REPORT OF THE ADVISORY COMMITTEE TO THE SURGEON GENERAL OF THE PUBLIC HEALTH SERVICE U-23 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Public Health Service Publication No. 1103 For sale by the Suprrintendent of Documents, U.S. Government Printing Office U~ashingmn. D.C., 20402 - Price $1.25 THE SURGEON GENERAL'S ADVISORY COMMITTEE ON SMOKING AND HEALTH Stanhope Bayne-Jones, M.D., LL.D. Walter J. Burdette, M.D., Ph. D. William G. Cochran, M.A. Emmanuel Farber, M.D., Ph. D. Louis F. Fieser, Ph. D. Jacob Furth, M.D. John B. Hickam, M.D. Charles LeMaistre, M.D. Leonard M. Schuman, M.D. Maurice H. Seevers, M.D., Ph. D. . . . 111 COMMITTEE STAFF Professional Staff Eugene H. Guthrie, M.D., M.P.H. Peter V. V. Hamill, M.D., M.P.H. Staff Director Medical Coordinator Alexander Stavrides, M.D. Jack Walden Special Assistant to the Director Information Officer Mort Gilbert Jane Stafford Editorial Consultant Editorial Consultant Helen A. Johnson Benjamin E. Carroll Administrative Oficer Biostatistical Consultant Secretarial and Technical Staff Helen Bednarek Alphonzo Jackson Mildred Bull Jennie Jennings Grace Cassidy Martha King Rose Comer Sue Myers Jacqueline Copp Irene Orkin Adele Rosen Margaret Shanley Don R. Shopland Elizabeth Welty Edith Waupoose iv Foreword Since the turn of the century, scientists have become increasingly inter- ested in the effects of tobacco on health. Only within the past few decades, however, has a broad experimental and clinical approach to the subject been manifest; within this period the most extensive and definitive studies have been undertaken since 1950. Few medical questions have stirred such public interest or created more scientific debate than the tobacco-health controversy. The interrelationships of smoking and health undoubtedly are complex. The subject does not lend itself to easy answers. Nevertheless, it has been increasingly apparent that answers must be found. As the principal Federal agency concerned broadly with the health of the American people, the Public Health Service has been conscious of its deep responsibility for seeking these answers. As steps in that direction it has seemed necessary to determine, as precisely as possible, the direction of scientific evidence and to act in accordance with that evidence for the benefit of the people of the United States. In 1959, the Public Health Service assessed the then available evidence linking smoking with health and made its findings known to the professions and the public. The Service's review of the evidence and its statement at that time was largely focussed on the relationship of cigarette smoking to lung cancer. Since 1959 much addi- tional data has accumulated on the whole subject. Accordingly, I appointed a committee, drawn from all the pertinent scientific disciplines, to review and evaluate both -this new and older data and, if possible, to reach some definitive conclusions on the relationship be- tween smoking and health in general. The results of the Committee's study and evaluation are contained in this Report. I pledge that the Public Health Service will undertake a prompt and thorough review of the Report to determine what action may be appropriate and necessary. I am confident that other Federal agencies and nonofficial agencies will do the same. The Committee's assignment has been most difficult. The subject is com- plicated and the pressures of time on eminent men busy with many other duties has been great. I am aware of the difficulty in writing an involved technical report requiring evaluations and judgments from many different professional and technical points of view. The completion of the Com- mittee's task has required the exercise of great professional skill and dedica- tion of the highest order. I acknowledge a profound debt of gratitude to the Committee, the many consultants who have given their assistance, and the members of the staff. In doing SO, I extend thanks not only for the Service hut for the Nation as a whole. SURGEON GENERAL " Table of Contents FOREWORD . . . . . . . . . . . . . . . . . . ACKNOWLEDGMENTS . . . . . . . . . . . . . PART I INTRODUCTION, SUMMARIES AND CONCLUSIONS Chapter 1 Introduction . . . . . . . . . . . . Chapter 2 Conduct of the Study . . . . . . . . Chapter 3 Criteria for Judgment . . . . . . . . Chapter 4 Summaries and Conclusions . . . . . PART II EVIDENCE OF THE RELATIONSHIP OF SMOKING TO HEALTH Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Consumption of Tobacco Products in the United States . . . . . . . . . . . . Chemical and Physical Characteristics of Tobacco and Tobacco Smoke . . . . Pharmacology and Toxicology of Nico- tine . . . . . . . . . . . . . . . . Mortality . , . . . . . . . . . . . . Cancer . . . . . . . . . . . . . . . Non-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pul- monary Emphysema . . . . . . . . . Cardiovascular Diseases . . . . . . . Other Conditions . . . . . . . . . . Characterization of the Tobacco Habit and Beneficial Effects of Tobacco . . . Psycho-Social Aspects of Smoking . . . Morphological Constitution of Smokers. Chapter 11 Chapter 12 Chapter 13 Chapter 14 Chapter 15 Page V ix 3 11 17 23 43 47 67 77 121 259 315 335 347 359 381 vii ACKNOWLEDGMENTS During this study the -4dvisory Committee on Smoking and Health has had the constant support of individual s. groups and institutions throughout a broad range of professional and technical occupations. In many cases the contributions of these individuals involved considerable personal. pro- fessional or financial sacrifice. In every case the contributions lessened the burden of the Committee and increased the authorit>- and completeness of the Report. In this space it is impossible to assign priorities or special emphasis to individual contributions or contributors. The Committee. however, does acknowledge with gratitude and deep appreciation-and with sincere apologies to any individual inadvertently omitted--the substantial coopera- tion and assistance of the follo\ving: ACKERMAN, LAUREN, \I.D.-Professor of Pathology, Washington University School of Medicine, St. Louis, MO. ALBERT, ROY E., M.D.--Associate Professor, Department of Industrial Medi- cine, New York University Jledical Center, New York, N.Y. ALLEN, GEORGE V.-President and Executive Director, The Tobacco Insti- tut3, Inc., Washington, D.C. ALLING, D. W., M.D.-Statistician, National InsGtute of Allergy and Infec- tious Diseases, U.S. Public Health Service, Bethesda, Md. AMERICAN CANCER SOCIETY, New York, N.Y. AMERICAN TOBACCO Co., lYew York,N.Y. AXDERSON, AUGUSTUS E., Jr., M.D.--Senior Attending Internist, Research Laboratory, Baptist Memorial Hospital, Jacksonville, Fla. ANDERVONT, HOWARD B., SC. D.-Chief, Laboratory of Biology, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. ARTHUR D. LITTLE, INC., Cambridge, Mass. ASCARI, WILLIAM, M.D.-Pathologist, Presbyterian Hospital, New York, N.Y. AsHFoRD, THOMAS-P., M.D.-Instructor in Surgery, College of Medicine, University of Utah. Salt Lake City, 1.tah. ASTIN, ALEXANDER W., Ph. D.-Research Associate, National Merit Scholar- ship Corporation, Evanston, Ill. ?I~ERB.~CH, OSCAR, M.D.-Senior Medical Investigator, Veterans Adminis- tration Hospital, East Orange, N.J. ljAIL&R, JOHN C. III: &M.D.-Head, Demopraphv Section, Biometry Branch, National Cancer Institute, U.S. Public Healih Service. Bethesda, Md. NhTTIST~, S. P.-Pharmacologist, Arthur D. Little, Inc., Cambridge, Mass. AEARMAK, JACOB E., Ph. D.-Professor of BioFtatistics. L'nirersit! of >lin- nesota School of Public Health, Minneapolis, Mimi. REERE, GILBERT W., Ph. D.-Statistician, National Academv of S(+nres. Rja- tional Research Council. Washinpton, D.C. ix BELL, FRANK A., Jr.,-Program Director for the Engineer Career Develop- ment Committee, Office of the Chief Engineer, U.S. Public Health Service, Washington, D.C. BERKSON, JOSEPH, M.D.-Head, Division of Biometry and Medical Statistics, Mayo Clinic, Rochester, Minn. BEST, E. W. R., M.D., D.P.H.-Chief, Epidemiology Division, Department of National Health and Welfare, Ottawa, Canada. BLUMBERG, J., Brig. Gen.-Director, Armed Forces Institute of Pathology, Washington, D.C. BOCKER, DOROTHY, M.D.-Bibliographer, Reference Section, National Li- brary of Medicine, U.S. Public Health Service, Bethesda, Md. BRAUNWALD, EUGENE, M.D.-Chief, Cardiology Branch, National Heart Institute, U.S. Public Health Service, Bethesda, Md. BRESLOW, LESTER, M.D.-Chief, Division of Preventive Medical Services, California Department of Public Health, Berkeley, Calif. BROWN AND WILLIAMSON TOBACCO CORP., Louisville, Ky. BROWN, BYRON WM., Jr., Ph. D.-Associate Professor, Biostatistiea Division, School of Public Health, University of Minnesota, Minneapolis, Minn. BUTLER, WILLIAM T., M.D.-Clinical Investigator, Laboratory of Clinical Investigations, National Institute of Allergy and Infectious Diseases, U.S. Public Health Service, Bethesda, Md. CANADIAN DEPARTMENT OF NATIONAL HEALTH AND WELFARE, Ottawa, Canada. CANADIAN DEPARTMENT OF VETERANS AFFAIRS, Ottawa, Canada. CARON, Herbert S., Ph. D.-Cleveland Veterans Administration Hospital. Cleveland, Ohio CARNES, W. H., M.D.-Professor and Head of Department of Pathology, College of Medicine, University of Utah, Salt Lake City, Utah. CARRESE, LOUIS M.-Program Planning Officer, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. CASTLEMAN, BENJ.4MIN, M.D.-Department of Pathology, Massachusetts General Hospital, Boston, Mass. CHADWICK, DONAI.D R., M.D.-Chief, Division of Radiological Health, U.S. Public Health Service, Washington, D.C. CLARK, KESNETH, Ph. D.-Consultant, Office of Science and Technology. Executive Office of the President, Washington, D.C. COBB, SIDNEY, M.D.-Program Director, Survey Research Center, University- of Michigan, Ann Arbor. Mich. COMROE, JULIUS H., M.D.-Professor of Physiology and Director of the Cardiovascular Research Institute, University of California, San Francisco. Calif. COONS CARLETON S., Ph. D.-Curator of Ethnology, University of Pennsyl- vania Museum, Philadelphia, Pa. COOPER, W. CURK, M.D.-Professor, Occupational Medicine, School of Public Health, Berkeley, Calif. CORNFIELD: JEROME-Acting Chief, Biometrics Research Branch, National Heart Institute, U.S. Public Health Service, Bethesda, Md. DAMON, ALBERT, M.D.-Associate Professor, Department of Epidemiology, Harvard University School of Public Health, Cambridge, Mass. X DAWSON, JOHN M.-Statistician, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. DIPAOLO, JOSEPH A., Ph. D.-Senior Cancer Research Scientist, Rowe11 Park Memorial Institute, Buffalo, N.Y. DOBBS, GEORGE, M.D.-Associate Chief, Division of Scientific Opinions, Federal Trade Commission, Washington, D.C. DOLL, RICHARD, M.D.-Director, Medical Research Council's Statistical Research Unit, University College Hospital Medical School, London, England o DORN, HAROLD F.-Chief, Biometrics Research Branch, National Heart Institute, U.S. Public Health Service, Bethesda, Md. DOYLE, JOSEPH T., M.D.-Direotor, Cardiovascular Health Center, Albany- Medical College, Union University, Albany, N.Y. DUNHAM, LUCIA J., M.D.-Medical Officer, Laboratory of Pathology. Na- tional Cancer Institute, U.S. Public Health Service, Bethesda, Md. EBERT, RICHARD V., M.D.-Professor and Head, Department of Medicine, University of ,irkansas Medical Center, Little Rock, Ark. EDDY, NATHAN B., M.D.-Executive Secretary, Committee on Drug Addic- tion and Narcotics, National Academy of Sciences, National Research Council, Washington, D.C. EISENBERG, HENRY, M.D.-Director of Chronic Diseases, Connecticut State Department of Health, Hartford, Conn. ELLIOTT, JAMES LLOYD, M.D.-Assistant Chief, Bureau of Medical Services, U.S. Public Health Service, Silver Spring, Md. ENDICOTT, KENNETH M., M.D.-Director, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. FALK, HANS L., Ph. D.-Acting Chief, Carcinogenesis Studies Branch, Na- tional Cancer Institute, U.S. Public Health Service, Bethesda, Md. FILLEY, GILES F., M.D.-Associate Professor of Medicine, University of Colorado Medical Center, Denver, Colo. FISHER, RUSSELL SYLVESTER, M.D.-Chief Medical Examiner, State of Maryland, Baltimore, Md. FORAKER, ALVAN G., M.D.-Pathologist, Baptist Memorial Hospital, Jack- sonville, Fla. FOX, BERNARD H., Ph. D.-Research Psychologist, Division of Accident Pre- vention, U.S. Public Health Service, Washington, D.C. FRAZIER, TODD M., SC. M.-Director, Bureau of Biostatistics. Baltimore City Health Department, Baltimore, Md. GARFINKEL, LAWRENCE, M.A.-Chief, Field and Special Projects, Statistical Research Section, Medical Affairs Department, ijmerican Cancer Society, Inc., New York, N.Y. %LIAM, ALEXANDER, M.D.-Professor of Epidemiology. The Johns Hop- kins University, Baltimore, Md. GOLDBERG, IRVING D., M.P.H.-Assistant Chief, Biometrics Branch. National Institute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Md. GOLDSMITH, JOHI\`. M.D.-Head. Air Pollution Medical Studies, California Department of Public Health, Berkeley, Calif. `Deceased. xi ~OI.DSTEIY, HYMEN, Ph. D.-Chief, Biometrics Branch, National Institute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Md. GRAH.431, SAXON. M.D.-Associate Cancer Research Scientist, Roswell Park Memorial Institute, Buffalo, N.Y. GREENBERG, BERUARD G., Ph. D.-Professor of Biostatistics. School of Public Health. University of North Carolina, Chapel Hill, N.C. GROSS. PAUL, M.D.-Research Pathologist. Industrial Hygiene Foundation, Mellon Institute. Pittsburgh, Pa. HAENSZEL, WrLrr.AM-Chief, Biometrv Branch, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. HAINER, RAYMOND M., Ph. D.-Research Physical Chemist, A. D. Little Inc.. Cambridge, Mass. HALL, ROBERT L.. Ph. D.-Program Director, Sociology and Social Psy- chology, National Science Foundation, Washington, D.C. HAIXSTAIL D.kvtD-Actuary, The National Center for Health Statistics, U.S. Public Health Service, Washington, D.C. HAMMOND, E. CUYLER, SC. D.-Director, Statistical Research Section, Medi- cal Affairs Department, American Cancer Society, Inc., New York, N.Y. HAMPERL, H.. M.D.-Director of the Pathology Institute, University of Bonn, Bonn, Germany. HARTWELL, JON.4TH.4N L., Ph. D.-Chief, R esearch Communications Branch, National Cancer Institute, U.S. Public Health Service, Silver Spring, Md. HAYDEK. ROBERT G.. Ph. D.-Research Psychologist, Behavioral Sciences Section, Division of Community Health Services, U.S. Public Health Service, Washington, D.C. HEIMANN. HARRY, M.D.-Chief, Division of Occupational Health, U.S. Public Health Service, Washington, D.C. HEINZELMJNN, FRED. Ph. D.-Assistant Chief, Behavioral Sciences Section, Division of Community Health Services, U.S. Public Health Service, Washington, D.C. HELLER, JOHN R., Jr.. M.D.-President and Chief Executive Officer, Sloan- Kettering Institute for Cancer Research, New York, N.Y. HERMAN, DORIS L., M.D.-Pathologist, Tumor Tissue Registry, Cancer Com- mission, California Medical Association, Los Angeles, Calif. HERROLD: K.~THERISE, M.D.-Medical Director, Laboratory of Pathology. National Cancer Institute. I.S. Public Health Service, Bethesda, Md. HESTON, WALTER E.: M.D.. Ph. D.-Chief, Laboratory of Biology, National Cancer Institute, T7.S. Public Health Service, Bethesda, Md. HIGGINS, 1.t~ T. T.. M.D.-Professor of Epidemiology and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pa. HOCHRC->I> GODFREY, Ph. D.-Chief, Behavioral Sciences Section, Division of Community Health Services: U.S. Public Health Service, Washington. D.C. HOCKETT. ROBERT C.: Ph. D.