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- cinogenicity to mice and to rats in many laboratories, both by application to the skin and by subcutaneous injection. Bioassays in different labora- tories, often on independently prepared samples, are remarkably consistent and place a series of hydrocarbons in the same relative order of potency. A compilation (and its supplement) prepared by J. L. Hartwell (16) of the IKational Cancer Institute lists 2108 compounds of which 481 were reported to cause malignant tumors in animals. All but one of the polycyclic hydro- carbons listed in Table 2 as having been identified in tobacco smoke have already been documented in the Hartwell report and can be assigned a rating as very potent ( + + + + ), potent ( + + + ) , moderately carcino- genic I, + + ), or weakly carcinogenic ( + ) (31). Many other such com- pounds studied are reported in the Hartwell survey and in another by :Irthur D. Little, Inc. (31). The rating assigned to dibenzo (a,;) pyrene is based on experiments with over 10,000 inbred mice in which one subcutaneous injection in the groin of 0.5 mg. of hydrocarbon in tricaprylin produced 50 percent sarcomas at the injection site in 14 weeks and 98 percent tumors in 24 weeks (20). Benzo(a)pyrene is one of the two most potent of the seven carcinogens detected in tobacco smoke and it is present in much larger quantity than any of the other carcinogens listed. Two polycyclic hydro- carbons isolated from tobacco smoke but not yet adequately tested for carcinogenicity are: benzo (j ) Auoranthene and dibenzo (a,l) pyrene. Identification of benzo (a)pyrene is reported in 19 separate investiga- tions; the amount given in the table per 1000 cigarettes (70 mm. long, Neighing about 1.0 g. each) is the average of 10 values selected on the basis of the quality of criteria used for identification (31). Compounds 1, 2, 3, 4, and benzo (j) fluoranthene were identified in one laboratory over a period of years and are listed together in a review by Van Duuren (44). Isolation of the three heterocyclic carcinogens (5,6,7) is reported by Van Duuren (45). Because of losses in the process of fractionation and purification, the amount of carcinogens reported in a given investigation may be less than the amount actually present. Wy d n er and Hoffman (50) investigated this point by adding a known amount of radioactive C"-1abelled benzo(a)pyrene to a smoke condensate and applied the usual procedure for isolation of benzo(a)pyrene, which involved, in the last stages, chromatographing twice on silica gel and four times on paper. The activity of the benzo(a) pyrene finally isolated indicated a loss of 3540 percent of carcinogen during proc- essing. Th e amount of benzo(a) pyrene given in Table 2 thus should be multiplied by a factor of 1.5 to give the estimated true amount. Probably the amounts of the other carcinogens in smoke are also at least 1.5 times the reported amounts. Relatively little work has been done on the components of smoke produced with cigars and pipes. Table 3 summarizing a comparative study made in one laboratory (5) indicates that the amount of benzo(a)pyrene, the only carcinogen in the group studied, increases sharply from cigarettes to cigars to pipes. 57 TABLE 3.-Polycyclic hydrocarbons isolated from tobacco smoke [,,g. pm 1000 g. of tobxcm consumrd~ COCARCINOGENS Assays of tobacco smoke tars for carcinogenicity are done by applying a dilute solution of tar in an organic solvent with a camel's hair brush to the backs of mice beginning when the animals are about six weeks old. Applica. tion is repeated three times a week for a period of a year or more. The results of a number of such assays present a puzzling anomaly: the total tar from cigarettes has about 40 times the carcinogenic potency of the benzo( a) pyrene present in the tar. The other carcinogens known to be present in tobacco smoke are, with the exception of dibenzo(a,i) pyrene, much less potent than benzo (a) pyrene and they are present in smaller amounts. Apparently, there. fore, the whole is greater than the sum of the known parts (27, 33,49). One possible or partial explanation of the discrepancy is that the tar con. tains compounds which, although not themselves carcinogenic, can enhance the cancer-producing properties of the carcinogens. Berenblum and Shubik (3), reporting on cocarcinogenesis. described the potentiating effect of croton oil, which itself is noncarcinogenic except in certain strains of mice (4a), on the action of hydrocarbon carcinogens. Phenol is reported to have a similar potentiating effect (4. 50) and, as noted above. cigarette smoke contains considerable phenolic material. Long-chain fatty acid esters (39) and free fatty acids (19) have been shown to function as cocarcinogens, and sub. stances of both types occur abundantly in tobacco smoke. It is possible that the potentiatinp action of croton oil is due to the presence of fatty acids and their esters. A further observation of possible importance is that some poly cyclic hydrocarbons. though very weak or inactive as carcinogens, are capable of initiating malignant growth under the influence of a promoter. Thus henz (a) anthracene, identified in cigarette smoke, is verv weak or inactive in initiating malignant growth by itself. but initiates carcinogenesis under the influence of croton oil as promoter (15). If more were known about the possible cocarcinogenicity of the many inactive components of tobacco smoke, some of the apparent discrepancy between isolation and bioassay data might disappear. It is possible that some of the carcinogenicity of smoke is due to hydroperoxides formed from un- saturated smoke components and destroyed in the isolation procedures. Furthermore both sets of data are far from precise; for example, one esti- mate of the amount of the highly potent dibenzoi a,i)pyrene per 1000 cigarettes (Table 2) is 0.02~~. and another is 1Opg. However. it is not necessary to wait for an exact balance