe-1 6NxN 245oEl-5 0.668E-5 7 pH x pH 2.662 J3-2 0.875 E-2 8NxpH -7.078 E-t 1.664 E-4 9NxBAP -1.T70 EL9 0.2TIE4 bs:; Cbmmhdon (m&&y); VWA-very wed mcih (u&g); N-nicoh (n@g); and BAP-bearo[+ymm Born Bayme (26). Tobacco-Specific N-Nitrosamines During tobacco curing, fermentation, and burning, nornicotine gives rise to N'-nitrosonomicotine (NNN), nicotine to NNN and to 4-(N- methyl-N-nitrosamino)-l-(3-pyridil)-1-butanone (NNK), and anatabine to N'-nitrosoanatabine (NAT). NNN is a moderately active carcinogen, inducing tumors in the respiratory tract of mice, rats, and hamsters. NNK is a strong carcinogen, inducing lung carcinoma in each of the three animal species (75, 84, 86). The concentration of these carcino- gens in cigarette smoke is very high in comparison with usual environmental exposures, being 1 to 35 ppm in tobacco and 1 to 9 erg in the smoke of a cigarette (57). These tobacco-specific N-nitrosamines may play a role in the development of several types of human cancer. NNN is metabolically activated by human liver microsomes (76) and, together with NNK and NAT, may be formed in wivo from the tobacco alkaloids. Other Mutagenic or Co-mutagenic Agents It is generally believed that tumor initiators are mutagens that can be detected by one or more short-term biological assays (2, 103). A number of fractions of cigarette smoke condensate are positive in the Ames assay system (93, 101). The agents responsible for this activity have not been fully identified, but probably include products of protein pyrolysis (119). Ames test activity, however, does not predict the activity of fractions in the mouse skin carcinogenesis assay. Fractions of smoke condensate that show activity as complete carcinogens (89) or in a promotion assay that would detect skin carcinogens as well as tumor promoters (24) are not correspondingly active in the Ames system (Table 4). It cannot be determined whether the unidentified mutagens in cigarette smoke are an important cause of lung cancer in 37 TABLE 4.-Comparison of mutagenic and tumor-promoting activity of fractions of cigarette smoke condensate whole eondeneate Beeollatiblted Bmea before, insoluble Baaee after, iduble Bmen, ether soluble Bass, water soluble week acid.9$ iMobible Weak ad4 e&r soluble Strong acidq iaaohble Strong aci4 ether soluble strong aei& water Eoluble Neutrala, 80% methuwl dubie Neutde, cyclobexane mluble Neutrala, nitrome~ duble 100 89 21 26 11 1 30 5 2 <1 <2 2 51 2 humans; however, added exposure to any tumor initiators probably carries an incremental risk of cancer. Weak Acids Cigarette smoke contains weak organic acids that exhibit tumor- promoting or cocarcinogenic activity (24,74,176). The concentration of very weak acids in cigarette smoke condensates was one of the terms predictive of the skin carcinogenic activity of smoke condensates (Table 3). Of the weak acids, catechol appears to be the most important on the basis of concentration and activity (74,176). It is probable that the weakly acidic constituents of smoke act as tumor promoters or cocarcinogens rather than as tumor initiators, This is true for phenols and for catechol (27, 176). There is no reason to believe that tumor promoters or other types of cocarcinogens exhibit either a cumulative or an irreversible effect. Indeed, for tumor promotion in mouse skin by croton oil, clear thresholds for frequency of application and for the amount of promoter in each applied dose are apparent (26). If this is also true for man, the risk of very small doses of weak acids might be negligible. Phenol (1.26, 188), but not catechol (29), can be selectively removed by filters. The extent to which the cocarcinogenic weak acids are reduced by selective filtration cannot be determined at this time. 33 Nicotine Nicotine exhibits neither complete carcinogenic activity nor tumor- promoting activity. The nicotine content of cigarette smoke condensate did not affect its carcinogenic activity when suspended in beeswax- tricaprylin pellets implanted in rat lungs (48); however, in mouse skin bioassays, this alkaloid is an important cocarcinogen (20). Not only is nicotine active in models with other compounds such as BaP and 12-O- tetradecanoylphorbol-X%-acetate (TPA), but also the measured carcino- genic potency of cigarette smoke condensates appears to depend on the nicotine content of the "tar." Of all of the individual compounds of smoke condensates assayed in the smoking and health program of the National Cancer Institute, nicotine was most closely related to carcinogenic activity (62, 63, 64, 65). In the simplest predictive model developed by Bayne, every term but one involved nicotine concentra- tion, pH, or the concentration of crude condensate (Table 3). The availability of nicotine to the tissues depends on the pH and concentra- tion of condensate. Hence, available nicotine was a factor of all but one term of the prediction model. Nicotine may also play a role in the development of oral cancer in tobacco chewers. Aqueous extracts or unburned tobacco exhibit tumor- promoting activity when tested on mouse skin. This activity depends on the presence of nicotine acting together with a fraction having a molecular weight greater than 13,000 daltons (21). In