--Associate Scientific Director, Tobacco Indus- try Research Committee: New York, N.Y. HORN, DASIEL: Ph. D.-Assistant Chief for Research, Cancer Control Pro- gram, Division of Chronic Diseases, U.S. Public Health Service, Washing- ton, D.C. xii HORTON, ROBERT, J. M.: M.D.-Chief, Field Studie: Branch, Dix-ision of Air Pollution, U.S. Public Health Service, Cincinnati. Ohio. HUEPER, WILHELM C., M.D.-Chief, I? nvironmental Cancer Section. Sa- tional Cancer Institute, U.S. Public Health Service, Bethesda, Told. IPSEN, JOHANI~ES, Ph. D.-Professor of Medical Statistics Henry Phipps ln- stitute, University of Pennsylvania. Philadelphia, Pa. ISBELL, HARRIS, M.D.-Professor of Clinical PharmacoloF)-. I'niversity of Kentucky Medical School. Lexington, KY. ISKRANT, ALBERT P.-Chief, Developmental Research Yecticjrl. Division of Accident Prevention, U.S. Public Health Service, Washington. D.C. JANUS, ZELDA-Statistician, National Cancer Institute, 1..S. Public Health Service, Bethesda, Md. JOSIE, G. H., SC. D., M.P.H.-Chief, Epidemiolo=)- Divi.;iotr. Department of National Health and Welfare. Ottawa, Canada. KAHN, HAROLD A.-Statistician, Biometrics Research Branch. National Heart Institute, U.S. Public Health Service. Bethesda. Md. CANNEL, W. B., M.D.-Associate Director, Heart Disease Epidemiology Study, National Heart Institute. U.S. Public Health Service. Framingham. Mass. KELEMEN, GEORGE, M.D.-Research Associate, hlassachusetts Eye and Ear Infirmary, Harvard University Medical School. Boston, 3iass. KELLEY, HAROLD H., Ph. D.-Professor, Department of Psychology, Uni- versity of California, Los Angeles, Calif. KENSLER, CHARLES J., Ph. D.-Senior Vice President, Life Sciences Division, Arthur D. Little, Inc., Cambridge, Mass. KESSELMAN, AvIva-Statistician, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. KLEINERMAN, JEROME, M.D.-Associate Director, Medical Research Depart- ment, St. Luke's Hospital, Cleveland, Ohio KNIGHT, VERNON, M.D.-Clinical Director, National Institute of Allergy and Infectious Diseases, U.S. Public Health Service, Bethesda, Md. KNUTTI, RALPH E., M.D.-Director, National Heart Institute. U.S. Public Health Service, Bethesda, Md. KOTIN, PAUL, M.D.-Associate Director of Field Studies, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. KREYBERG, LEIV, M.D.-Director of Institute for General and Experimental Pathology, University of Oslo, Oslo, Norway KRUEGER, DEAN E.--Statistician, Biometrics Research Branch, National Heart Institute, U.S. Public Health Service, Bethesda, Md. KUSCHNER, MARVIN, M.D.-Professor of Pathology and Director of Labora- tories, Bellevue Hospital Center. New York University Medical Center, New York, N.Y. LARSON, PAUL S., Ph. D.-Professor and Chairman of Department of Phar- macology, Medical College of Virginia, Richmond, Va. LEITER, JOSEPH, Ph. D.-Chief, Cancer Chemotherapy National Service Center, U.S. Public Health Service, Silver Spring, Md. rdEUCHTE~~~~~~~, CECILIE, M.D., Ph. D.-P f ro essor, EidgenGssische Tech- nische Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland . . . XIII LEUCHTENBERGER, RUDOLF, M.D.-Professor Eidgeniissische Technische Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland LEVIN, MORTON L.. M.D.-Professor of Epidemiology, Roswell Park Me- morial Institute, Buffalo, N.Y. LIEBOW, AVERILL A., M.D.-Professor of Pathology, Yale University School of Medicine, New Haven, Conn. LIGGETT & MYERS, INC., New York, N.Y. LILIENFELD, ABRAHAM, M.D.-Professor of Chronic Diseases, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Md. LISCO, HERMAN, M.D.-Cancer Research Institute, New England Deaconess Hospital, Boston, Mass. LITTLE, CLARENCE COOK, M.D.-Scientific Director, Tobacco Institute Re- search Committee, New York, N.Y. LOUDON, R. G., M.B.-Assistant Professor of Internal Medicine, The Uni- versity of Texas Southwestern Medical School, Dallas, Tex. MAR'OS, NICHOLAS E.-Statistician, Division of Occupational Health, U.S. Public Health Service, Washington, DC. MARDER, MARTIN, Ph. D.-Research Psychologist, Behavioral Sciences Sec- tion, Division of Community Health Services, U.S. Public Health Service, Washington, D.C. MATARAZZO, J. D., Ph. D.-Professor of Medical Psychology, Department of Medical Psychology, University of Oregon Medical School, Portland, Oreg. MCFARLAND, JAMES J., M.D.-Professor of Otolaryngology, School of Medi- cine, George Washington University Hospital, Washington, D.C. MCGILL, HENRY C., M.D.-Professor of Pathology, Louisiana State Uni: versity School of Medicine, New Orleans, La. MCHUGH, RICHARD B., Ph. D.-Associate Professor of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minn. MCKENNIS, HERBERT, Jr.-Professor of Pharmacology, Medical College of Virginia, Richmond, Va. MEDALIA, NAHUM Z., Ph. D.-Executive Secretary, Mental Health Small Grants Committee, National Institute of Mental Health, U.S. Public Health Service, Bethesda, Md. MEHLER, MRS. ANN-Research Assistant, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. MILLER, JACK, M.D.-Research Fellow in Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. MILLER, ROBERT W., M.D.-Chief, Epidemiology Section, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. MILLER, WILLIAM F., M.D.-Associate Professor of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. MITCHELL, ROGER S., M.D.-Associate Professor, University of Colorado School of Medicine, Denver, Colo. MURPHY, EDMOND A., M.D.-Attending Physician, The Moore Clinic, The Johns Hopkins University Hospital, Baltimore, Md. NASH, HARVEY. Ph. D.-Illinois State Psychiatric Institute, Northwestern University Medical School, Chicago, Ill. xiv NELSON, NORTON, Ph. D.-Professor and Chairman, Department of Indus- trial Medicine, New York University Medical Center, New York, N.Y. ORCHIN, MILTON, Ph. D.-Professor of Chemistry, University of Cincinnati, Cincinnati, Ohio. P. LORILLARD Co., New York, N.Y. PAFFENBARGER, RALPH S., Jr., M.D.-Medical Director, Field Epidemiology Research Section, National Heart Institute, U.S. Public Health Service, Framingham, Mass. PAUL, OGLESBY, M.D.-Chairman, Committee on Epidemiological Studies, Passavant Memorial Hospital, Chicago, Ill. PFAELZER, ANNE I.-Concord, Mass. PHILLIP MORRIS, INC., New York, N.Y. PICKREN, JOHN W., M.D.-Chief, Department of Pathology, Roswell Park Memorial Institute, Buffalo, N.Y. PIERCE, JOHN -4., M.D.-Associate Professor, Department of Medicine, Uni- versity of Arkansas Medical Center, Little Rock, Ark. POTTS, ALBERT M., M.D.-Professor of Ophthalmology, University of Chi- cago School of Medicine, Chicago, Ill. PRINDLE, RICHARD A., M.D.--Chief, Division of Public Health Methods, U.S. Public Health Service, Washington, D.C. R. J. REYNOLDS TOBACCO Co., Winston-Salem, N.C. REED, SHELDON C., Ph. D.-Professor of Zoology, Department of Zoology, University of Minnesota, Minneapolis, Minn. REMINGTON RAND, LTD. (Ottawa) ROOS, CHARLES A.-Head, Reference Services Section, National Library of Medicine, U.S. Public Health Service, Bethesda, Md. ROSEN, SAMUEL, M.D.-Chief, Pulmonary Mediastinal and ENT Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. ROSENBLATT, MILTON B., M.D.-Associate Clinical Professor of Medicine, New York Medical C 11 g o e e, and Visiting Physician, Metropolitan Hospital, New York, N.Y. Ross, JOSEPH, M.D.-Associate Professor of Medicine, University of Indiana School of Medicine and Head of Chest Division, Robert Long Hospital, Indianapolis, Ind. SANFORD, J. P., M.D.-Associate Professor of Internal Medicine, The Uni- versity of Texas Southwestern Medical School, Dallas, Tex. SAVAGE, I. RICHARD, Ph. D.-Professor of Statistics, Florida State University. Tallahassee, Fla. SCHIFFMAN, ZELDA-$Ckd Assistant to Executive Officer, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. SCHNEIDERMAN, MARVIN. A-Associate Chief, Biometry Branch, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. SCHWARTZ, JOHN THEODORE, M.D.-Head, Ophthalmology Project, Na- tional Institute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Md. SCOTT, OWEN-Executive Officer, National Institute of General Medical Sci- ences, U.S. Public Health Service, Bethesda, Md. SELICMAN, ARNOLD M., M.D.-Chairman, Department of Surgery, Sinai Hos- pital, Baltimore, Md. SELTSER, RAYMOND, M.D.-The Johns Hopkins IJniversity School of Public Health, Baltimore, Md. SELTZER, C~RI. C., Ph. D.-Research Associate in Physical Anthropology, Peabody Museum, Harvard University, Cambridge, Mass. SHAPIRO, HARRY, M.D.-Curator of Anthropology, American Museum of Natural History, New York: N.Y. SHUBIK, PHILLIPE, M.D.-Professor of Oncology, Chicago Medical School, Chicago, Ill. SILVETTE, HERBERT, Ph. D.-Visiting Professor of Pharmacology, Medical College of Virginia, Richmond, Va. SIRKEN, MONROE, Ph. D.-Acting Chief, Division of Health Records, The National Center for Health Statistics, U.S. Public Health Service, Wash- ington, D.C. SLOAN, &RGARET H.. M.D.-Special Assistant to Director, National Cancer Institute, IT.S. Public Health Service, Bethesda, Md. SPIEGELMAN, MoR'rrMER-Associate Statistician, Metropolitan Life Insurance Company, New York, N.Y. STALLOKES, REUEL, M.D.-University of California School of Public Health, Berkeley, Calif. STEINBERG, ARTHUR, Ph. D.-Biologist, Professor in Department of Biology, Western Reserve University, Cleveland, Ohio STEWART, HAROLD L.: M.D.-Chief, Laboratory of Pathology, National Can- cer Institute, U.S. Public Health Service, Bethesda, Md. STOCKS, PERCY, M.D.-World Health Organization Consultant, Former Chief Medical Statistician in the Office of the General Registrar (1933-50), London, England STOUT, ARTHUR P., M.D.-Professor Emeritus of Surgery, Laboratory of Sur- gical Pathology, College of Physicians and Surgeons, Columbia University. New York, N.Y. STOWELL, ROBERT, M.D., Ph. D.-Scientific Director, Armed Forces Institute of Pathology, Washington, D.C. SYME: SHERM.~N LEOYARD-SOciOIOgiSt, San Francisco Field and Training Station, I'.S. Public Health Service Hospital, San Francisco, Calif. TAEUBER, K. E.-Research Associate, Population Research and Training Center, University of Chicago, Chicago, Ill. TOBACCO IXSTITI-TE, INC.. Washington, D.C. TOB.~CCO INSTITUTE RESEARCH COMMITTEE, New York, N.Y. TOICL-HATA: GEORGE, Ph. D., D.P.H.-Chief of Epidemiology, St. Jude Re- search Hospital, Institute of Biology and Pediatrics, Memphis, Term., and Assistant Professor of Preventive Medicine, University of Tennessee, Col- lege of Rledicine. Memphis, Tenn. TOMPSETT, RALPH, M.D.-Professor of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Tex., and Director of Medical Education. Baylor University Medical Center, Dallas, Tex. TOTTEN, ROBERT S.. M.D.-Associate Professor of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. TURNER, CI.ACDE G.-Director, Tobacco Policy Staff, Agriculture Stabiliza- tion and Conservation Service. United States Department of Agriculture. Washington. D.C. xvi VINCENT, WILLIAM J.-Student, University of California, Los Angeles, Calif. VON SALLMANN, LUDWIG, M.D.-Chief, Ophthalmology Branch, National In- stitute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Md. VORWALD, ARTHUR, M.D.-Chairman, Department of Industrial Medicine and Hygiene, Wayne University College of Medicine, Detroit, Mich. WALKER, C. B., B.h.-Biostatistics Section, Research and Statistics Division, Department of National Health and Welfare, Ottawa, Canada WALLENSTEIN, MERRILL, Ph. D.-Chief, Physical Chemistry Division, Na- tional Bureau of Standards, Washington, D.C. WEBB, BLAIR M.: M.D.-Otolaryngologist and ENT Consultant at the National Institutes of Health, U.S. Public Health Service, Bethesda, Md. WEINSTEIN, HOWARD I., M.D.-Director, Division of Medical Review, Food and Drug Administration, Washington. D.C. WOOLSEY, THEODORE D.-Assistant Director, National Center for Health Statistics, U.S. Public Health Service, Washington, D.C. WYATT, JOHN P.: M.D.-Professor of Pathology, St. Louis University School of Medicine, St. Louis, MO. ZERZm4\`Y, FRED M., M.D.-Department of Maternal and Child Health. The Johns Hopkins School of Public Health, Baltimore, Md. ZUKEL, WILLIAM, M.D.-Associate Director, Collaborative Studies, National Cancer Institute. U.S. Public Health Service, Bethesda, Md. 114-422 o-64-2 xvii PART I Introduction, Summaries, and Conclusions Chapter 1 Introduction Chapter 1 Realizing that for the convenience of all types of serious readers it would he desirable to simplify language. condense chapters and bring opinions to the forefront. the Committee offers Part I as'surh a presentation. This Part includes: (a) an introduction comprising. amon? other items. a chro- nology especiallv pertinent to the subject of this study and to the establish- ment and activities of the Committee. (b ) a short account of how the study was conducted, cc) the chief criteria used in making judgments. and td t a brief overview of the entire Report. HISTORICAL NOTES AND CHRONOLOGY In the early part of the 16th century. soon after the introduction of tobacco into Spain and England by explorers returning from the New World. controversy developed from differin g opinions as to the effects of the human use of the leaf and products derived from it by combustion or other means. Pipe-smoking, chewing, and snuffing of tobacco were praised for pleasura- ble and reputed medicinal actions. At the same time, smoking was con- demned as a foul-smelling, loathsome custom. harmful to the brain and lungs. The chief question was then as it is now: is the use of tobacco bad or good for health, or devoid of effects on health? Parallel with the increas- ing production and use of tobacco, especially with the constantly increasing smoking of cigarettes, the controversy has become more and more intense. Scientific attack upon the problems has increased proportionatelv. The design, scope and penetration of studies have improved, and the yield of significant results has been abundant. The modern period of investigation of smoking and health is included within the past sixtv-three years. In 1900 an increase in cancer of the lung was noted particularly by vital statisticians. and their data are usually taken as the starting point for studies on the possible relationship of smoking and other uses of tobacco to cancer of the lung and of certain other organs. to diseases of the heart and blood vessels I cardiovascular diseases in pen- eral; coronary artery disease in particular) ~ and to the non-cancerous 1 non- neoplasticl diseases of the lower respiratory tract ( especially chronic bronchitis and emphysema 1, The next important basic date for starting comparisons is 1930. when the definite trends in mortality and disease-inci- dence considered in this Report became more conspicuous. Since then a great variety of investigations have heen carried out. Many of the chem- ical compounds in tobacco and in tobacco smoke have been isolated and tested. Numerous experimental studies in lower animals have been made by exposing them to smoke and to tars. gases and various constituents in tobacco and tobacco smoke. It is not feasible to submit human beings to 5 experiments that might produce ranters or other serious damage, or to expose them to possibly noxious agents over the prolonged periods under strictly controlled conditions that \vould be necessary for a valid test. Therefore. the main evidence of the effects of smoking and other uses of tobacco upon the health of human beings has been secured through clinical and pathological observations of conditions occurring in men, women and children in the course of their lives. and by the application of epidemio- logical and statistical methods by which a vast array of information has been assembled and analyzed. Amon? the epidemiological methods which have been used in attempts to determine whether smoking and other uses of tobacco affect the health of man: two types have been particularly useful and have furnished information of the greatest \-alue for the work of this Committee. These are (1 i retro- spective studies which deal with data from the personal histories and medical and mortality records of human individuals in groups: and I 2) prospective studies, in which men and w-omen are chosen randomly or from some special group. such as a profession, and are follo\ced from the time of their entrv into the study for an indefinite period. or until thev die or are lost on account of other events. Since 1939 there ha\-e been 29 retrospective studies of lung cancer alone which ha1.e varying degrees of completeness and validity. Following the publication of several notable retrospective studies in the years 1952-1956. the medical evidence tending to link cigarette smoking to cancer of the lung received particularly widespread attention. .4t this time, also. the critical counterattack upon retrospective studies and upon conclusions drawn from tllem was launched by unconvinced individuals and groups. The same types of criticism and skepticism have been. and are. marshalled against the meth- ods. findings, and conclusions of the later prospective studies. They will he discussed further in Chapter 3. Criteria for Judgment. and in other chapters, especially Chapter Z. Mortality. and Chapter 9. Cancer. During the decade 1950-1960. at various dates. statements based upon the accumulated evidence were issued by a number of organizations. These included the Rritish I\ledical Research Council: the cancer societies of Den- mark. Norwal. Sweden. Finland. and the Netherlands: the American Cancer Society: the .4merican Heart Association: the Joint Tuberculosis Council of Great Rritain : and the Canadian Yational Department of Health and Welfare. Th e consensus. publici!