of the two sets of data to draw a conclusion from each. The isolation experiments, taken 58 alone, indicate that cigarette smoke contains a number of identified chemicals which are carcinogenic to mice. The bioassavs suggest that cigarette smoke probably contains components which. actin g in a manner as yet undescribed, are involved in the induction of tumors in mice. Assessment of all conceivable synergistic effects presents a gigantic problem for exploration. Tobacco smoke contains considerable amounts of phenols and fatty acids, both of which, as previously mentioned, enhance the activity of known carcinogens. Cellulose acetate filters now in use remove `XL80 percent of acidic constituents of tobacco smoke. MECHANISM OF THE FORMATION OF CARCINOGENS Most of the carcinogenic compounds identified in cigarette smoke tar are not present in the native tobacco leaf but are formed by pyrolysis at the high burning temperature of cigarettes. Van Duuren (4.4) reports formation of benzo(a) pyrene and pyrene on pyrolysis of stigmasterol, a smoke com- HO Stigma&sol Benro(a)pyrene Pyrene ponent. Similar pyrolysis of pyridine or of nicotine gives dibenzo( a,j) acridine and dibenzo (a,h) acridine, both of which are carcinogenic (Table 2). Pyrolysis of nontobacco cigarettes made from vegetable fibers and spinach resulted in formation of benzo( a jpyrene (50). Hurd and co-workers (22) by careful experimentation have elaborated plausible mechanisms for the formation of polycyclic aromatics by pyrolysis of materials of low molecular weight at temperatures in the range 800-900" C. Postulated radical intermediates are: (a) CHz=C=kH - CH~-C+ZH (b) EH-cH=I~H - ~H=cHGH tc) CH=CH~H=CH These radicals can arise from propylene, toluene, picoline, or pyridine. A variety of polycyclic hydrocarbons can be generated by reaction of these radicals with themselves or with other small radicals present in the heating zone. For example, dimerization of (b ) should give benzene. 59 Jt thus appears that the pyrolysis of many organic materials can lead to the formation of components carcinogenic to mice. Cigarette paper con. sists essentially of cellulose. Pyrolysis of cellulose has been shown to produce henzo(a)pyrene. The observation (2') that treatment of tobacco with copper nitrate decreases the benzo (a) pyrene content of the cigarette smoke suggests a possibility for improvement by the use of additives or catalysts. The fact that side-stream smoke contains three times more benzo (a) pyrene than main-stream smoke has been cited (50) as evidence that more efficient oxidation could conceivably lower the content of carcinogenic hydrocarbons. THE G.4S PHASE The gas phase accounts for 60 percent of total cigarette smoke. Hobbs et al. ( 34, 35`1 found that 98.9 mole percent of the gas phase is made up of the following seven components: Yitrogen ____------- --------- ________. 73 mole percent Oxygen---- --------_____------_______ 10 Carbon-dioxide ____- -- _______-__----_ - 9.5 Carbon-monoxide--------------------- 4.2 Hydrogen---------------------------~ 1. Argon------------------------------. 0.6 Methane----------------------------- 0.6 98. 9 The approximately one percent of the gas phase not accounted for by the seven major constituents contains numerous compounds, no less than 43 of I\ hirh have been identified as present in trace amounts. Some of these are listed in Table 4 (1). TABLE 4.-Some gases found in cigarette smoke (1 (PPm) 100 NX) 5. cinl 2d 0. 5 Unknown l-one Sonc sonr Irritant Irritant Irritant Irritnnt Irritant Irntant Irritant Irritant r."known i;;itant Repiratory enzyme poison Unknown EFFECTS ON CILIARY ACTIVITY* An important line of investigation was opened up by the report by Hilding (1s) that cigarette smoke is capable of inhibiting the transport activity of ciliated cells such as found in the respiratory tract. It has been suggested ( 10. 17 I that failure of ciliary function to provide a constantly moving stream of mucus enables environmental carcinogens to reach the epithelial cells. Kensler and Battista t 28) describe development of a method of bioassay for inhibition of ciliary transport activity involving exposure of the trachea of a rabbit to the test material. The smoke from a regular cigarette was found to inhibit transport activity by 50 percent after exposure to two or three puffs. Several commercial filter cigarettes gave essentially the same result. The fact that these filters lower the phenol content by 70 to SO percent and trap about 4.0 percent of the particulate phase suggested that neither phenolic nor particulate materials are responsible for the inhibi- tion noted. The next trial was with an absolute filter. that is, one which removes the entire particulate phase and gives nonvisible gas. The obser- vation that such treatment did not significantly alter the inhibitory effect of the puff established that components of the gas phase are responsible for inhibition of ciliary transport activity. Assays of known components of the gas phase showed the followin g compounds to possess such activity: hydrogen cyanide, formaldehyde. acetaldehyde. acrolein, and ammonia, al- though no one of these occurs at levels high enough to produce the effect noted for smoke. Activated carbons differ markedly in their adsorption characteristics. Carbon filters previously employed in cigarettes do not have the specific power to scrub the gas phase. It has been reported that a filter containing special carbon granules removes gaseous constituents which depress ciliary activity (28) . PESTICIDES AND ADDITIVES Before 1930 practically the only insecticides used in the growing of to- bacco were lead arsenate and paris green (the mixed acetate-arsenite salt of copper). Analysis of 6 brands of American cigarettes purchased in 1933 showed a range of 7.5-26.4 parts of As,O, per million, with an average value of 13.9 ppm. (6). Cogbill and Hobbs (S) found that main-stream smoke of Cigarettes containing 7.1 pg. of arsenic per cigarette