addition, nicotine gives rise to carcinogenic N-nitrosamines during tobacco chewing (84). Data of Morosco and Coeringer (122) suggest that nicotine reduced serum alpharantitrypsin activity and elevated pancreatic elastase levels in dogs exposed to cigarette smoke. These workers believe that interference with the protease-protease inhibitor balance may be a factor in carcinogenesis (123). It must be pointed out that the relationship between carcinogenic activity of smoke condensates and their nicotine contents may be caused in part by the conversion of nicotine to tobacco-specific nitrosamines or to the co-occurrence of nicotine and some other unidentified carcinogen. For example, the nicotine level of tobacco is dependent on the amount of nitrate fertilizer used in tobacco culture (166). High levels of tobacco-specific nitrosamines were found in the unburned tobaccos usually raised with high levels of nitrogen fertilizer (77). The level of volatile nitrosamines in cigarette smoke also depends on nitrate fertilizer (170). One may postulate that the nicotine level of cigarette smoke condensates is an indicator of such nitrogenous carcinogens that were not measured directly. At present, however, there is no direct evidence that this is the case. In any event, the carcinogenic activity of mixtures of pure BaP and TPA are enhanced by the concomitant application of nicotine under conditions such that nitrosamine formation would not be expected (20). 39 Whether the cocarcinogenic effects of nicotine are important for man is a matter of speculation. Tumor-promoting activity of croton oil exhibits a threshold both for frequency of application and for the quantity of agent present with any given treatment (26). The animal studies in which nicotine acts as a cocarcinogen employ nearly lethal levels of nicotine administered once or twice a day. In contrast, smokers are exposed to a large number of low doses of nicotine daily. If a threshold amount of nicotine per dose is required for cocarcinogenic activity, human smokers may not be affected in a manner similar to that of the mouse skin system. Polonium 210 There have been repeated suggestions that "PO might contribute to the carcinogenic activity of cigarette smoke in man (137). Polonium levels in tobacco result primarily from the use of phosphate fertilizers that are contaminated with radium decay products, particularly mPb, a precursor of ~OPO (162,168). Very little uOPo is found in tobacco leaf, but some is transferred to the smoke. Yields of 10 to 15 fCi of alpha emitters were recently reported for experimental cigarettes and 490 fCi/gm for commercial cigarette smoke condensate (36). Most of the radioactivity was due to insoluble forms of ~Po. Cancer may arise from a single affected cell. It has been suggested that small amounts of insoluble nOPo concentrated in small areas might deliver an effective carcinogenic dose to a target cell (112). Harley et al. (71), however, found very few "hot spots" in the lungs of deceased smokers. Based on human experience with radon daughters, they assumed a lifetime risk of lung cancer of 1 x 10-Z for a dose of one rad/year. At most, the radioactivity they detected was estimated to explain only 10 percent of the lung cancers suffered by cigarette smokers. They consider polonium 210 a questionable risk factor in human carcinogenesis. Polonium 210 contamination of tobacco can be effectively reduced by selection of plant types and sources of phosphate fertilizer, and by removal using chelating agents (71,171). Volatile N-Nitrosamines Tobacco smoke contains a number of secondary and tertiary amines. These amines, together with nitrogen oxides, may give rise to the in &uo formation of nitrosamines. Although the formation of most nitrosamines is favored at low pH (llO), a small amount of volatile nitrosamines is found in cigarette smoke and may be formed in the lungs under normal conditions (30, 84, 170). The volatile N-nitrosa- mines are organ-specific carcinogens, which in mice give rise to tumors of the liver and kidney. At present, there is no reason to assume that volatile nitrosamines cause lung cancer in smokers. Nevertheless, it is prudent to limit the presence of any carcinogen in cigarette smoke. Volatile nitrosamines in smoke can be reduced by selective filtration and by limiting the nitrate content of tobaccos (SO, 121). Bladder Cancer The induction of bladder cancer in animals has been studied intensively over the past several decades. The bladder appears to be a particularly sensitive target for agents that are metabolized in the liver and excreted in the urine. Among the compounds known to produce bladder cancer in both man and animals is P-naphthylamine. The presence of Snaphthylamine in cigarette smoke has been demon- strated (85), along with other carcinogenic aromatic amines (129). The yield was so low, however, that they did not believe these agents contributed significantly to the risk of bladder cancer in smokers. The urine of 10 smokers and 21 nonsmokers was examined by Yamasaki and Ames (192) for mutagens or for substances that were converted to mutagens by rat liver microsomes. Increased levels of mutagens were found in the urine of seven smokers, but in none of the