- declared. \$-a< that smoking is an important health hazard. particularlv I\ ith respect to lunc cancer and cardiovascular disease. Early in 195-l. the Tnl)acco lndustrv Research Committee rT.1.R.C.i was established br representatives of tobacco manufacturers. growers. and srare- housemen to sponsor a program of research into questions of tobacco use and health. Since then. under a Scientific Director and a Scientific .4d\-isory Board composed of nine scientists \vho maintain their respective institutional affiliations. the Tobacco Industry Research Committee has conducted a grants-in-aid program. collected information. and issued reports. The I!.S. Public Health Service first became officially engaged in an appraisal of the available data on smoking and health in June. 19.36. when. under the instigation of the Surgeon General. a scientific Study Group on 6 the subject was established joint]\- hv the Sational Cancer Institute. the National Heart Institute. the American Cancer Societ!-. and the American Heart Association. .4fter appraising 16 independent itudies carried on in five countries over a period of 18 l-ears. this group concluded that there is a causal relationship between excessive smokin, CT of cirrarettrs and lung cancer. I Impressed b!- the report of the Study Committee and h\- other new evi- dence. Surgeon General Leroy E. Rurnev issued a statement on Jul\ 12. 1937. reviewing the matter and declaring that: "The Public Health service feels the weight of the e\-idenw is incwasin=l!- pointing in one dirrction: that excessive smoking is one of the ,rausative factors in lung cancer." `AFain. in a special article entitled "Smoking and I,ung Cancer--\ Statement of the Public Health Service." publi~hrd in the Jourrlal of the dnwrican Medical Association on IVovemher 2:;. 19.50. Surgeon General Rurne\- referred to his statement issued in 19.7; and reitrrated the brlief of the Public Health Service that: "The weight of e\-idence at l)resrtlt iml)lic,ates smoking as the principal factor in the increased incidence of lung ranwr." and that: "Ciga- rette smoking particular]\ is associated w-ith an irlcreasrd chance of de- veloping lung cancer." These quotations state the position of the Public Health Service taken in 19.57 and 19.59 on the qur>tion of fmokinp and health. That position has not chanFed in the succeeding years. during which several units of thr Serlire conducted rstensiw investigations on smoking and air pollution. and the Sewice maintairlrd a constant scrutinv of reports and ljuhlications in this field. ESTABLISHMENT OF THE CO~IMITTEE The immediate antecedents of the establichmrnt of the Surgeon Gen- eral's Advisory Committee on Smoking and Health began in mid-1901. On June 1 of that year. a letter was sent to the President of the I'nited States, signed by the presidents of the American Cancer Societv. the American public Health Association. the American Heart Association. and the Na- tional Tuberculosis Association. It urged the formation of a Presidential commission to study the "widespread implications of the tobacco problem." On January 4. 1962. representatives of the various organizations met with Surgeon. General Luther L. Terra-. \+ho short]\ thereafter proposed to the Secretary of Health. Education. and Welfare the formation of an advi- sory committee composed of "outstanding experts who would assess avail- able knowledge in this area [smokin g 1s. health] and make al)propriate rec- ommendations . . ." On April 16. the Surgeon General sent a more detailed proposal to the Secretary for the formation of the ad{-isor\- _ group. calling for re-evaluation of the Public Health Service position taken I~\- Dr. Rurnr! in the Journal of the American Medical Association. IId at the Se Dr. Tkrry felt the nerd for a new r\ice's position in the light of a number of si=nifirant dr\-elol)- `nents since 1939 which emphasized the need for further actiorl. He listed he as: 1. New studies indicating that smoking has maior adverse health effects. 2. Representations from national voluntary health agencies for action on the part of the Service. 3. The recent study and report of the Royal College of Physicians of London. 4. Action of the Italian Government to forbid cigarette and tobacco ad- vertising: curtailed advertising of cigarettes by Britain's major tobacco companies on TV; and a similar decision on the part of the Danish tobacco industry. 5. A proposal by Senator Maurine Neuberger that Congress create a com- mission to investigate the health effects of smoking. 6. A request for technical guidance by the Service from the Federal Trade Commission on labeling and advertising of tobacco products. 7. Evidence that medical opinion has shifted significantly against smoking. The recent study and report cited by Surgeon General Terry was the highly important volume: "Smoking and Health-Summary and Report of the Royal College of Physicians of London on Smoking in Relation to Cancer of the Lung and Other Diseases." The Committee of the Royal College of Physicians dealing with these matters had been at its work of appraisal of data since April 1959. Its main conclusions, issued early in 1962, were: "Cigarette smoking is a cause of lung cancer and bronchitis, and probably contributes to the development of coronary heart disease and various other less common diseases. It delays healing of gastric and duodenal ulcers." On June 7, 1962, the Surgeon General announced that he was establishing an expert committee to undertake a comprehensive review of all data on smok- ing and health. The President later in the same day at his press conference acknowledged the Surgeon General's action and approved it. On July 24. 1962. the Surgeon General met with representatives of the American Cancer Society. the American College of Chest Physicians, the .imerican Heart Association, the American Medical Association, the Tobacco Institute. Inc.. the Food and Drug Administration. the National Tuberculosis Association. the Federal Trade Commission, and the President's Office of Science and Technology. At this meeting, it was agreed that the proposed work should be undertaken in two consecutive phases, as follows: Phase I-An objective assessment of the nature and magnitude of the health hazard. to be made by an expert scientific advisory committee which would review critically all available data but would not conduct new research. This committee would produce and submit to the Surgeon General a technical report containing evaluations and conclusions. Phase II-Recommendations for actions were not to be a part of the Phase I committee's responsibility. No decisions on how Phase II would be conducted were to be made until the Phase I report was available. It was recognized that different competencies would be needed in the second phase and that many possible recommendations for action would extend beyond the health field and into the purview and competence of other Federal agencies. The participants in the meeting of July 27 compiled a list of more than 150 scientists and physicians workin, 0 in the fields of biology and medicine. 8 rvith interests and competence in the broad range of medical sciences and with capacity to evaluate the element. = and factors in the complex relation- ship between tobacco smoking and health. During the next month. these lists were screened by the representatil-es of organizations present at the July 27 meetin?. Any organization could \-et0 any of the names on the list. no reasons being required. Particular care was taken to eliminate the names of any persons \vho had taken a public position on the questions at issue. From the final list of names the Surgeon General selected ten men who agreed to serve on the Phase I committee. which was named Tlrc Surgeon General's Advisory Committee on Smoking and Health. The com- mittee members. their positions. and their fields of competence are: Stanhope Bayne-Jones. M.D.. LL.d.. I Retired 1. Former Dean. Yale School of Medicine i 193.5-40 I _ former President. Joint Administrative Board. Cor- rlell University. New York Hospital Medical Center (1947-52 I : former president. Socjetv of Ameriran Bacteriologi$ts I 1929 \. and American Societ! of Pathologv and Bacteriolog! I 19401. Field: Nature and Causation of N-ease in Human Populations. Dr. Bayne-Jones served also as a special consultant to the Committee staff. Walter J. Burdette. M.D.. Ph. D.. Head of Deljartment of Surgery. Uni- \rrsitv of Itah School of Medicine. Salt Lake Cit\-. Fields: Clinical 8 f:uperimental Surgery; Genetics. William G. Cochran. M.A.. Professor of Statistics. Harvard University. Field: Mathematical Statistics. lcith Special .4pplication to Biological I'rohlems. Emmanuel Farber. M.D.. Ph. D.. Chairman. Department of Pathology. t-rliversity of Pittsburgh. Field: E. p . Y el imental and Clinical Pathology. Louis F. Fieser. Ph. D.. Sheldon Emory. Professor of Organic Chemistry. II arvard University. Field: Ch emistry of Carcinogenic Hydrocarbons. Jacob Furth, M.D.. Professor of Pathology. Columbia University. and ljirector of Pathology Laboratories, Francis Delafield Hospital, skew York. u.Y. Field: Cancer Biology. John B. Hickam, M.D.. Chairman, Deljartment of Internal Medicine. Uni- `c'rsity of Indiana, Indianapolis. Fields: Internal Medicine. Physiology of "ardiopulmonary Disease. Charles LeMaistre. M.D.. Professor of Internal Medicine, The IIniversit) "I Texas Southwestern Medical School. and Medical Director. Woodla\l n Hos- Vital. Dallas, Texas. Fields: Internal Medicine. Pulmonary Diseases, I'rt.\.entive Medicine. Leonard M. Schuman, M.D.. Professor of Epidemiology. I-niversity of "ilsnesota School of Public Health. Minneapolis. Field: Health and its ti ' d Ionship to the Total Environment. 1. t' \hrice H. Seevers. M.D., Ph. D.. Ch `.lliversity of Michigan, Ann Arbor. airman. Department of Pharmacology. Field: PharmacoloFy of Anesthesia "11(1 Habit-Forming Drugs. (`hairman: Luther L. Terry, 1,f.D.. Surgeon General of the United States Public Health Service. 9 Vice-Chairman : James M. Hundley. X'I.D.. Assistant Surgeon General for Operations, United States Public Health Service. Staff Director Medical Coordinator Eugene H. Guthrie. M.D., M.P.H. Peter V. V. Hamill, M.D., M.P.H. Public Health Service Public Health Service 10 Chapter 2 Conduct of the Study Chapter 2 CONDUCT OF THE STUDY The work of the Surgeon General's Advisory Committee on Smoking and Health was undertaken. organized. and pursued with independence. a deep sense of responsibilitv. and with full appreciation of the national importance of the task. The Committee's constant desire was to carrl. out in its own way. with the best obtainable advice and cooperation from experts outside its membership. a thorough and objectit-e review and evaluation of available information about the effects of the use of various forms of tobacco upon the health of human beings. It d esired that the Report of its studies and judp- ments should be unquestionably the product of its labors and its authorship. With an enormous amount of assistance from 155 consultants. from members and associates of the supportin, c staff. and from several organizations and institutions. the Committee feels that a document of adequate scope. integrity. and individuality has been produced. It is emphasized. however. that the content and judgments of the Report are the sole responsibility of the Committee. At the outset, the Surgeon General emphasized his respect for the freedom of the Committee to proceed with the study and to report as it saw fit, and he pledged all support possible from the United States Public Health Service. The Service, represented chiefly by his office. the National Institutes of Health, the National Library of Medicine. the Bureau of State Services, and the Na- tional Center for Health Statistics, furnished the able and devoted personnel that constituted the staff at the Committee's headquarters in Washington, and provided an extraordinary variety and volume of supplies, facilities and re- sources. In addition, the necessary financial support was made available by the Service. It is the purpose of this section to present an outline of the important features of the manner in which the Committee conducted its study and com- posed this Report. A retrospective outline of procedures and events tends to convey an appearance of orderliness that did not pertain at all times. A plan was adopted at the first meeting of the Committee on November g-10, 1962, but this had to b e modified from time to time as new lines of inquiry led into unanticipated explorations. At first an encyclopedic approach was con- sidered to deal with all aspects of the use of tobacco and the resulting effects, with all relevant aspects of air pollution, and all pertinent characteristics of the external and internal environments and make-up of human beings. It was soon found to be impracticable to attempt to do all of this in any reason- able length of time, and certainly not under the urgencies of the existing situation. The final plan was to give particular attention to the cores of prob- lems of the relationship of uses of tobacco, especially the smoking of ciga- rettes, to the health of men and women, primarily in the United States, and 13 to deal with the material from both a general viewpoint and on the basis of d' isease categories. As may be seen in a glance at the Table of Contents of this Report, the main topical divisions of the study were: o Tobacco and tobacco smoke, chemical and physical characteristics (Chapter 6 ) . o Nicotine: pharmacology and toxicology (.Chapter 7). o Mortality, general and specific, according to age, sex, disease, and smok. ing habits. and other factors (Chapter 8). o Cancer of the lungs and other organs; carcinogenesis; pathology, aud epidemiology (Chapter 9). o Non-neoplastic diseases of the respiratory tract, particularly chronic bronchitis and emphysema. with some consideration of the effects of air pollution (Chapter 10). o Cardiovascular diseases. particularlv coronary artery diseases iChapter 11 I. o Other conditions. a miscellany including gastric and duodenal ulcer, perinatal disorders. tobacco amblyopia, accidents (Chapter 12). o Characterization of the tobacco habit and beneficial effects of tobacco i Chapter 13'1. o Psy-cho-social aspects of smoking i Chapter 14`). o Morphological constitution of smokers (Chapter 15). As the primary duty of the Committee was to assess information about smoking and health. a major general requirement was that of making the information available. That requirement was met in three ways. The first and most important was the bibliographic service provided by the National Library- of Medicine. .