contains 0.031 pg. per puff. This amount would be equivalent to 0.25 pg. of arsenic per cigarette (8 puffs), and hence a smoker consuming 2.5 packs of such cigarettes per day might inhale 12.5 pg. of arsenic per day. By comparison, analysis of the atmosphere of New York City over a 12-year period indicated an average content of 100-400 pg. of arsenic per 10 cubic meters, which is an approxi- mate daily intake per person (38). Extensive Federal efforts to discourage the use of arsenicals for the control of tobacco hornworms on the growing tobacco crop resulted in a sharp de- `This tapir is disrussel~ more fully in ~haptrr IO. 61 cline in the arsenic content of cigarettes after 1950. Thus, the average arsenic content of 17 brands of cigarettes analyzed in 1958 was 6.2 ppm. of As,O, (14). It seems unlikely that the amount of arsenic derived even from unfiltered cigarettes is sufficient to present a health hazard. Chemicals recommended by the Department of Agriculture for the control of tobacco insects are: malathion, parathion, Endosulfan, DDT, TDE, end&, dieldrin, Guthion, aldrin, heptachlor, Diazinon, Dylox, Sevin, and chlordane (42a). Trace amounts of TDE and endrin have been detected in commercial cigarettes and cigarette smoke. Guthion and Sevin residues were detected in main-stream cigarette smoke at levels approximating 0.3 percent and l percent of that added to cigarettes prior to smoking. Tobacco treated with Guthion and Sevin at the recommended levels showed no measurable con- tamination of main-stream cigarette smoke (4b). (For discussion of car- cinogenicity of tobacco pesticides, see Chapter 9.) Cigarette manufacture in the United States includes use of additives such as sugars, humectants, synthetic flavors, licorice, menthol, vanillin, and rum. Glycerol and methylglycerol are looked on with disfavor as humectants be- cause on pyrolysis they yield the irritants acrolein and methylyglyoxal. Additives have not been used in the manufacture of domestic British cigarettes since the Customs and Excise Act of 1952, Clause 176, and probably longer, inasmuch as Section 5 of the Tobacco Act of 1842 imposed a widespread prohibition on the use of additives in tobacco manufacture. SUMMARY Of the several hundred compounds isolated from the tobacco leaf, two groups are specific to tobacco. One of these groups includes the alkaloid nicotine and related substances. The other includes compounds described as isoprenoids. Cigarette smoke is an heterogeneous mixture of gases, uncon- densed vapors, and particulate matter. In investigating chemical composition and biological properties, it is necessary to deal separately with the particulate phase and gas phase of smoke. Components of the particulate phase other than the higher polycyclics include aliphatic and alicyclic hydrocarbons, terpenes and isoprenoid hydro- carbons, alcohols and esters, sterols, aldehydes and ketones, acids, phenols and polyphenols, alkaloids, nitrogen bases, heterocyclics, amino acids, and inorganic chemicals such as arsenic. potassium, and some metals. Seven polycyclic compounds isolated from cigarette smoke have been estahlished to be carcinogenic. They are shown in Table 2. The over-all carcinogenic potency of tobacco tar is many times the effect which can be attributed to substances isolated from it. The d'ff 1 erence may be associated in part with the presence in tobacco smoke of cocarcinopens, several of which have been identified as smoke components. Components of the gas phase of cigarette smoke have been shown to pro- duce various undesirable effects on test animals or organs, one of which is suppression of ciliary transport activity in trachea and bronchi. 62 REFERENCES 1. Albert, R. E., Nelson, N. Special report to the Surgeon General's Ad- visory Committee on Smoking and Health. 2. Alvord, E. T., Cardon, S. Z. The inhibition of formation of 3,4-benzpy- rene. Brit J Cancer 10: 49%506, 1956. 3. Berenblum. I.. Shubik, P. The role of croton oil applications, associated with a single painting of a carcinogen, in tumour induction of the mouse skin. Brit J Cancer 1: 379-82. 1947. 1. Boutwell, R., Bosch. D. K. The tumor-promoting action of phenol and related compounds for mouse skin. Cancer Res 19: 413-24, 1959. 4a. Boutwell, R., Bosch, D. K., and Rusch, H. P. On the role of croton oil in tumor formation. Cancer Res 17: 71, 1957. 4b. Bowery, T. G., Guthrie, F. E. Determination of insecticide residues on green and flue-cured tobacco and in main-stream cigarette smoke. Agriculture and Food Chem 9( 3) : 193-7, 1961. 5. Campbell, J. M., Lindsey, A. J. P o ycyclic hydrocarbons in cigar smoke. 1 Brit J Cancer 11: 192-5, 1957. 6. Carey, F. P.. Blodgett. G.: Satterlee, H. S. Preparation of samples for determination of arsenic. 0. xygen-bomb combustion method. Industr Eng Chem Anal Ed 6. 327-30. 193-1. 7. Clemo, G. R. Some aspects of the chemistry of cigarette smoke. Tetra- hedron 3: 168-74, 1958. 8. Copbill, E. C., Hobbs, M. F,. Transfer of metallic constituents of ciga- rets to the main-stream smoke. Tobacco Sci 1: 68-73: 1957. 9. Dauben, W. G., Thiessen, W. E., Resnick. P. R. Cembrene, A 14-mem- bered ring diterpene hydrocarbon. J Amer Chem Sot 84: 2015-6, 1962. 10. Falk, H. L.. Tremer, H. M., Kotin, P. Effect of cigarette smoke and its constituents on ciliated mucus-secreting epithelium. J Nat Cancer Inst 23: 999-1012, 1959. 11. Fieser, L. F., Fieser, M. Topics in organic chemistry. New York, Reinhold, 1963, p. 43-56. 12. Fieser, L. F., Greene, T. W., Bischoff, F., Lopez, G., Rupp, J. J. [Com- munication to the editor] A carcinogenic oxidation product of choles- terol. J Amer Chem Sot 77: 3928-9, 1955. 13. Grossman, J. D.. Deszyck, E. J., Ikeda, R. M., Bavley, A. A study of pyrolysis of solanesol. Chem Industr 1950-1962. la. Guthrie, F. E., McCants, C. B., Small, H. G., Jr, Arsenic content of commercial tobacco, 1917-1958. Tobacco Sci 3: 624, 1959. 15. Hadler, H. I., Darchun, V., Lee, K. Initiation and promotion activity of certain polynuclear hydrocarbons. J Nat Cancer Inst 23: 1383-7, 1959. 