nonsmokers. If promutagens in urine are responsible for the bladder cancers occurring in cigarette smokers, it is possible that certain individuals are particularly sensitive to bladder carcinogenesis by cigarette smoke. If true, this sensitivity may be exploited for disease prevention. Large quantities of mutagen-containing urine can be collected from sensitive individuals. Isolation and identification of the promutagens might permit removal of the precursors from cigarette smoke. Laryngeal Cancer Hamsters develop laryngeal cancer after long-term inhalation of diluted cigarette smoke (17, 50, 52). The effect is dose related and has been used to compare different cigarettes. Tobacco-specific nitrosa- mines induce cancer in the trachea and lungs of hamsters and may be of particular importance in the induction of human cancer of the larynx (84). Other carcinogens and cocarcinogens of cigarette smoke that are active in the mouse skin bioassay system may also contribute to induction of laryngeal cancer. Both organ systems involve epithelial tissue directly exposed to the carcinogenic mixture. Other Cancers Cigarette smoking is also associated with cancer of the kidney, pancreas, oral cavity, and esophagus (173). No animal model of these cancers has been developed to the point where it could be used for quantitative comparisons of different types of cigarettes. Oral cavity and esophageal tumors may be induced by direct exposure to smoke carcinogens. NNN, when given in the drinking water of rats, induces cancer of the esophagus (84). This finding suggests that tobacc+ 41 specific nitrosamines may be active as "contact" carcinogens. Alterna- tively, the carcinogens might be produced through metabolism at distant sites, such as the liver, and then transported to the target site, where they can be further activated. Pancreatic cancer was induced in hamsters with diisopropylnitrosamine (134). This observation suggests the possibility of a similar action of smoke nitrosamines. Any carcinogen in cigarette smoke might contribute to induction of cancer distant from the exposure site. To this extent, elimination of the carcinogens causing lung cancer or bladder cancer would reduce the induction of cancer in other organs as well. Alcohol usage and cigarette smoking show synergistic effects in the induction of cancer in the upper digestive tract (113,172). The effect of alcohol in this circumstance may result from the induction of microsomal enzymes, which are believed to metabolize carcinogens to their active forms (213). Early End Points Suggestive of Carcinogenic Potential It is generally considered that the induction of cancer requires a specific genotoxic event that may be preceded or followed by ill- defined and less specific epigenetic changes that enhance the manifea- tation of the genetic event (182). In the two-stage carcinogenesis system of mouse skin, the first step-initiation-appears to be genotoxic, and the second step-promotion-appears to be epigenetic. Several other forms of cocarcinogenesis have been described (16). Tobacco smoke owes its carcinogenic activity to several carcinogens and cocarcinogens (24,87,176,188). Agents capable of producing genetic change can often be detected by mutagenesis assay systems (2). Most carcinogens are mutagens. Conversely, agents capable of inducing mutations are suspect as possible carcinogens. Cigarette smoke condensates and some of their fractions are mutagenic in the Ames salmonella assay systems (93, 119). These fractions are clearly of interest because they possess the capability of inducing genetic changes that might lead to tumor formation. Mutagenesis assays may provide a basis for the quantita- tive comparisons of new cigarettes when the relative importance of the genetic and epigenetic factors in smoke-induced cancer is understood. The Ames test gives poor results for fractions of smoke condensate that appear to be most active in systems designed to detect tumor- promoting activity (Table 4). Furthermore, mutagenesis assays of a series of experimental cigarettes have not provided consistent results (167). The complexity of carcinogenesis by tobacco smoke condensates renders mutagenesis assays of uncertain value for quantitative comparisons of relative carcinogenicity. Several in vitro systems measure the transformation of normal cells into malignant cells after exposure to carcinogens. These systems are sensitive to both genetic and epigenetic processe s (90,186). Such assays 42 may prove to be useful short-term indicators of the relative potency of different types of cigarette smoke. The toxicity of most experimental smoke condensates may interfere with the conduct of such studi=, however. Experimental cigarettes that yield smoke condensates with a wide range of carcinogenic activity are now available. It should be possible to determine the usefulness of in vitro systems with this material. For organ-specific carcinogens, the DNA repair test is a good predictor of relative carcinogenic activity (186). Most chemicals that are carcinogenic to mouse skin selectively destroy the sebaceous glands of the treated skin (23). The sebaceous gland suppression assay is a good predictor of the activity of experimental smoke