\s th e annotated monograph by Larson, Haag, and Silvette-compiled from more than 6.000 articles published in some 1,200 journals up to and largely into 1959-was available as a basic reference source. the National Library of Medicine was requested to compile a bibliog raphy thy author and by subject) covering the world literature from 1958 to the present. In compliance with this request, the National Library of Medicine furnished the Committee bibliographies containing approximately 1100 titles. Fortunately. the Committee staff was housed in the National Library of Medicine on the grounds of the National Institutes of Health, and through this location had ready access to books and periodicals, as well as to scientists working in its field of interests. Modern apparatus for photo-reproduction of articles was used constantly to provide copies needed for studv by members of the Committee. In addition, the members drew upon the libraries and bibliographic services of those institutions in which thev held academir positions. A considerable volume of copies of reports and a number of special articles were received from a variety of additional sources. All of the major companies manufacturin, u cigarettes and other tobacco products were invited to submit statements and any- information pertinent to the inquiry. The replies vvhich were received were taken into consideration by the Committee. Through a system of contracts with individuals competent in certain fields, special reports were prepared for the use of the Committee. Through these 14 sources much valuable information was obtained: some of it new and hitherto unpublished. In addition to the special reports prepared under rontracts. many con- ferences, seminar-like meetings. consultations, visits and correst,ondence made available to the Committee a large amount of material and a consider- able amount of well-informed and well-reasoned opinion and advice. To deal in depth and discrimination with the topics listed aho\-e. the Com- mittee at its first meeting formed subcommittees with much overlapping in membership. These subcommittees were the main forces engaged in collec- tion. analysis. and evaluation of data from published reports. contractual reports. discussions at conferences. and from some new prospective studies reprogrammed and carried out generousll- at the request of the Committee. These will be acknowledged more fullv elsewhere in this Report. The first formulations of conclusions \qere made by these subcommittees. and these were submitted to the full Committee for revision and adoption after debate. At the beginning. and until the Committee began to meet routinely- in Pxesutive session, it had the advantage of attendance at its meetings of ob- servers from other Federal agencies. There were representatives from the following agencies: Executive Office of the President of the United States. Federal Trade Commission, Department of Commerce. Department of Agri- culture. and the Food and Drug Administration. Ser\-ing as more than ob- servers and reporters to their agencies. \$hen they were present or by written communication, the)- supplied the Committee with much useful information. There were an uncounted number of meetings of subcommittees and other lesser gatherings. Between November 1962 and December 1063. the full Committee held nine sessions each lasting from two to four days in Washing- ton or Bethesda. The main matters considered at the meetings in October, November, and December 1963 were the review and revision of chapters. critical scrutiny of conclusions, and the innumerable details of the composi- tion and editing of this comprehensive Report. 714-422 O-64-3 15 Chapter 3 Criteria for Judgment Chapter 3 CRITERIA FOR JUDGMENT In making critical appraisals of data and interpretations and in formulat- ing its own conclusions, the Surgeon General's Advisory Committee on Smoking and Health-its individual members and its subcommittees and the Committee as a whole-made decisions or judgments at three levels. These levels were: I. Judgment as to the validity of a publication or report. Entering into the making of this judgment were such elements as estimates of the com- petence and training of the investigator, the degree of freedom from bias, design and scope of the investigation, adequacy of facilities and resources, adequacy of controls. II. Judgment as to the validity of the interpretations placed by investigators upon their observations and data, and as to the logic and justification of their conclusions. III. Judgments necessary for the formulation of conclusions within the Committee. The primary reviews, analyses and evaluations Of publications and unpub- lished reports containing data, interpretations and conclusions of authors were made by individual members of the Committee and, in some instances, by consultants. Their statements were next reviewed and evaluated by a subcommittee. This was followed at an appropriate time by the Committee's critical consideration of a subcommittee's report, and by decisions as to the selection of material for inclusion in the drafts of the Report, together with drafts of the conclusions submitted by subcommittees. Finally, after re- peated critical reviews of drafts of chapters, conclusions were formulated and adopted by the whole Committee, settin g forth the considered judgment of the Committee. It is not the intention of this section to present an essay on decision-making. Nor does it seem necessary to describe in detail the criteria used for making scientific judgments at each of the three levels mentioned above. All mem- bers Of the Committee were schooled in the high standards and criteria im- Illicit in making scientific assessments; if any member lacked even a small Part of such schooling he received it in good measure from the strenuous debates that took place at consultations and at meetings of the subcommittees and the whole Committee. CRITERIA OF THE EPIDEMIOLOGIC METHOD It is advisable, however, to discuss briefly certain criteria which. although applicable to all judgments involved in this Report. were especially significant for judgments based upon the epidemiologic method. In this inquiry the 19 epidemiologic method was used extensively in the assessment of causal fac- tors in the relationship of smoking to health among human beings upon whom direct experimentation could not be imposed. Clinical, pathological and ex- perimental evidence was thoroughly considered and often served to suggest an hypothesis or confirm or contradict other findings. When coupled with the other data. results from the epidemiologic studies can provide the basis upon which judgments of causality may be made. In carrying out studies through the use of this epidemiologic method, many factors, variables, and results of investigations must be considered to deter- mine first whether an association actually exists between an attribute or agent and a disease. Judgment on this point is based upon indirect and direct measures of the suggested association. If it be shown that an asso- ciation exists, then the question is asked: "Does the association have a causal significance?" Statistical methods cannot establish proof of a causal relationship in an association. The causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. To judge or evaluate the causal significance of the association between the attribute or agent and the disease, or effect upon health, a number of criteria must be utilized. no one of which is an all-sufficient basis for judgment. These criteria include : a) The consistency of the association b) The strength of the association c) The specificity of the association d) The temporal relationship of the association e) The coherence of the association These criteria were utilized in various sections of this Report. The most extensive and illuminating account of their utilization is to be found in Chapter 9 in the section entitled "Evaluation of the Association Between Smoking and Lung Cancer". CAUSALITY Various meanings and conceptions of the term cause were discussed vigorously at a number of meetings of the Committee and its subcommit- tees. These debates took place usually after data and reports had been studied and evaluated, and at the times when critical scrutiny was being given to conclusions and to the wording of conclusive statements. In addi- tion, thoughts about causality in the realm of this inquiry were constantly and inevitably aroused in the minds of the members because they were preoccupied with the subject of their investigation-"Smoking and Health." Without summarizing the more important concepts of causality that have determined human attitudes and actions from the days even before t2ristotle, through the continuing era of observation and experiment. to the statistical certainties of the present atomic age. the point of view of the Committee with regard to causality and to the language used in this respect in this report may be stated briefly as follows: 1. The situation of smoking in relation to the health of mankind includes a host ( v-ariable man) and a complex agent (tobacco and its products, partic- 20 ularly those formed by combustion in smoking). The prohe of this inquirv is into the effect. or non-effect. of components of the agent upon the tissues. organs. and various qualities of the host which might: a\ improve his well- being. b I let him proceed normally. or c I injure his health in one way or another. To obtain information on these points the Committee did its best. with extensive aid. to examine all available sources of information in puhli- cations and reports and through consultation w-ith well informed persons. 2. When a relationship or an association between smoking. or other uses of tobacco, and some condition in the host was noted. the significance of the association was assessed. 3. The characterization of the assessment called for a specific term. The chief terms considered were "factor." "determinant." and "cause." The Committee agreed that Mhile a factor could he a source of variation. not all sources of variation are causes. It is recognized that often the coexistence of several factors is required for the occurrence of a disease. and that one of the factors may plav a determinant role. i.e.. without it the other factors I as genetic susceptibility 1 are impotent. Hormones in breast cancer can play such a determinant role. The word cause is the one in general usage in connection with matters considered in this study. and it is capable of convey- ing the notion of a significant, effectual. relationship between an agent and an associated disorder or disease in the host. 4. It should be said at once, however, that no member of this Committee used the word "cause" in an absolute sense in the area of this study. Although various disciplines and fields of scientific knowledge were repre- sented among the membership, all members shared a common conception of the multiple etiology of biological processes. No member was so naive as to insist upon mono-etiology in pathological processes or in vital phenom- ena. All were thoroughly aware of the fact that there are series of events in occurrences and developments in these fields. and that the end results are the net effect of many actions and counteractions. 5. Granted that these complexities were recognized, it is to he noted clearly that the Committee's considered decision to use the words "a cause," or "a major cause," or "a significant cause," or "a causal association" in certain conclusions about smoking and health affirms their conviction. 21 Chapter 4 Summaries and Conclusions Contents A. BACKGROUND _4ND HIGHLIGHTS .......... Kinds of Evidence .................. Evidence From the Combined Results of Prospective Studies . Other Findings of the Prospective Studies ...... Excess Mortality ................. Associations and Causality ............... The Effects of Smoking: Principal Findings Lung Cancer ... .... ..... : : : : : . . Chronic Bronchitis and Emphysema ......... Cardiovascular Diseases .............. Other Cancer Sites ................ The Tobacco Habit and Nicotine ........... The Committee's Judgment in Brief .......... B. COMMENTS AND DETAILED CONCLUSIONS .... (A Guide to Part II of the Report) Chemistry and Carcinogenicity of Tobacco and Tobacco Smoke . Characteriza&t bf.th.e ,Tdbacco Habit : : : : : : : : : : Pathology and Morphology ............... Mortality. ...................... Cancer by Site .................... Lung Cancer ................... Oral Cancer. ................... Cancer of the Larynx ............... Cancer of the Esophagus .............. Cancer of the Urinary Bladder ........... Stomach Cancer .................. Non-Neoplastic Res iratory Diseases, Particularly Chronic Bronchitis and Pu monary Emphysema P ........ Cardiovascular Disease ................. Other Conditions ................... Peptic Ulcer ................... Tobacco Amblyopia ................ Cirrhosis of the Liver ........... Maternal Smoking and infant Birth Weight ..... Smoking and Accidents .............. Morphological Constitution of Smokers ......... Psycho-Social Aspects of Smoking ............ List of Tables 1. Deaths from selected disease categories, United States, 1962 . 2. Expected and observed deaths for smokers of cigarettes only and mortality ratios in seven prospective studies . . . . . 