16. Hartwell, J. L. S urvey of compounds which have been tested for car- cinogenic activity, Federal Security .4gency, Public Health Service Pub No. 149, 1951. 583 p, 17. Hilding, A. C. On cigarette smoking, bronchial carcinoma and ciliary action. 3. Accumulation of cigarette tar upon artificially produced 714-422 O-64-6 63 deciliated islands in the respiratory epithelium. Ann Othol 65: 116 30, 1956. 18. Hilding. A. C. On cigarette smoking. bronchial carcinoma and ciliary action. 2. Experimental study on the filtering action of cow's lungs, the deposition of tar in the bronchial tree and removal by ciliary action, New Eng J Med 251: 1155-60, 1956. 19. Holsti. P. Tumor promoting effects of some long chain fatty acids in experimental skin carcinogenesis in the mouse. Acta Path Microbial Stand -16: 51-8, 1959. 20. Homburger, F., Tregier, A. Modifying factors in carcinopenesis. Progr Exp Tumor Res 1: 31 l-28, 1960. 21. Hurd, C. D., Macon, A. R. Pyrolytic formation of arenes. 4. Pyrolysis of benzene, toluene and radioactive toluene. J -\mer Chem Sot 84: 4524-6, 1962. 22. Hurd, C. D., Macon, A. R., Simon. J. I.. Levetan, R. V. Pyrolytic forma- tion of arenes. 1. Survey of general principles and findings. J Amer Chem Sot 84: 4509-15, 1962. 23. Hurd, C. D., Simon, J. I. Pyrolytic formation of arenes. 3. Pyrolysis of pyridine: picolines and methylpyrazine. J Amer Chem Sot 84: 4519-24, 1962. 24. Johnstone, R. A. W., Plimmer, J. R. The chemical constituents of to- bacco and tobacco smoke. Chcm Rev 59: 885-936, 1959. 25. Keith, C. H.: Newsome, J. R. Quantitative studies on cigarette smoke. 1. An automatic smoking machine. Tobacco 144: (13) 26-32. May 29, 1957. 26. Keith, C. H., Newsome, J. R. Quantitative studies on cigarette smoke, 2. The effect of physical variables on the weight of smoke. Tobacco 144 (14) : 26-31, Apr 5, 1957. 27. Kennaway, E., Lindsey, A. J. Some possible exogenous factors in the causation of lung cancer. Brit hIed Bull 14: 124-31, 1958. 28. Kensler, C. J., Battista, S. P. Components of cigarette smoke with ciliary- depressant activity. New Eng J Med 269: 1161-1166, 1963. 29. Kosak, A. I., Swinehart. J. S., Taber. D., Van Duuren, B. L. Stig- master01 in cigarette smoke. Science 125: 991-2, 1957. 30. Langer, G.. Fisher, N. A. Concentration and particle size of cigarette- smoke particles. AM&\ Arch Industr Health 13: 372-8: 1956. 31. Liggett & Myers Tobacco Co. Arthur D. Little, Inc. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 32. Lindsey, A. J. Some observations upon the chemistry of tobacco smoke. In: James, G., Rosenthal. T.. eds. Tobacco and health. Springfield, Ill.. Thomas, 1962. Chapter 2: p. 21-32. 33. Orris, L., Van Duuren, B. L.. Kosak. A. I.. Nelson. N.: Schmitt, F. L. The carcinogenicity~ for mouse skin and the aromatic hydrocarbon content of cigarette-smoke condensates. J Nat Cancer Inst 21: 557-61, 1958. 34. Osborne, J. S., Adamek, S.. Hobbs: M. E. Some components of gas phase of cigaret smoke. Anal Chem 28: 211-5, 1956. 64. 35. Philippe, R. J.. Hobbs, M. E. Some components of the gas phase of cigaret smoke. Anal Chem 2::: 2002-6. 1936. 36. Roberts. D. L.. Rowland, R. I,. >Iacrccyclic diterpenes a and B-4, 8, 13.Duvatriene -I.:<-dials from tobacco. J Org Chem 27: 396%95, 1962. 37. Ro\$land, R. L.. Rodgman. A.. Schumacher. J. 5.. Roberts. D. L., Cook, L. 0.. Walker. W. E. 1063 I In press). ;$". * Less than 1 pack. 3 m-34. ' 35 plus. 3 More than 1 pack. 0 About 1 pack. 7 More than 1 pack. TABLE 4.-Mortality ratios for current smokers of cigars only, by amount smoked Number per day For current pipe smokers (Table 5), men smoking less than 10 pipefuls per day have death rates very close to those of non-smokers. For heavy pipe smokers (10 or more per day) two studies show increases of 15 and 12 per- cent in death rates, hut the other two studies show little or no increase. The over-all mortality ratio of 1.05 does not differ statistically from unity. The *Statistical significance throughout this report refers to the 5 percent level un- less otherwise specified. In testing whether an observed mortality ratio of smokers relative to non-smokers is greater than unity, the probability is calculated that a ratio as large as or larger than the observed ratio would occur by chance if the smokers and non-smokers were drawn from two populations having the same death rate. If this proba- bility is less than 0.05 (5 percent) the observed increase in the death rate of smokers relative to non-smokers is said to be statistically significant at the 5 percent level. The results of significance tests will be quoted only for mortality ratios in which the number of deaths r&es a doubt as to whether the difference from unity could be due to sampling errors. 86 British doctors study gives a mortality ratio of 0.91 for cigar and pipe smokers together (presumably mostly pipe smokers) who consume more than 14 gms. of tobacco daily. TABLE L-Mortality ratios for current smokers of pipes only, by amount smoked Study -__- Owr-all Pipes per day ratio %tFs g U.S. Canadian Men in 25 veterans veterans states ______ _______ __-- l-9....---- __....___ --.___--- ___...__. --.._ 1.00 1.03 1.07 0.92 1.01 1001 mOIe.---.....-......------....-..---. 