condensates as carcinogens in mouse skin (22). Chronic Obstructive Lung Disease No animal models for chronic obstructive lung disease are available to measure the potency of smoke from various types of cigarettes. Long-term inhalation studies with hamsters, dogs, and primates have not given rise to disease states comparable to emphyse- ma observed in humans (17,50,52,114). In two experiments, Sprague- Dawley and CD rats exposed to cigarette smoke for 6 to 26 months developed emphysematous changes (104,12d. Similar results were not reported in other long-term studies with rats (44,68). A number of pulmonary function tests have been evaluated as measures of early lung disease in man (31, 61, 73, 100, 135, 154. Thus far, similar tests have not proved useful as animal assays. They might, however, be useful in comparing the effects of different types of cigarettes on human smokers. Exposure of CD rats to whole tobacco smoke for 6 months led to a loss of lung parenchymal tissue distal to the terminal airways (124). This was indicated by a 21 percent decrease in parenchymal tissue and 12 percent decrease in alveolar surface area. Recent evidence suggests that emphysema results from a shift in the balance of elastase production and elastase inhibition in the lung (97). A few individuals with genetically determined very low levels of alphal-antitrypsin, an elastase inhibitor, are particularly prone to develop the disease (58). When purified elastase is instilled into the lungs of dogs, emphysematous changes appear in as little as 96 minutes (96,98). Cigarette smoke can act on this system in two ways. In vitro tests with cigarette smoke condensate show that this material suppressed the antiprotease activity of human serum, pulmonary lavage fluid, and purified human alphal-antitrypsin (94). The suppression of protease inhibitors by cigarette smoke is blocked by the presence of phenolic antioxidants, suggesting that oxidants or free radicals of the smoke were responsible for the effect (107). In one study, the serum levels of alphal-antitrypsin in smokers were higher than in nonsmokers (76). Another study found, however, that immediately after smoking, serum alphal-antitrypsin activity was reduced in smokers (95). Likewise, the activity of alphai-antitrypsin in lung lavage fluid from Sprague Dawley rats was reduced by 30 to 40 percent after 3 to 6 puffs of cigarette smoke. Similar reductions were observed in lavage fluid from the lower respiratory tract of asymptomatic smokers (58). Even greater differences were seen between smokers and nonsmokers with idiopathic pulmonary fibrosis. Cigarette smoke also stimulates the release of elastase from macrophages in vitro and in &VU and from polymorphonuclear leukocytes in vitro (19,1&9,185). Thus, smoke may increase the elaboration of elastase in the lung and at the same time suppress its inactivation. The techniques used in these studies could he applied to smoke from various types of cigarettes; they might then serve as short-term end points to evaluate relative cigarette risk. Dogs exposed to cigarette smoke through tracheostomies for 600 days had significantly higher levels of pancreatic elastase than sham- smoked controls (122). The greatest effects were seen in animals exposed to higher nicotine cigarettes, although the blood carboxyhem- oglobin levels were the same for both higher and lower nicotine smokers (Figure 1). The lower nicotine cigarettes in this study were produced by removal of the alkaloid by a commercial process (65). It cannot he stated with confidence that other constituents were not removed as well. Sudden Death Due to Cardiovascular Disease Animal Models No animal model permitting the quantitative comparison of death rates due to cardiovascular disease induced by different types of cigarettes is presently available. Long-term inhalation studies using smoke-exposed rats, hamsters, dogs, and primates have been conducted (17,& 50,52,68,104,114). None has provided an end point comparable to sudden death observed in human smokers. There are, however, several avenues of investigation whose intermediate experimental observations might indicate a mechanism for mortality caused by cardiovascular effects. Much attention has been given to changes induced by nicotine-induced catecholamine release (138, 156, 160). Methods to follow these effects in animals are well established. Other short-term end points being studied include lipoprotein levels (79), alteration of arterial morphology (9, 10, 32, 111), and changes in arachidonic acid metabolism (12, 82). These procedures might be adapted for estimation of the relative potency of various types of cigarettes, but there is no direct evidence that any of these changes are either necessary or sufficient indicators of the risk of sudden death due to heart disease. 44 30- -z 5 25- g Y 2 5 20- Y g 15- ?! f `O- 5- 0 oooE32 - I 1, I t I 1 CODE13 colm?OL FIGURE l.-Effect of cigarette smoke differing in selected chemical components on pancreatic elastase levels in beagle dogs after a 6OOday exposure protocol of 12 cigarettes per day, 7 days per week. Bars indicate mean *SD. Animals exposed to code 32 (hiih-nicotine) and code 13 (low-nicotine) cigarettes diff'ered significantly (p