24 Page 25 26 28 2 30 33: 31 E ;"3 33 33 34 34 ;; 37 37 37 i; 38 26 29 Chapter 4 This chapter is presented in two sections. Section A contains background information, the gist of the Committee's findings and conclusions on tobacco and health, and an assessment of the nature and magnitude of the health hazard. Section B presents all formal conclusions adopted by the Committee and selected comments abridged from the detailed Summaries that appear in each chapter of Part II of the Report. The full scope and depth of the Committee's inquiry may be comprehended only by study of the complete Report. A. BACKGROUND AND HIGHLIGHTS In previous studies, the use of tobacco. especially cigarette smoking, has been causally linked to several diseases. Such use has been associated with increased deaths from lung cancer and other diseases, notably coronary artery disease, chronic bronchitis, and emphysema. These widely reported findings, which have been the cause of much public concern over the past decade, have been accepted in many countries by official health agencies, medical associations, and voluntary health organizations. The potential hazard is great because these diseases are major causes of death and disability. In 1962, over 500,000 people in the United States died of arteriosclerotic heart disease (principally coronary artery disease), 41,000 died of lung cancer, and 15,000 died of bronchitis and emphysema. The numbers of deaths in some important disease categories that have been reported to have a relationship with tobacco use are shown in Table 1. This table presents one aspect of the size of the potential hazard; the degree of association with the use of tobacco will be discussed later. Another cause for concern is that deaths from some of these diseases have been increasing with great rapidity over the past few decades. Lung cancer deaths, less than 3,000 in 1930, increased to 18,000 in 1950. In the short period since 1955, deaths from lung cancer rose from less than 27,OOO to the 1962 total of 41,000. This extraordinary rise has not been recorded for cancer of any other site. While part of the rising trend for lung cancer is attributable to improvements in diagnosis and the changing age-composition and size of the population, the evidence leaves little doubt that a true increase in lung cancer has taken place. Deaths from arteriosclerotic, coronary, and degenerative heart disease rose from 273,000 in 194.0, to 3%,000 in 1950, and to 578,000 in 1962. Reported deaths from chronic bronchitis and emphysema rose from 2,300 in 1945 to 15,000 in 1962. The changing patterns and extent of tobacco use are a pertinent aspect of the tobacco-health problem. 25 TABLE l.-Deaths from selected disease cattgories, United States, 1962 Cause of death* ( Total ( Males ( Fcmales Depcnerative nnd arteriosclerotir heart disease, including cwona~y dkease (420, 422)~~..~.....~........~.~~~.....~~~~..~.~~-~~~~~- . ..- Hypertensive heart disuse (44~33) ..... .._ .... ..__.__..._____ .. ..__. cnnccr ofllmn (163.3)~ .......... _. ... .._ ..... ..__. ...... . ... .._ .... rirrIwis of liver (581) ......... .._ ... _....._ ..... .._ .. .._.__ ....... . Qronchitis andcmphysrma (502, 527.1). .._ .... _......._._. .......... Stomach and duoilcnal nlcrrs (510-1)~~- .__ .._ .._ ............. .._ ... Csnrrr ofhladdrr (lS1)..~..............................~ ........... CancProforal carity (140-8). .. .._. _...._ .......................... Canrerofrso~ham (150) ..... .._ ......... ................ .._ ..... CanrPr or IarynY (161) ........ _......._ .._ ............. .._ ....... 5i7 9tR 62: 176 41.376 21.824 15. 104 12.278 R. OR1 Ii, 481 5. OPR 34R, Ml4 22% 314 26.6,54 35, R22 35,312 fi. nr4 14.323 7. 495 12.93i 2.167 8, RX 3.332 5. 575 2. Yh? 4.920 1. 561 3.973 1,115 2, Ii? 245 All Pause.5 . . . . . ..-..... ~~ _......._.. -.- . . . . . . . . . . . . . . . . .._.. /1,p3i+Gq- `International Statistical Classifkation numbers in parentheses. 761. !Til Nearly 70 million people in the United States consume tobacco regularly. Cigarette consumption in the United States has increased markedly since the turn of the Century, when per capita consumption was less than 50 cigarettes a year. Since 1910, when cigarette consumption per person (15 years and older) was 138, it rose to 1,365 in 1930, to 1,828 in 1940, to 3,322 in 1950, and to a peak of 3,986 in l%l. The 1955 Current Population Survey showed that 68 percent of the male population and 32.4 percent of the female population 18 years of age and over were regular smokers of cigarettes. In contrast with this sharp increase in cigarette smoking, per capita use of tobacco in other forms has gone down. Per capita consumption of cigars declined from 117 in 1920 to 55 in 1962. Consumption of pipe tobacco, which reached a peak of 2\/, lbs. per person in 1910, fell to a little more than half a pound per person in 1962. Use of chewing tobacco has declined from about four pounds per person in 1900 to half a pound in 1962. The background for the Committee's study thus included much general information and findings from previous investigations which associated the increase in cigarette smoking with increased deaths in a number of major disease categories. It was in this setting that the Committee began its work to assess the nature and magnitude of the health hazard attributable to smoking. KINDS OF EVIDENCE In order to judge whether smoking and other tobacco uses are injurious to health or related to specific diseases. the Committee evaluated three main kinds of scientific evidence: 1. Animal experiments.-In numerous studies, animals have been exposed to tobacco smoke and tars, and to the various chemical compounds they con- tain. Seven of these compounds (polycyclic aromatic compounds) have been established as cancer-producing (carginogenic), Other substances in tobacco and smoke, though not carcinogenic themselves, promote cancer production or lower the threshold to a known carcinogen. Several toxic or irritant gases contained in tobacco smoke produce experimentally the kinds of non-can- cerous damage seen in the tissues and cells of heavy smokers. This includes 26 suppression of ciliary action that normally cleanses the trachea and bronchi, damage to the lung air sacs, and to mucous glands and goblet cells which produce mucus. 2. Clinical and autopsy studies.-Observations of thousands of patients and autopsy studies of smokers and non-smokers show that many kinds of damage to body functions and to organs, cells, and tissues occur more fre- quently and severely in smokers. Three kinds of cellular changes-loss of ciliated cells, thickening (more than two layers of basal cells), and presence of atypical cells--are much more common in the lining layer (epithelium) of the trachea and bronchi of cigarette smokers than of non-smokers. Some of the advanced lesions seen in the bronchi of cigarette smokers are probably premalignant. Cellular changes regularly found at autopsy in patients with chronic bronchitis are more often present in the bronchi of smokers than non-smokers. Pathological changes in the air sacs and other functional tissue of the lung (parenchyma) have a remarkably close association with past history of cigarette smoking. 3. Population studies.-Another kind of evidence regarding an association between smoking and disease comes from epidemiological studies. In retrospective studies, the smoking histories of persons with a specified disease (for example, lung cancer) are compared with those of appropriate control groups without the disease. For lung cancer alone, 29 such retrospec tive studies have been made in recent years. Despite many variations in de- sign and method, all but one (which dealt with females) showed that pro- portionately more cigarette smokers are found among the lung cancer patients than in the control populations without lung cancer. Extensive retrospective studies of the prevalence of specific symptoms and signs--chronic cough, sputum production, breathlessness, chest illness, and decreased lung function-consistently show that these occur more often in cigarette smokers than in non-smokers. Some of these signs and symptoms are the clinical expressions of chronic bronchitis, and some are associated more with emphysema; in general, they increase with amount of smoking and decrease after cessation of smoking. Another type of epidemiological evidence on the relation of smoking and mortality comes from seven prospective studies which have been conducted since 1951. In these studies, large numbers of men answered questions about their smoking or non-smoking habits. Death certificates have been obtained for those who died since entering the studies, permitting total death rates and death rates by cause to be computed for smokers of various types as well as for non-smokers. The prospective studies thus add several im- portant dimensions to information on the smoking-health problem. Their data permit direct comparisons of the death rates of smokers and non- smokers, both overall and for individual causes of death, and indicate the strength of the association between smoking and specific diseases. Each of these three lines of evidence was evaluated and then con- sidered together in drawing conclusions. The Committee was aware that the mere establishment of a statistical association between the use of tobacco and a disease is not enough. The causal significance of the use of tobacco in relation to the disease is the crucial question. For such judgments all three 27 lines of evidence are essential, as discussed in more detail on pages 26-27 of this Chapter, and in Chapter 3. The experimental, clinical, and pathological evidence, as well as data from population studies, is highlighted in Section I3 of this Chapter, which in turn refers the reader to specific places in Part II of the Report where this evidence is presented in detail. In the paragraphs which follow, the Committee has chosen to summarize the results of the seven prospective population studies which, as noted above, constitute only one type of evidence. They illustrate the nature and potential magnitude of the smoking-health problem, and bring out a number of factors which are involved. EVIDENCE FROM THE COMBINED RESIJLTS OF PROSPECTIVE STUDIES The Committee examined the seven prospective studies separately as well as their combined results. Considerable weight was attached to the con- sistency of findings among the several studies. However, to simplify presen- tation, only the combined results are highlighted here. Of the 1,123,OOO men who entered the seven prospective studies and who provided usable histories of smoking habits (and other characteristics such as age), 37,391 men died during the s&sequent months or years of the studies. No analyses of data for females from prospective studies are presently available. To permit ready comparison of the mortality experience of smokers and non-smokers, two concepts are widely used in the studies-excess deaths of smokers compared with non-smokers, and mortality ratio. After adjustments for differences in age and the number of cigarette smokers and non-smokers, an expected number of deaths of smokers is derived on the basis of deaths among non-smokers. Excess deaths are thus the number of actual (observed) deaths among smokers in excess of the number expected. The mortality ratio, for which the method of computation is described in Chapter 8, measures the relative death rates of smokers and non-smokers. If the age- adjusted death rates are the same, the mortality ratio will be 1.0; if the death rates of smokers are double those of non-smokers, the mortality ratio will be 2.0. (Expressed as a percentage, this example would be equivalent to a 100 percent increase.). Table 2 presents the accumulated and combined data on 14 disease cate- gories for which the mortality ratio of cigarette smokers to non-smokers was 1.5 or greater. The mortality ratio for male cigarette smokers compared with non-smokers, for all causes of death taken together, is 1.68, representing a total death rate nearly 70 percent higher than for non-smokers. (This ratio includes death rates for diseases not listed in the table as well as for the 14 disease categories shown.) In the combined results from the seven studies, the mortality ratio of cig arette smokers over non-smokers was particularly high for a number of diseases: cancer of the lung (10.8), b ronchitis and emphysema (6.1), can- 28 T.~BLE 2.l-Expected and observed deaths for smokers of cigarettes onty and mortality ra.tios in seven prospective studies Underlying cause of death rsnwr of 1~ (162-3) I._._.______________.------...-.---.---.... .=.- 170.3 Icronchitis and emphysema (502, 521.1). __..._._.____.....__--...... 89. 5 c'anr~roflarynx (161) . . ..____ -.-- __.. __-- _.__________ _.- ._______.... 14.0 0181cRncw (140-8).~.....~~~....-~-..~----.~~~~~~~.~..-~-~.~~~-~.... 37.0 rnncer or Psophaglls (Irn)~ __---.---.._......._.-.-.---..-....-.--... 33.7 Plomnch and duodenal ulcers (540, 541) _ _ _ __ .._... _____ -. . . ..___ _ _ 105.1 IQhu circulatory diseases (451~661._____ __...._._____.___...-----.- 254.0 rwrhosis of liver (al) __-- _....._ ..____ _..._.......___._......-- 169.2 (`Rnw of bladder (181). __..__.._.__ .._.______ _ . . . .._____._......._ 111.6 r`oronary artery discaw (420). _ _________. __._______.. -.- ______ _.... 6,430. 7 Whrr heartdiseasPs (421-2.43~)......-.---.-..--....--.-.-------.. 526.0 llrrwtwsise heart (440-3) . .._____________ -- __._______._._._________ 4(ro. 2 (it nrrsl arteriosclerosk (GO) ______.___________._.-....----.......... 210. 7 ~nnwrofkidmy (lIM)-------......-------.-...-...-.-~---.........- 79.0 AIIrause8~~.~ ____ ---- _______. -- . . . . ..____...._.. . .._~ _._. __... -.. 15,653 0 Obwrved Mortality deaths ratio 1,833 546 1:: 113 294 E 216 Il. li7 E 310 23,E 10.8 6.1 5.4 4.1 3.4 2.8 2.6 2. 2 1.9 1.7 l.i 1.5 1. 