1.15 1.12 1.01 0. i6 1.05 MORTALITY RATIOS AT DIFFERENT AGES As indicated previously, the mortality ratios presented in previous tables for different groups of smokers represent a kind of average over the age- distribution of the smokers concerned, and do not necessarily apply to smokers of any specific age. For cigarette smokers, the studies show that the mortality ratio declines with increasing age, being higher for men aged 40-50 than for men over 70. This effect is illustrated in Table 6 from the study of men in 25 states, which gives the mortality ratio computed separately for five age classes. The drop in mortality ratio with each increase in age appears fairly con- sistently for every amount of smoking. For smokers of cigarettes only as a whole, the death rate is more than double that for non-smokers in the age range 40-49, but only about 20 percent higher for men over 80. The pic- ture is, of course, different if we look at the absolute excess in death rates at different ages. Owing to the marked increase in death rates with age, the absolute excess also increases steadily with increasing age. A more thorough investigation of the relation between death rates and age for different groups of smokers has been made by Ipsen and Pfaelzer (14). If th e o arl 1 g `th m of the age-specific death rate is plotted against age, the resulting points lie reasonably close to a straight line. For the U.S. TABLE &-Mortality ratios by age group for current smokers of cigarettes only, men in 25 States Number of cigarettes per day Age at start of study 4Cb49 50-59 es369 70-79 ss89 - ___~ `~..--~......~~-.-~....-~.-.~...~..~~~.... $-$Q~~:~~ `~lQ.-....~~~~~.--_~....~.-~~~~~~~-~~-.~~~ -___ _ .._.. . . . . . . . . . . ..--....---. 2. 27 1.44 1.40 1. 40 1.08 2.22 3.06 2.12 2.05 1. 2.37 94 1.78 1.60 1.63 1. 1.48 1.28 50 0. 1.65 1. 53 16 ______ ________ m amOUnts~----...-..--....---.-.--..-.-- 2.33 2.06 1.70 1.47 1. 22 87 veterans study, Figure 1 shows the points and fitted lines for non-smokers and for current smokers of cigarettes only. (The lines were fitted by the standard method of least squares, weighting each point by the number of deaths involved.) If the lines for cigarette smokers and non-smokers were parallel, this would imply that the mortality ratio of the smokers to the non-smokers was constant at all ages, because the vertical distance between the two lines at any age is the log of the mortality ratio for that age. In Figure 1, however, DEATH RATE (logarithmic scale) PLOTTED AGAINST AGE, PROSPECTIVE STUDY OF MORTALITY IN U.S. VETERANS AGE IN YEARS FIGURE 1. 88 the slope is slightly less steep for the cigarette smokers than for the non- smokers. This indicates that the mortality ratio is declining with increased age- Table 7 shows these slopes (increase in the natural logarithm of the death rate for each 5-year increase in age) computed from six of the studies. The salient features are as follows: (1) In each study the slope for cigarette smokers is smaller than the slope for non-smokers; (2) Within the cigarette smokers the slope tends to decline, with some inconsistencies, as the amounts smoked become greater; (3) for cigar or pipe smokers the slopes are closer to those for non-smokers. TABLE 7.-Increase in natural logarithm of death rate per 1,000 man-years for each S-year increase in age, 6 prospective studies Type of smoking British Men in 9 U.S. California California Men in 25 doctors states veterans occups- tional 1 Le@on 1 ~ States 2 _______~_____ -___ Non-smokers _. _ _ ..-.. ,593 ,474 ,499 ,469 502 ,490 Ciaarcttes by amount per day. ,492 42i ,448 ,436 : 476 ' .438 I- ______ l-9 ._...__.--...._..___-..-. 516 : 551 ::: 490 ' 1454 : ii: 567 10-m. __..... ~.. .._........_. : 471 ,445 21-39x . . . . ..~..-..___-.....-. 477 40+ -......-......._..-_~...~~ :401 :E . . . . . . ..`"i. ....e--:"";- -...:"`" :t: ,401 _______ rigors..............-.....-... Pipes _.__..._.__.._ _ __....._ __ } .m { :E 463 .._._...._.. .-..__._.... 1458 ..___.._.... _-..__...... ,457 ,458 I "Cigarettes" includes "cigarettes and other" and current and m-smokers ' First 10 months' experience. AGE AT WHICH SMOKING WAS STARTED The study of U.S. veterans and the study of men in 25 states provide data on the death rates of current smokers of cigarettes only, classified by the age at which the person started to smoke. Since in both studies the men who start to smoke early tend to smoke greater amounts per day than men who start later in life, the mortality ratios to non-smokers are presented separately for different amounts of smoking (Table 8). TABLE EL-Mortality ratios by age at which smoking was started and by amount smoked for current smokers of cigarettes only Age started to smoke Number of cigarettes per day Over-all ratio 1-B 10-20 21-39 a+ U.S. veterans: Under 20.-e- ____.____ _____ .._____._ -- *24..- ..__.. 2.Sor -__- . . ..__ _..._.__ _..._ Men in over.. __..___..._.___...._---.... 25 States: Under 15 _._..._ -- . . . . . ..__..______.._. E-19 -_...___ -- __......_ _.._______ ____ 20-24~..~.~~. ~orover __._ .._____..____ _.___ -- -- . ..___ _..___._. _____--_______ 1.60 1.89 2. 16 2. 45 1.96 1.40 1. 72 1. 87 2. 23 1. 72 1. 15 1.50 1.47 1. 11 1.39 1.79 `2.23 ' 2.21 2. 15 2.17 1.75 ' 1.83 ' 2.01 2. 38 1.99 1.25 Il.52 2 1.62 1.93 1. 59 1.03 ' 1.36 2 1.45 1. 56 1.34 ' 19-19 cigarettes per day. ' WV cigarettes per day. 89 For a fixed amount of smoking, the mortality ratios (with one exception) exhibit a consistent and rather striking increase as the age at which smoking was started decreases. Th' 1s increase appears in all smoking groups of Table 8. For men who started smoking cigarettes under the age of 20, the over-all death rate was about twice that for non-smokers, whereas for those who did not start until they were over 25 the death rate was only about 35 percent higher. MORTALITY RATIOS BY DURATION OF SMOKING Three studies have some data available on the number of years during which the subjects had smoked. Th e comparison of mortality ratios for different lengths of time smoked is of interest in relation to two questions raised by Dorn (6) in an earlier analysis of the U.S. veterans' data. Is there a minimum period of use during which no effect on the death rate is notice. able? Is there a maximum period after which no increase in the relative death rate is perceptible? For current cigarette smokers the results (Table 9) are not clear-cut. In the U.S. veterans study, men smoking for less than 15 years had death rates about the same as non-smokers. There is a rise of about 50 percent in the mortality ratio for those who had smoked 15-35 years, with a further rise for those smoking longer than 35 years. The study of men in nine states shows a rise from under 25 years to 25-34 years duration, but no further rise thereafter. In the Canadian study the mortality ratio with cigarette smokers is just as high for durations less than 15 years as for durations of 15-29 years, though there is a rise (to 1.73) for smokers of cigarettes only who have been smoking more than 30 years. TABLE 9.