5 1.5 1.68 I .AbridePd Irom Tablp 26, Chapter 8: Mortality. ' lntwnational Statistical Classiflcatlon numkrs in parentheses 1 Includes all other causes of death as well as those hstcd above. cer of the larynx (5.4), oral cancer (4.1), cancer of the esophagus (3.4), peptic ulcer (2.8), and the group of other circulatory diseases (2.6). For coronary artery disease the mortality ratio was 1.7. Expressed in percentage-form, this is equivalent to a statement that for coronary artery disease, the leading cause of death in this country, the death rate is 70 percent higher for cigarette smokers. For chronic bronchitis and rmphysema, which are among the leading causes of severe disability, the death rate for cigarette smokers is 500 percent higher than for non-smokers. For lung cancer, the most frequent site of cancer in men, the death rate is nearly 1,000 percent higher. Other Findings of the Prospective Studies In general, the greater the number of cigarettes smoked daily, the higher the death rate. For men who smoke fewer than 10 cigarettes a day, accord- ing to the seven prospective studies, the death rate from all causes is about 40 percent higher than for non-smokers. For those who smoke from IO to 19 cigarettes a day, it is about 70 percent higher than for non-smokers; for these who smoke 20 to 39 a day, 90 percent higher; and for those who smoke 40 or more, it is 120 percent higher. Cigarette smokers who stopped smoking before enrolling in the seven stud- ie.3 have a death rate about 40 percent higher than non-smokers, as against 70 Percent higher for current cigarette smokers. bef Men who began smoking ore age 20 have a substantially higher death rate than those who began arter age 25. Compared with non-smokers, the mortality risk of cigarette Jmokers, after adjustments for differences in age, increases with duration of smoking (number of years), and is higher in those who stopped after age 55 than for those who stopped at an earlier age. In ho studies which recorded the degree of inhalation. the mortality ratio for a given amount of smoking was greater for inhalers than for non-inhalers. fie ratio of the death rates of smokers to that of non-smokers is highest 29 at the earlier ages (40-50) re p resented in these studies, and declines with increasing age. Possible relationships of death rates and other forms of tobacco use were also investigated in the seven studies. The death rates for men smoking less than 5 cigars a day are about the same as for non-smokers. For men smoking more than 5 cigars daily, death rates are slightly higher. There is some indication that these higher death rates occur primarily in men who have been smoking more than 30 years and who inhale the smoke to some degree. The death rates for pipe smokers are little if at all higher than for non-smokers, even for men who smoke 10 or more pipefuls a day and for men who have smoked pipes more than 30 years. Excess Mortality Several of the reports previously published on the prospective studies included a table showing the distribution of the excess number of deaths of cigarette smokers among the principal causes of death. The hazard must be measured not only by the mortality ratio of deaths in smokers and non- smokers, but also by the importance of a particular disease as a cause of death. In all seven studies, coronary artery disease is the chief contributor to the excess number of deaths of cigarette smokers over non-smokers, with lung cancer uniformly in second place. For all seven studies combined, coronary artery disease (with a mortality ratio of 1.7) accounts for 45 per- cent of the excess deaths among cigarette smokers, whereas lung cancer (with a ratio of 10.8') accounts for 16 percent. Some of the other categories of diseases that contribute to the higher death rates for cigarette smokers over non-smokers are diseases of the heart and blood vessels, other than coronary artery disease, 14 percent; cancer sites other than lung, 8 percent; and chronic bronchitis and emphysema, 4 percent. Since these diseases as a group are responsible for more than 85 percent of the higher death rate among cigarette smokers, they are of particular interest to public health authorities and the medical profession. ASSOCIATIOM AND CAUSALITY The array of information from the prospective and retrospective studies of smokers and nonsmokers clearly establishes an association between cigarette smoking and substantially higher death rates. The mortality ratios in Table 2 provide an approximate index of the relative strength of this association, for all causes of death and for 14 disease categories. In this inquiry the epidemiologic method was used extensively in the assessment of causal factors in the relationship of smoking to health among human beings upon whom direct experimentation could not be imposed. Clinical, pathological, and experimental evidence was thoroughly considered and often served to suggest an hypothesis or confirm or contradict other findings. When coupled with the other data, results from the epidemiologic 30 studies can provide the basis upon which judgments of causality may be made. It is recognized that no simple cause-and-effect relationship is likely to exist between a complex product like tobacco smoke and a specific disease in the variable human organism. It is also recognized that often the coexistence of several factors is required for the occurrence of a disease, and that one of the factors may play a determinant role; that is, without it, the other factors (such as genetic susceptibility) seldom lead to the occurrence of the disease. THE EFFECTS OF SMOKING: PRINCIPAL FINDINGS Cigarette smoking is associated with a 70 percent increase in the age- specific death rates of males, and to a lesser extent with increased death rates of females. The total number of excess deaths causally related to cigarette smoking in the U.S. population cannot be accurately estimated. In view of the continuing and mountinp evidence from many sources, it is the judgment of the Committee that cigarette smoking contributes sub- stantially to mortality from certain specific diseases and to the overall death rate. Lung Cancer Cigarette smoking is causally related to lune cancer in men; the mapni- tude of the effect of cigarette smoking far outweighs all other factors. The data for women. though less extensive, point in the same direction. The risk of developing lung cancer increases with duration of smoking and the number of cigarettes smoked per day, and is diminished by dis- continuing smoking. ' In comparison with non-smokers, average male smokers of cigarettes have approximately a 9- to lo-fold risk of developing hmg cancer and heavy smokers at least a fO-fold risk. The risk of developing cancer of the lung for the combined group of pipe smokers, cigar smokers, and pipe and cigar smokers is greater than for non-smokers, but much less than for cigarette smokers. Cigarette smoking is much more important than occupational exposures in the causation of lung cancer in the general population. Chronic Bronchitis and Emphysema Cigarette smoking is the most important of the causes of chronic bronchi- tis in the United States, and increases the risk of dying from chronic bron- chitis and emphysema. A relationship exists between cigarette smoking and emphysema but it has not been established that the relationship is causal. Studies demonstrate that fatalities from this disease are infrequent among non-smokers. For the bulk of the population of the United States, the relative importance of cigarette smoking as a cause of chronic broncho-pulmonary disease is much greater than atmospheric pollution or occupational exposures. 114-422 O-64-4 31 Cardiovascular Diseases It is established that male cigarette smokers have a higher death rate from coronary artery disease than non-smoking males. Although the causative role of cigarette smoking in deaths from coronary disease is not proven, the Committee considers it more prudent from the public health viewpoint to assume that the established association has causative meaning than to suspend judgment until no uncertainty remains. Although a causal relationship has not been established, higher mortality of cigarette smokers is associated with many other cardiovascular diseases, including miscellaneous circulatory diseases, other heart diseases, hyper- tensive heart disease, and general arteriosclerosis. Other Cancer Sites Pipe smoking appears to be causally related to lip cancer. Cigarette smoking is a significant factor in the causation of cancer of the larynx. The evidence supports the belief that an association exists between tobacco use and cancer of the esophagus, and between cigarette smoking and cancer of the urinary bladder in men, but the data are not adequate to decide whether these relationships are causal. Data on an association between smoking and cancer of the stomach are contradictory and incomplete. THE TOBACCO H.~BIT AND NICOTINE The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetuated by the pharmacological actions of nicotine. Social stimulation appears to play a major role in a young person's early and first experiments with smoking. No scientific evidence supports the popular hypothesis that smoking among adolescents is an expression of rebellion against authority. Individual stress appears to be associated more with fluctuations in the amount of smoking than with the prevalence of smok- ing. The overwhelming evidence indicates that smoking-its beginning, habituation, and occasional discontinuation-is to a very large extent psy- chologically and socially determined. Nicotine is rapidly changed in the body to relatively inactive substances with low toxicity. The chronic toxicity of small doses of nicotine is low in experimental animals. These two facts, when taken in conjunction with the low mortality ratios of pipe and cigar smokers, indicate that the chronic toxicity of nicotine in quantities absorbed from smoking and other methods of tobacco use is very low and probably does not represent an important health hazard. The significant beneficial effects of smoking occur primarily in the area of mental health, and the habit originates in a search for contentment. Since no means of measuring the quantity of these benefits is apparent, the Com- mittee finds no basis for a judgment which would weigh benefits against hazards of smoking as it may apply to the general population. 32 THE COMMITTEE'S JUDGMENT IN BRIEF On the basis of prolonged study and evaluation of many lines of converging evidence, the Committee makes the following judgment: Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action. B. COMMENTS AND DETAILED CONCLUSIONS (A Guide to Part II of the Report) All conclusions formally adopted by the Committee are presented at the end of this section in bold-faced type for convenience of reference. In the interest of conciseness, the documentation and most of the discussion are omitted from this condensation. Together with the tab& of contents which appear at the beginning of each chapter in Part II, it is intended as a guide to the Report. CHEMISTRY AND CARCINOGENICITY OF TOBACCO AKD TOBACCO SMOKE Condensates of tobacco smoke are carcinogenic when tested by application to the skin of mice and rabbits and by subcutaneous injection in rats ( Chap- ter 9, pp. 143-145). Bronchogenic carcinoma has not been produced by the application of tobacco extracts, smoke, or condensates to the lung or the tracheobronchial tree of experimental animals with the possible exception of dogs (Chapter 9, p. 165). Bronchogenic carcinoma has been produced in laboratory animals by the administration of polycyclic aromatic hydrocarbons, certain metals, radio- active substances, and viruses. The histopathologic characteristics of the tumors produced are similar to those observed in man and are predominantly of the squamous variety (Chapter 9, pp. 166-167). Seven polycyclic hydrocarbon compounds isolated from cigarette smoke have been established to be carcinogenic in laboratory animals. The results of a number of assays for carcinogenicity of tobacco smoke tars present a puzzling anomaly: the total tar from cigarettes has many times the carcino. genie potency of benzo (a) pyrene present in the tar. The other carcinogens known to be present in tobacco smoke are, with the exception of dibenzo (a,ij pyrene, much less potent than benzo (a) pyrene and they are present in smaller amounts. Apparently, therefore, the whole is greater than the sum of the known parts. This discrepancy may possibly be due to the presence of cocarcinogens in tobacco smoke, and/or damage to mucus production and ciliary transport mechanism (Chapter 6, p. 61, Chapter 9, p. 144 and Chap- ter 10, pp. 267-269). There is abundant evidence that cancer of the skin can be induced in man by industrial exposure to soots, coal tar, pitch, and mineral oils. All of these 33 contain various polycyclic aromatic hydrocarbons proven to be carcinogenic in many species of animals. Some of these hydrocarbons are also present in tobacco smoke. It is reasonable to assume that these can be carcinogenic for man also (Chapter 9, pp. 146-148). Genetic factors play a significant role in the development of pulmonary adenomas in mice. It is possible that genetic factors can influence the smok- ing habit and the response in man to carcinogens in smoke. However, there is no evidence that they have played an appreciable role in the great increase of lung cancer in man since the beginning of this century (Chapter 9, p. 190). Components of the gas phase of cigarette smoke have been shown to pro- duce various undesirable effects on test animals or organs. One of these effects is suppression of ciliary transport activity, an important cleansing function in the trachea and bronchi (Chapter 6, p. 61 and Chapter 10, pp. 267-270). CHARACTERIZATION OF THE TOBACCO HABIT The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetuated by the pharmacological actions of nicotine on the central nervous system. Nicotine-free tobacco or other plant materials do not satisfy the needs of those who acquire the tobacco habit (Chapter 13, p. 354) . The tobacco habit should be characterized as an habituation rather than an addiction. Discontinuation of smoking, although possessing the difficul- ties attendant upon extinction of any conditioned reflex, is accomplished best by reinforcing factors which interrupt the psychogenic drives. Nicotine substitutes or supplementary medications have not been proven to be of major benefit in breaking the habit (Chapter 13, p. 354). PATHOLOGY AND MORPHOLOGY Several types of epithelial changes are much more common in the trachea and bronchi of cigarette smokers, with or without lung cancer, than of non- smokers and of patients without lung cancer. These epithelial changes are (a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance of atypical cells with irregular hyperchromatic nuclei. The degree of each of the epithelial changes in general increases with the number of cigarettes smoked. Extensive atypical changes have been seen most frequently in men who smoked two or more packs of cigarettes a day. Women cigarette smokers, in general, have the same epithelial changes as men smokers. However, at given levels of cigarette use, women appear to show fewer sty-pica1 cells than do men. Older men smokers have more atypical cells than younger men smokers. Men who smoke either pipes or cigars have more epithelial changes than non-smokers, but have fewer changes than cigarette smokers consuming approximately the same amount of tobacco. Male ex-cigarette smokers have less hyperplasia and fewer atypical cells than current cigarette smokers. It may be concluded, on the basis of human and experimental evidence, that some of the advanced epithelial hyperplastic lesions with many atypical 34 cells, as seen in the bronchi of cigarette smokers, are probably premalignant (Chapter 9, pp. 167-173 ) . Typing of Tumors.---Squamous and oval-cell carcinomas (Group I of Kreyberg's classification) comprise the predominant types associated with the increase of lung cancer in the male population. In several studies, adenocarcinomas (Group II) h ave also shown a definite increase, although to a much lesser degree. The histological typing of lung cancer is reliable, but the use of the ratio of histological types as an index of the magnitude of increase in lung cancer is of limited value (Chapter 9, pp. 173-175). Functional and PuthoZogicaZ Changes.