-Mortality ratios for current smokers by type of smoking and by length of time smoked Number of years smoked Typr of smoking U.S. veterans Canadian veterans Men in 9 States <15 1 15-24 2534 35f <15 / 15-29 so+ -<25 2&34 35+ -j-~~-~~~--.--- Cignrettes only __ 0.92 I 1.52 1.50 1.88 1.52 j 1.41 1. 73 1.46 1. 74 l.iS Cigarettes and other .._._...... 1.07 1.41 1. 33 1. 49 1. 24 1.27 1.22 ____... _.__.___ _-.-.... Cigars only O.Y2 I 0.94 0. 95 1. 12 1.06 0.81 1.31 ______. _-__.___ _-...... Pipes only. ._... ~~. 1.01 1.34 0. 97 1.07 1.36 0.93 1.09 ___.__.. ______. - _-...... Thus, all three studies show some increase in the mortality ratios with longer duration of smoking, but the pattern is irregular. In a further break. down of the data by amount smoked, Hammond and Horn (10) found no trend with duration for men smoking more than a pack a day, but the other two studies show an upward trend for this group of smokers. For cigar smokers the only groups showing an increase in death rates over non-smokers are those smoking for the longest period (Table 9). The in- creases of 12 percent for the 35 years or over group in the U.S. study and of 90 31 percent for the 30 years or over group in the Canadian study are both statistically significant. For pipe smokers no trend with duration of smoking is discernible. The two figures which stand out (1.34 in the U.S. study and 1.36 in the Canadian study) are both based on relatively small numbers of deaths. INHALATION 0F SMOKE In two of the studies the subjects were questioned as to whether they inhaled. In the study of men in 25 states each subject was asked to place himself in one of the four classes: do not inhale, inhale slightly, inhale moderately, inhale deeply. In the Canadian veterans study the subject simply classified himself as an inhaler or non-inhaler. For current smokers of cigarettes only in the U.S. study, 6 percent of the subjects stated that they did not inhale, 14 percent inhaled slightly, 56 percent moderately and 24 percent deeply. In the Canadian study 11 percent classified themselves as non-inhalers. Since inhalation practices may vary with the amount smoked, the results for cigarette smokers (Table 10) are given separately for different amounts. For the men in 25 states an increase in the degree of inhaling for a fixed amount of smoking is in general accompanied by an increase in the mortality ratio. The relation of inhalation to mortality appears quite marked: for instance, non-inhalers who smoke 20-39 cigarettes daily have mortality ratios no higher than moderate or deep inhalers who smoke l-9 cigarettes daily. With the very heavy smokers (LM)+ ) the figures in Table 10 suggest that the mortality ratio may remain the same for non-, slight, and moderate inhalers. The ratios of 2.05 (non-) and 1.97 (slight) are, however, based on only 26 and 41 deaths, respectively. TABLE lO.-Mortality ratios for smokers of cigarettes only by inhalation status and amount of smoking Cigarettes per day Degree of inhalation Overcall ratio 1-9 l&l9 !2G39 JO+ ~-___~ 1.29 1.46 1. 56 2. 05 1.49 1.2Q 1.68 1.34 1. 97 1.6s 1.84 2.01 1.87 1.61 1.82 1. 88 1. 76 2. 18 2. 50 2. m 1.05 1.35 2 `1.50 1.11 31.03 . . ..__ . . . . . 1.08 ~1.71 . ..-------.- 1. 52 ' &Omts are lifetime maximum amounts smoked. ' *D-20 cigarettes per day. ' over 20 ci garettes per day. Looking along the rows of the U.S. veterans study it will be seen that for each degree of inhalation the mortality ratio increases with the amount *moked. Ipsen and Pfaelzer (14) have shown that the logarithms of the 16 death rates at age 61 (app roximately the average age) can be adequately rep- 91 resented as an additive function of the amount of smoking and the degree of inhalation (although other types of mathematical relationship would also fit the data). In their analysis, the average change in logarithm of death rate from "no inhalation" to "deep inhalation" is as great as the difference be. tween consumption of less than 10 cigarettes and consumption of more than 40 cigarettes daily. In the Canadian data the inhalers have higher mortality ratios than the non-inhalers for each amount of smoking. No trend with amount of smok. ing appears for the non-inhalers, but the ratios in this row are based on rather small numbers of deaths. For cigar smokers (current and ex-smokers) in the 25-state study 19 per. cent stated that they inhaled to some extent. The mortality ratio is 0.89 for non-inhalers and 1.37 for inhalers. The latter increase of 37 percent (based on 91 deaths) is statistically significant, but as the data have not been sub classified by amount of smoking the result may be partially a reflection of the increase in death rates noted in Table 4 for heavy cigar smokers. In the Canadian study, 13 percent of the cigar smokers classified themselves as in- halers, but the number of deaths is insufficient to present a breakdown of the mortality ratio by inhalation status. Among the pipe smokers there were 28 percent who inhaled in the U.S. study and 18 percent in the Canadian study. The U.S. mortality ratios are 0.8 for non-inhalers and 1.0 for inhalers; the Canadian data contain too few deaths to allow a breakdown by inhalation. Ex-CIGARETTE SMOKERS For men who had stopped smoking prior to the date of enrollment, Table 11 gives the mortality ratios from five studies for "cigarette only" smokers and "cigarette and other" smokers. The corresponding results for current cigarette smokers (from Table 2) are given for comparison. The distinc- tion between current and ex-smokers is not of course clear cut, since some current smokers may have stopped after enrolling in the study and some ex. smokers may have later resumed smoking. With one exception, the mortality ratios for ex-smokers lie consistently be- low those for current smokers and above those for non-smokers. In inter- preting comparisons of ex-smokers and current smokers there are at least three relevant factors. If smoking is injurious to health, cessation of smok, ing would be expected to reduce the mortality ratio. Secondly, some men stop smoking because of illness. In the 25-State study, over 60 percent of the men who had stopped smoking within a year prior to entry stated that a disease or physical complaint was one of the reasons for stopping (12). This factor would tend to make mortality ratios for ex-smokers higher than those for current smokers. F' ma 11 y, ex-smokers may have previously smoked smaller amounts than current smokers. This factor is not the explanation of the drops in mortality ratios in Table 11. In a further breakdown by amount of smoking, made for the three largest studies, the mortality ratio for ex-smokers is consistently below that for current smokers for each amount smoked. 92 TABLE Il.-Mortality ratios for ex-smokers and current smokers of cigarettes British Men in 9 U.S. Canadian Men in 25 doctors states veterans veterans states Ex-cigarettes.......---.-.................. 1.04 / Current cigarettes _.... _________.......... 1.44 / Ex-Cigarettes and other .._............._... Current cigarettes and others- .._.......... TABLE 12.-Mortality ratios jar ex-smokers of cigarettes orzly by number of years since smoking was stopped and by amount smoked Study Number of years stopped Current ____- / l-l / 1-9 j 5-9 I 10+ smokers <1 1 These dtrta are from Hammond and Horn, 1958. TABLE 13.-Mortality ratios for ex-cigarette smokers by number of years of smoking, U.S. veterans study Cigarettes per day Number of years of smoking Cl5 I lb24 Age at which smoking was stopped <45 4554 55+ ______ l-20 -_...__.__. _.________________________________ ___._ 1.09 1.24 1.51 . . ..__._._.- zO+ .-..__. ._._________________------------.---- . . . .._ 1. 12 1.59 1.86 . . ..__._.... Some supplementary analyses throw a little further light on this topic. In the two American Cancer Society studies (Table 12) a breakdown is given by the number of years since smoking was stopped. Except for the smokers of under one pack a day in the 25-State study, the mortality ratio for men who had stopped less than a year is higher than that for current smokers. Thereafter the ratio drops steadily as the interval since smoking was stopped increases. In the U.S. veterans study, further breakdowns are available by the numbers of years during which the ex-smokers were smoking and by the age at which smoking was stopped (Table 13)) as well as by the amount of smoking. The mortality ratios are about the same for those smoking less than 15 years as for those smoking 15-24 years. Thereafter the ratios rise with longer durations of smoking. Table 13 also shows that mortality ratios were higher for those who stopped smoking at later ages. 93 Ex-CIGAR AND PIPE SMOKERS Mortality ratios for smokers of cigars only and pipes only who had stopped smoking prior to the date of entry are given in Table 14, the ,.or. responding ratios for current smokers being included for comparison. For ex-cigar smokers the mortality ratios are higher than those for non. smokers and higher than those for current smokers in all four studies pr,, sented. The same is true for ex-pipe smokers with the exception of the Canadian study. The interpretation of this result is not clear to US. According to Ham. mond and Horn (10) and Dorn (6)) the explanation may be that a sub. s.tantiaI number of cigar and pipe smokers give up because they become ill: some data from cigarette smokers that support this explanation have re cently been analyzed by Hammond (12). Further analysis of the B.S. veterans data indicates that mortality ratios run highest in ex-smokers who smoked heavily and for a long time. TABLE 14.-Mortality ratios GOT ex-smokers of cigars only and pipes only and for current cigar and pipe smokers Type of smoker British doctors Ex-cigar....~...............~~~..~~~~~~.~ .- . .._....___. Current cigar ....... .._...___.___---- .... ._._ ........ Ex-pipe..........-.-...--...-...- ...... ..- ' 1.12 Current pipe.........---- .............. ..- ' 0.95 _________ 1.05 1.30 1. 17 1. 10 1.07 1. 11 1.24 0.91 ~~~~% 1.29 1.38 1.01 1.23 1.05 1.06 1. 10 0. .!a 1 Pipe and cigar combined. EVALUATION OF SOURCES OF DATA THE STUDY POPULATIONS Various reasons dictated the particular choices made of the seven study populations, considerations of feasibility playing an important role. None of the populations was designed, in particular, to be representative of the U.S. male population. ,!ny answer to the question "to what general popula- tions of men can the results be applied?", must involve an element of un- verifiable judgment. However, three of the studies have populations with widespread geographic distribution within the United States, as do the British and Canadian studies within their respective countries. Taken as a whole, the seven populations offer a substantial breadth of sampling of the type of men and environmental exposures to be found in North America and Britain, as well as providing some variation in methodological approach, although the basic plan was similar in all studies. The seven studies differ considerably in size. They vary also in the extent to which they are free from methodological weakness. The studies of men in nine states and men in 25 States, for instance, suffer from the difficulties 94 that the populations studied are hard to define, that the smokers and non- smokers were recruited by a large number of volunteer workers, and that completeness in the reporting of deaths was hard to achieve, since this de- pends on reports from the volunteers. On the other band these studies have the advantage of being large and of having a broad geographic