-Cigarette smoke produces signif- icant funtional alterations in the trachea, bronchus, and lung. Like several other agents, cigarette smoke can reduce or abolish ciliary motility in experi- mental animals. Postmortem examination of bronchi from smokers shows a decrease in the number of ciliated cells. shortening of the remaining cilia, and changes in goblet cells and mucous glands. The implication of these morphological observations is that functional impairment would result. In animal experiments, cigarette smoke appears to aflect the physical rharacteristics of the lung-lining layer and to impair alveolar (air sac) stability. Alveolar phagocytes ingest tobacco smoke components and assist in their removal from the lung. This phagocytic clearance mechanism breaks down under the stress of protracted high-level exposure to cigarette imoke, and smoke components accumulate in the lungs of experimental animals (Chapter 10, pp. 269-270). The chronic effects of cigarette smoking upon pulmonary function are manifested mainly by a reduction in ventilatory function as measured by :he forced expiratory volume (Chapter 10, pp. 289-292). Histopathological alterations occur as a result of tobacco smoke exposure n the tracheobronchial tree and in the lung parenchyma of man. Changes -egularly found in chronic bronchitis-increase in the number of goblet ,ells, and hypertrophy and hyperplasia of bronchial mucous glands-are nore often present in the bronchi of smokers than non-smokers. Cigarette smoke produces significant functional alterations in the upper and lower iirways to the lungs. Such alterations could be expected to interfere with he cleansing mechanisms of the lung. Pathological changes in pulmonary parenchyma, such as rupture of lveolar septa (partitions of the air sacs) and fibrosis, have a remarkably lose association with past history of cigarette smoking. These latter changes :annot be related with certainty to emphysema or other recognized diseases `t the present time (Chapter 10, pp. 270-275). MORTALITY The death rate for smokers of cigarettes only, who were smoking at the ime of entry into the particular prospective study, is about 70 percent higher ban that for non-smokers. The death rates increase with the amount smoked. "or groups of men smoking less than 10, 10-19, 20-39, and 40 cigarettes md over per day, respectively, the death rates are about 40 percent, 70 per- 35 cent, 90 percent, and 120 percent higher than for non-smokers. The ratio of the death rates of smokers to non-smokers is highest at the earlier ages (&J- 50) represented in these studies, and declines with increasing age. The same effect appears to hold for the ratio of the death rate of heavy smokers to that of light smokers. In the studies that provided this information, the mortality ratio of cigarette smokers to non-smokers was substantially higher for men who started to smoke under age 20 than for men who started after age 25. The mortality ratio was increased as the number of years of smoking in. creased. In two studies which recorded the degree of inhalation, the mar. tality ratio for a given amount of smoking was greater for inhalers than for non-inhalers. Cigarette smokers who had stopped smoking prior to enroll- ment in the study had mortality ratios about 1.4 as against 1.7 for current cigarette smokers. The mortality ratio of ex-cigarette smokers increased with the number of years of smoking and was higher for those who stopped after age 55 than for those who stopped at an earlier age (Chapter 8, p. 93). The biases from non-response and from errors of measurement that are difficult to avoid in mass studies may have resulted in some over-estimation of the true mortality ratios for the complete populations. In our judgment, however, such biases can account for only a part of the elevation in mortality ratios found for cigarette smokers (Chapter 8, p. %). Death rates of cigar smokers are about the same as those of non-smokers for men smoking less than five cigars daily. For men smoking five or more cigars daily, death rates were slightly higher (9 percent to 27 percent) than for non-smokers'in the four studies that gave this information. There is some indication that this higher death rate occurs primarily in men who have been smoking for more than 30 years and in men who stated that they inhaled the smoke to some degree. Death rates for current pipe smokers were little if at all higher than for non-smokers, even with men smoking 10 or more pipefuls per day and with men who had smoked pipes for more than 30 years. Ex- cigar and ex-pipe smokers, on the other hand, showed higher death rates than both non-smokers and current pipe or cigar smokers in four out of five studies (Chapter 8, p. 94). The explanation is not clear but may be that a substantial number of such smokers stopped because of illness. Mortality by Cause of De&.--In the combined results from the seven prospective studies, the mortality ratio of cigarette smokers was particularly high for a number of diseases. There is a further group of diseases, including some of the most important chronic diseases, for which the mortality ratio for cigarette smokers lay between 1.2 and 2.0. The explanation of the moderate elevations in mortality ratios in this large group of causes IS not clear. Part may be due to the sources of bias previously mentioned or to some constitutional and genetic difference between cigarette smokers and non-smokers. There is also the possibility that cigarette smoking has some general debilitating effect, although no medical evidence that clearly supports this hypothesis can be cited (Chapter 8, p. 105) . In all seven studies, coronary artery disease is the chief contributor to the excess number of deaths of cigarette smokers over non-smokers, with lung cancer uniformly in second place (Chapter 8, p. 108). 36 For cigar and pipe smokers combined, there was a suggestion of high mortality ratios for cancers of the mouth, esophagus, larynx and lung, and for stomach and duodenal ulcers. These ratios are, however, based on small numbers of deaths (Chapter 8, p. 107). CANCER BY SITE Lung Cancer Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. The risk of developing lung cancer increases with duration of smoking and the numher of cigarettes smoked per day, and is diminished by discontinuing smoking. The risk of developing cancer of the lung for the combined group of pipe smokers, cigar smokers, and pipe and cigar smokers, is greater than for non-smokers, h u much less than for cigarette t smokers. The data are insufficient to warrant a conclusion for each group individually (Chapter 9, p. 196). Oral Cancer The causal relationship of the smoking of pipes to the develop ment of cancer of the lip appears to he established. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of tobacco use, their causal implications cannot at present be stated (Chapter 9, pp. 204-205). Cancer of the Larynx Evaluation of the evidence leads to the judgment that cigarette smoking is a significant factor in the causation of laryngeal cancer in the male (Chapter 9, p. 212). Cancer of the Esophagus The evidence on the tobacco-esophageal cancer relationship sup- Ports the belief that an association exists. However, the data are not adequate to decide whether the relationship is causal (Chapter 9, p. 218). Cancer of the Urinary Bladder Available data suggest an association between cigarette smoking and urinary bladder cancer in the male but are not sufficient to support a judgment on the causal significance of this association (Chapter 9, p. 225). 37 Stomach Cancer No relationship has been established between tobacco use and stomach cancer (Chapter 9, p. 229). NON-NEOPLASTIC RESPIRATORY DISEASES, PARTICULARLY CHRONIC BRONCHITIS AND PULMONARY EMPHYSEMA Cigarette smoking is the most important of the causes of chronic bronchitis in the United States, and increases the risk of dying front chronic bronchitis. A relationship exists between pulmonary emphysema and cig- arette smoking but it has not been established that the relationship is causal. The smoking of cigarettes is associated with an increased risk of dying from pulmonary emphysema. For the bulk of the population of the United States, the impor. tance of cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than that of atmospheric pollution or occupational exposures. Cough, sputum production, or the two combined are consistently more frequent among cigarette smokers than among non-smokers. Cigarette smoking is associated with a reduction in ventilatory function. Among males, cigarette smokers have a greater preva- lence of breathlessness than non-smokers. Cigarette smoking does not appear to cause asthma. Although death certification shows that cigarette smokers have a moderately increased risk of death from influenza and pneumonia, an association of cigarette smoking and infectious diseases is not otherwise substantiated (Chapter 10, p. 302). CARDIOVASCULAR DISEASE Smoking and nicotine administration cause acute cardiovascular effects similar to those induced by stimulation of the autonomic nervous system, but these effects do not account well for the observed association between cigarette smoking and coronary disease. It is established that male cigarette smokers have a higher death rate from coronary disease than non-smoking males. The association of smoking with other cardiovascular disorders is less well established. If cigarette smoking actually caused the higher death rate from coronary disease, it would on this account be responsible for many deaths of middle-aged and elderly males in the United States. Other factors such as high blood pressure, high serum cholesterol, and excessive obesity are also known to be associated with an unusually high death rate from coronary disease. The causative role of these factors in coronary disease, though not proven, is suspected strongly enough to be a major reason for taking countermeasures against them. It is also more prudent to assume that the established association between cigarette smoking and coro- 38 nary disease has causative meaning than to suspend judgment until no un- certainty remains (Chapter 11, p. 327). Male cigarette smokers have a higher death rate from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance. OTHER CONDITIONS Peptic Ulcer Epidemiological studies indicate an association between cigarette smoking and peptic ulcer which is greater for gastric than for duodenal ulcer (Chapter 12, p. 340). Tobacco Amblyopia Tobacco amblyopia (dimness of vision unexplained by an or- ganic lesion) has been related to pipe and cigar smoking by clini- cal impressions. The association has not been substantiated by epidemiological or experimental studies (Chapter 12, p. 342). Cirrhosis of the Liver Increased mortality of smokers from cirrhosis of the liver has been shown in the prospective studies. Tbe data are not sufficient to support a direct or causal association (Chapter 12, p. 342). Maternal Smoking and Infant Birth Weight Women who smoke cigarettes during pregnancy tend to have babies of lower birth weight. Information is lacking on the mechanism by which this decrease in birth weight is produced. It is not known whether this decrease in birth weight has any influence on the biological fitness of the newborn (Chapter 12, p. 343). Smoking and Accidents Smoking is associated with accidental deaths from fires in the home. No conclusive information is available on the effects of smoking on traffic accidents (Chapter 12, p. 345). MORPHOLOGICAL CONSTITUTION OF SMOKERS The available evidence suggests the existence of some morpbolog ical differences between smokers and non-smokers, but is too meager to permit a conclusion (Chapter 15, p. 387). 39 PSYCHO-SOCIAL ASPECTS OF SMOKING A clear cut smoker's personality has not emerged from the results so far published. While smokers differ from non-smokers in a variety of charac- teristics, none of the st,dies has shown a single variable which is found solely in one group and is completely absent in another. Nor has any single varia- ble been verified in a sufficiently large proportion of smokers and in suffi. ciently few non-smokers to consider it an "essential" aspect of smoking. The overwhelming evidence points to the conclusion that smok. . mg-its beginning, habituation, and occasional discontinuation-is to a large extent psychologically and socially determined. This does not rule out physiological factors, especially in respect to habituation, nor the existence of predisposing constitutional or hereditary factors (Chapter 14, p. 377). PART II Evidence of the Relation Between Smoking and Health Chapter 5 Consumption of Tobacco Products in the United States List of Tables Page TABLE 1. Tobacco products: Consumption per capita, 15 years and over, United States, 1900-1962 . . . . . . . 45 TABLE 2. Filter tip cigarettes: estimated output and percentage distribution . . . . . . . . . . . . . . . . . . 46 Chapter 5 CONSUMPTION OF TOBACCO PRODUCTS IN THE UNITED STATES The U.S. Department of Agriculture estimates that the total number of persons in the United States, including overseas members of the Armed Forces, who consume tobacco on a regular basis is close to 70 million ( 1). Consumption of tobacco products per capita. 15 years and over: has risen from 7.42 pounds in 1900 to 10.85 pounds in 1962. Cigarette consumption increased steadily from 1910. when the per capita consumption was 138 cigarettes, to the 1962 figure of 3.9.58. Per capita cigar consumption re- mained steady at slightll- over 100 in the first two decades of the century. hut started to decrease in 1921. The figure for 1920 is 117, and for 1962 it is 55. Per capita consumption of pipe tobacco remained steady until the mid-1940's. In 1945 the figure was 1.59 pounds. but in 1962 it was just over half a pound (0.56 I. Consumption of chewing tobacco showed a de- cline durin? about the same period, from 1.09 pounds per capita in 1945 to 0.50 in 1962. Consumption of snuff has shown very little change (2) [Table 1). TABLE I.--Consumption of tobacco products per person aged 15 years and over in the United States for selected years, 1900-1962 1:: ' 611 I, 365 1.828 3, 322 3,888 3,986 3.958 Starting in 1050, production of filter tip cigarettes began to rise. Un- official estimates for 1950 show that only about half of one percent of ciga- rettes produced were filter tip. In 1952, unofficial estimates show 1.3 per- cent of cigarettes produced were filter tips. 27.6 percent. In 1956 the figure had reached From 1958 on, official estimates, based on figures reported to the Department of Agriculture by the industry, show a continuous in- crease from 45 3 percent filter tip cigarettes produced in 1958 to 54.6 percent Produced in 1462 ( 3 I (Table 2) . 45 TABLE T-Estimated output of filter-tip cigarettes and percentage of total cigarette production, United States, 1950-1962 Filter-tip cigarettes (billions) 1950.........~......-. 1951....~..-......-- .. 1952-........-......- - 1953........- ......... 1951.................. lY55 __ .. .._ __ ......... 19.56.. ... .._ .......... / 2. 2 3.0 5. fi 12.4 36.9 77.0 116.9 Perw$ of Percent of total 16% 3 9.0 213.0 45.3 238.8 48. 7 253.0 277. 1 % 292.5 54.8 *Data from 1958 through 1962 arc official estimates from Censu.a of Manufactsrern. Source: U.S. Department of .4griculture, Economic Research Service. REFERENCES I. U.S. Department of Agriculture. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 2. U.S. Department of Agriculture. Economic Research Service. Tobacco products. Consumption per capita. 15 years and over, United States, 1900-62. 3. U.S. Department of Agriculture. Economic Research Service. The tobacco situation. March 1962, March 1963, September 1963. Chapter 6 Chemical and Physical Characteristics of Tobacco and Tobacco Smoke 7 14-422 o-64-5 Contents CHEMISTRY OF TOBlCCO ............... COMPOSITION OF CIGARETTE SMOKE ........ COMPOUNDS OF THE PARTICULA4TE PH.4SE OTHER THAN HIGHER POLYCYCLICS ............ Aliphatic and Alicyclic Hydrocarbons .......... Terpenes and Isoprenoid Hydrocarbon .......... Alcohols and Esters .................. Sterols ........................ Aldehydes and Ketones. ................ Acids ........................ Phenols and Polyphenols ................ Alkaloids, Nitrogen Bases, and Heterocyclics ....... Amino Acids ..................... Inorganic Components ................. Noncarcinogenic Aromatic Hydrocarbons ......... CARCINOGEXIC HYDROC.4RBONS -4ND HETEROCY- CLICS IN TOB-4CC0 SMOKE ............. COCARCINOGENS .................... MECHAXISM OF THE FORM-4TlON OF CARCINOGEXS . THE GAS PHASE .................... EFFECTS ON CILIARY ACTIVITY ........... PESTICIDES AND -4DDITIVES ............. SUMMARY ....................... REFERESCES ...................... List of Tables TABLE 1. Major classes of compounds in the particulate phase of cigarette smoke . . . . . . . . . . . . . . TABLE 2. Carcinogenic polycyclic compounds isolated from cigarette smoke . . . . . . . . . . . . . . . . TABLE 3. Polycyclic hydrocarbons isolated from tobacco smoke . . . . . . . . . . . . . . . . . . . . TABLE 4. Some gases found in cigarette smoke . . . . . . . Page 49 50 55 58 59 60 61 61 62 63 51 56 58 60 4a Chapter 6 Tobacco is an herb which man has smoked for over 300 years. The plant was given the generic name Nicotiana after Jean Nicot. French ambas- sador to Portugal, who in 1560 publicly extolled the virtue of tobacco as a curative agent. The species Nicotiuna tabacum is now the chief source of smoking tobacco and is the only species cultivated in the United States. CHEMISTRY OF TOBACCO The tobacco leaf contains a complex mixture of chemical components: cellulosic products, starches, proteins, sugars, alkaloids, pectic substances, hydrocarbons, phenols. fatty acids, isoprenoids, sterols, and inorganic min- erals. Many of the several hundred components isolated have been found to occur also in other plants. Two groups of components are specific to tobacco and have not as yet been isolated from other natural sources. One includes the alkaloid nicotine and the related companion substances nornicotine, mvosmine, and anabasine. These nitrogen-containing substances are all Nicotine Nornicotine Mycmmine Anabaaine basic and hence extractable with acid. Seven members of a second group of compounds fairly distinctive to tobacco have been isolated and charac- terized (1962-63) by D. L. Roberts and R. L. Rowland(36). They are de- scribed as isoprenoids, since the structures are divisible into units of isoprene, the building principle of rubber, of the red pigment of the tomato, and of the yellow pigment of the carrot, as illustrated in the following formulas: c Isoprenoid tobacco component 4 Isoprene units Although none of the 7 isoprenoid components of tobacco has been isolated from another source, the hydrocarbon cembrene from a pine exudate has the same 14-membered ring with the same complement of an isopropyl group at Cl and methyl groups at G, CB, and CIZ (9). 49 COMPOSITION OF CIGARETTE SMOKE Cigarette smoke is an heterogeneous mixture of gases, uncondensed vapors, and liquid particulate matter (32). As it enters the mouth the smoke 1s a concentrated aerosol with millions or billions of particles per cubic centimeter t 25, 30). The median size of the particles is about 0.5 micron ( 1) . For purposes of investigating chemical composition and biological properties? smoke is separated into a particulate phase and a gas phase, and the gas phase is frequently subdivided into materials which condense at liquid-air tempera. ture and those which do not. Th e 1 arge quantities of material required for investigation of the chemical components are prepared on smoking machines t 25) in which large numbers of cigarettes are smoked simultaneously in a fashion designed to simulate average smoking habits, and a yellow-brows condensate known as tobacco tar is collected in traps cooled to the temperature of dry ice ( -70" C.) or liquid nitrogen (-196" C.). The tar thus contains all of the particulate phase of smoke as well as condensable components of the gas phase. The amount of tar from the smoke of one cigarette is between 3 and 40 mg., the quantity varyin g according to the burning and condensing conditions, the length of the cigarette, the use of a filter, porosity of paper, content of tobacco, weight and kind of tobacco. An important factor determining the composition of cigarette smoke is the temperature in the burning zone. While air is being drawn through the cigarette the temperature of the burning zone reaches approximately 884" C. and when the cigarette is burning without air being drawn through it the temperature is approximately 835' C. (42). The smoke generated during puffing, when air is being drawn through the cigarette, is called main-stream smoke; that generated when the cigarette is burning at rest is called side- stream smoke. At the temperatures cited extensive pyrolytic reactions occur. Some of the many constituents of tobacco are stable enough to distil un. changed, but many others suffer extensive reactions involving oxidation. dehydrogenation, cracking, rearrangement, and condensation. The large number and variety of compounds in tobacco smoke tar is reminiscent of the composition of the tar formed on carbonization of coal, which in many cases is conducted at temperatures lower than those of a burning cigarette. It is thus not surprising that some 500 different compounds have been identified in either the particulate phase of cigarette smoke or in the gas phase. In one study (50) regular cigarettes (70 mm. long, about 1 g. eachj with. out filter tips produced 17-40 mg. of tar per cigarette. In another investiga- tion (43) 174,000 regular size American cigarettes afforded a total of 4 kg. of tar, an average of 23 mg. per cigarette. In still another study (31) 34,000 7O-mm. cigarettes were smoked mechanically on a constant puff-volume type machine with which 35-ml. puffs, each of two seconds duration, were taken at one minute intervals from each cigarette. Eight puffs were required to smoke each cigarette to an average butt length of 30 mm. The smoke M-as condensed in a series of three glass traps cooled in liquid air. The conden. sate was rinsed out of the traps with ether, water, and hexane. The yield of condensate nonvolatile at 25" C. and 25 mm. of mercury was 20.9 mg. per cigarette. 50 Procedures for gross separation into basic, acidic, phenolic, and neutral fractions and for further processing of these fractions vary from laboratory to laboratory. The criteria upon which identification is based also vary. The most reliable identifications are based upon an ultraviolet absorption spec- trum and/or a fluorescence spectrum in good agreement over the entire range \tith that of an authentic sample and include one or more of the following: Rf value observed in a paper chromatogram 111) ; order of elution from alumina; mass spectrometry. COMPOUNDS OF THE PARTICULATE PHASE OTHER THAN HIGHER POLYCYCLICS This brief summary is based largely on the comprehensive review by Johnstone and Plimmer of the Medical Research Council at Exeter Uni- irraity. England ( 24 I. It should be noted that water constitutes 27 percent Ilf the particulate phase. Th e major groups of compounds included are .ho\tn in Table 1. ALIPHATIC AND ALKYCLIC HYDROCARBONS Almost all of the possible hydrocarbons, C, through C,, saturated and urr+aturated, straight-chain and branched-chain, have been reported to be prcaen, in tobacco smoke. Intermediate, normally liquid paraffins are pres- ent. All the C,, through C,, n-a lkanes have been identified, as well as the CZ: and C,!,-c',, isoparaffins. T4BL.E I.--Major classes of compounds in the particulate phase of cigarette smoke Percent in Sumber 01 particu- comwmd late* phase - 7.7-12.8 1 25 5.3-8.3 18 8. 5 21 4. 9 0.44 El 1. G-3. 8 45 Toxic action on lung Some irritant Possible irritation Some irritant Some irritant Some carcinogenic Irritant and possibly cocarcinokxnic TERPENES AND ISOPRENOID HYDROCARBONS isoPrene, the basic unit of the terpenes and of higher terpenoids has been !dcntified in mprrthadiene. cigarette smoke (34) as have its dimers, dipentene and 1,8-p- and shown t The triterpene squalene, consisting of six isoprene units o b hilit! of its be* e present in smoke (47) is of interest because of the possi- mg cyclized to polycyclic compounds and because of its ready 51 CHa CE4 CHa C& HaC CH: CHa CHa Squalene reaction with air to form hydroperoxides (which would be destroyed during attempted isolation ) ; a hydroperoxide derived from cholesterol has been shown to be carcinogenic i cancer-causing) : at least under certain conditions of administration I 12) . Phytadienes. products of the dehydration of the diterpene alcohol phytol, are also present in smoke and subject to air oxida- tion to hydroperoxides. C& Crt CH: CHIOH HsC Phytol ALCOHOLS ANT) ESTERS A wide variety of mono- and dihydric alcohols, both aliphatic and aro- matic, are present in tobacco smoke. Solanesol, a primary alcohol con- taining 9 isoprene units, has been found in both tobacco and tobacco smoke; 20 g. of pure material was isolated from 10 lbs. of flue-cured aged tobacco (0.44 percent). Grossman et al i 13) found that pyrolysis of solanesol at 500" C. gives isoprene, its dimer dipentene, and other terpenoid products and concluded that the alcohol is the source of terpenoid compounds which are important factors in the flavor of tobacco smoke. Ethylene glycol and glycerol have been found present in smoke, but it is not clear from the literature whether they are present in smoke from un- treated tobacco or arise from addition of these humectant substances to tobacco to improve moistness. Many common esters, such as the ethyl esters of the C2, C,, and C, fatty acids, are present in smoke. Higher fatty- acids are found both as free acids and as esters. STEROLS Stigmasterol, p-sitosterol, and r-sitosterol have been isolated from to- bacco smoke. Indeed the sterol fraction is reported (29) to constitute approximately 0.15 percent of whole tar. The sterols are of interest as possible precursors of polyc)-clic aromatic hydrocarbons and because of the evidence, noted above. that sterol hydroperoxides can be carcinogenic. ALDEHYDES AND KETONES Most common aldehydes of low molecular weight (acetaldehyde, pro- pionaldehyde, acetone, methyl ethyl ketone, etc.) have been found present 52 -4 CHlOH HIC I 5oo"= Ad + Isoprene I-&C `-.2Hz Dipentene (major product) Solanesol \ 6 (3 HsC' CHa C& &C /`hII., CH, I H:C J&C HIC CHa in tobacco smoke, as have such dicarbonyl compounds as glyoxal and di- acetyl. Dipalmityl ketone exemplifies ketones of high molecular weight isolated from tobacco smoke. 0 16' C& Dipalmityl ketone ACIDS A large number of volatile and nonvolatile acids of low molecular weight are present in tobacco smoke. Fatty acids of chain length C,, to C,, are reported to constitute 1 percent of the whole tar and the bulk of these acids are present in the free form (46). Unsaturated fatty acids and keto acids `e.g., pyruvic acid) are also present. 53 PHENOLS AND POLYPHENOLS Since the phenols and polyphenols present in tobacco leaf play an im. portant role in the curing and smoking quality of tobacco, a great deal of investigative work has been done on the estimation, separation, and ident& cation of complex tobacco phenols such as rutin and chlorogenic acid. The presence of simple phenols in tobacco smoke was established as early as 1871. The phenol content of smoke became of increasing importance with OH HO H? \ - 0 CH- CH~O~co,H - ir HOi OH Rharnnoae Rutin Chlorogenic acid the demonstration that phenol and substituted phenols can function as cocarcinogens; that is, they promote the appearance of skin tumors in mice following application of a single initiating dose of a known carcinogen (4). Furthermore, the smoke from one cigarette contains as much as 1 mg. of phenols (7). In add t i ion to simple alkylphenols, naphthols, and the poly. phenols, resorcinol and hydroquinone are also present. ALKALOIDS, NITROGEN BASES, AND HETEROCYCLICS Pyridine, nicotine, nornicotine, and other substituted pyridine bases con. stitute some 8-15 percent of whole tar; nicotine and nornicotine constitute about 7-8 percent of the total tar. The companion bases are products of the pyrolysis of the alkaloids present in tobacco leaf. Quinoline and three poly-cyclic heterocyclic compounds have also been identified in smoke (45) and will be discussed later since the three polycyclic compounds are carcino- genic. `4 pentacyclic compound related to xanthene, namely 1,8,9peri- naphthoxanthene. has been identified in smoke (45). 1,8,9-Perinaphthoxanthene AMINO ACIDS Although tobacco leaf contains a number of amino acids, relatively few have been found present in smoke; among these are glutamine and glutamic acid. 54 INORGANIC COMPONENTS It is estimated that the main-stream smoke from one cigarette contains about 150 1j.g. of metallic constituents. which are mainly potassium (90 tIercent I _ sodium (5 percent I, and traces of aluminum, arsenic, calcium. and copper. Arsenic is reported to be present to the extent of 0.3-1.4 pg. in the smoke of one cigarette. Th e inorganic compounds are most likely chlorides. but metals themselves may be present. Apparently bery-ilium is present in tobacco in trace quantities. but is not 1 olatilized in the smoking process ( 4s ) . Nickel is present in cigarettes in trace amounts and may occur in main-stream smoke to a small extent, l:robably as the chloride (31 t . Spectrographic analysis has shown the presence of chromium in smoke at a level of less than 0.06 ;tg. per cigarette. This level appears too low to represent a hazard 148). IVONCARCINOGENIC AROMATIC HYDROCARBONS The aromatic h>-drocarbons present in tobacco smoke have received an enormous amount of attention since some of them are carcinogenic. Toncarcinogenic hydrocarbons of smoke containing one to three rings include benzene. toluene and other alkplbenzenes, acenaphthene, acenaph- thylene. flnorene. anthracene. and phenanthrene. Hydrocarbons of estab- lished carcinopenicity to mice all contain from four to six condensed rings. Ifowever. no less than 27 hydrocarbons containing four or more `condensed rings which have been tested for carcinopenicity with negative results have heen isolated from tobacco smoke tar. As methods of separation and identification improve, it is almost certain that additional hydrocarbons will be found present in smoke, because almost every conceivable ring system has been demonstrated to be present and the number of possible alkylated polycyclics is very large indeed. CARCINOGENIC HYDROCARBONS AND HETEROCYCLICS IN TOBACCO SMOKE In 1925-30 Kennaway et al. in seeking to identify the active substance in high-boiling fractions of coal tar distillates of established carcinogenicity to mice, discovered that dibenzo(a,h)anthracene (for formula, see Table 21 prepared by synthesis evokes skin cancer when applied to the skin of mice (11). The hydrocarbon was recognized as different from the carcino- gen of coal tar because its fluorescent spectrum did not match the character- istic three-banded spectrunr of the tars. In 1933 Cook and co-workers i 11) isolated the coal tar constituent responsible for the characteristic fluorescence and identified it as benzota) pyrene. the carcinogens now known. It is one of the most potent of all 55 TABLE 2.--Carcinogenic Polycyclic Compounds Isolated From Cigarette Smoke Compound 1. Benzo(s)pyrene 2. Dibenzo(s,i)pyrene 3. Dibenao(s,h)snthrscene 4. Benao(c)phenanthrene 5. Dibens(s,j)acridine 6, Dibenz(a,h)acridine 7. 7H-Dibenzo(c,g)carbszole structllre ' I / / (Id?? : 1; > w I> `I \ ' \ / Carcino- genicity Amount reported, rg/KMM cigarettes ++++ ++++ ++ 16 (ave. of 10 reports) 0.02-10 (2 reports) (1 retort) ot- not stated + 2.7 (1 report) 0.1 (1 report) 0.7 (1 report) 56 Since the discovery of carcinogenic hydrocarbons, a large number of polycyclic hydrocarbons and heterocyclic analogs have been tested for car- cinogen