representa- tion of the U.S. male population, while the second study is the only one that attempts to investigate many other relevant variables in which smokers and non-smokers may differ. In the California occupational study the focus of interest is occupational differences in lung cancer mortality, smoking history being recorded primarily in order to be able to adjust comparisons among different occupational groups for differences in amount smoked. In the analysis we have not attempted to rate the studies as to over-all quality or to assign differential weights to their results, except that in the smaller studies it is recognized that mortality ratios are subject to larger sampling errors. Our attitude is to attach importance only to results that appear to be generally confirmed by the studies. Some idea of the relative death rates in these studies as compared with the 1960 white male population of the United States is given in Table 15, which shows the age-adjusted death rates for ages 35 and over, using the age dis- tribution of the U.S. white male population as a standard. (The choice of 1960 for the comparison is arbitrary, but the white male rate changed little between 1955 and 1960.) In all studies the death rates for non-smokers are markedly below those of U.S. white males in 1960. Even the smokers of one pack of cigarettes or more daily have death rates that average slightly below the U.S. white male figure. To some extent this is to be expected, since hospitalized and other seriously ill persons are not recruited in such studies. The sizes of the differ- ences appear, however, surprising for the studies with United States popula- tions. Hammond and Horn (lo), in a special investigation on this ques- tion, concluded that the discrepancy in their study was due to the screening out of sick persons in recruiting plus probably a selection towards men of higher economic levels. Th ey point out that their death rates are substantially above those for males who had held ordinary life insurance policies for from TABLE 15.-Age-adjusted death rates per 1,000 man-years for current smokers of cigarettes only (aged 35 and over), by amount smoked, in seven studies and for U.S. white males Study Current smokers of cigarettes only U.S. white males, 1960 Less than 1 pack 1 pack or more 19. 2 23.2 22.9 `22.4 ' 27.1 ' 22.6 18. 1 23 9 22.9 ' 14.2 ' 18.0 1 22. A 16.4 16. 3 22.9 22.1 24.2 22.9 1 18.5 2 19.2 22.9 ' These 6qures may be too low by about 1.7 percent, since the person-years included so& contribution by men who had not been fully traced. used in the computation 714-422 o-64--8 95 5 to 15 years. The U.S. veterans' study population also came mainly from the middle and upper socioeconomic classes (6). Another reason might be a failure to trace all deaths. In mass studies it is almost impossible to devise infallible provisions for recording every death. The study directors were, however, experienced in handling this problem and it seems unlikely that more than, say, 5 percent of the deaths would be missed. (Moreover, in the studies of veterans it is to the family's advantage to report the death.) Another contribution probably came from the failure to obtain data for some members of the population. Evidence on this point is available from the British doctors and the U.S. veterans' studies, in which death rates for the complete population (respondents and non-respondents) are available. In these studies the death rate for the whole population exceeded that in the respondents, but by only 5 percent to 10 percent, so that non-response appears unlikely to be a major cause of the discrepancy. So far as interpretation of results is concerned, the discrepancy raises two points. It is clear that the seven prospective studies involve popula- tions which are healthier than U.S. males as a whole. Secondly, the low death rates for non-smokers suggest the possibility that the studies recruited unusually healthy groups of non-smokers. In the case of the five studies which had clearly defined populations, this selection would arise only if the non-smokers who refused to enter the study had death rates much higher than those who were enrolled. This point is discussed in the next section. NON-RESPONSE BIAS In all five studies that had a clearly defined target population, sizeable pro. portions of the population were omitted. The major reason was failure to answer the questionnaire; in addition, certain replies were rejected as too incomplete. The percentages of the populations for which usable replies were obtained were approximately as shown in Table 16. TABLE 16.-Percentages of usable replies in five studies British doctors U.S. veterans California CMiali;ia Canadian occupa- veterans tional 68 68, 85 85 56 57 In the U.S. veterans study, 68 percent replies were obtained from the 19% questionnaire. A second questionnaire, sent in 1957, enrolled an addi- tional 17 percent, for whom data are available during the period 1957-60. In the two American Cancer Society studies it is not possible to present meaningful percentages, since each research volunteer selected her own small part of the study population from among her acquaintances. The possible effects of these amounts of non-response on the mortality ratios have received little discussion. Some pieces of information about % non-respondents are available in two studies. From a recent sample, Doll (4) states that (a) the death rate of non-respondents in the British doctors study is higher than that of respondents; (b) consequently the death rate for respondents is lower than that of British doctors as a whole, perhaps by as much as 5 percent to 10 percent; (c) there are relatively more smokers among the non-respondents than among the respondents. In the U.S. vet- erans' study, the death rate for the whole study population exceeded that for the original 68 percent responders by 7 percent in 1958 and 5 percent in 1959. From this study one can also calculate mortality ratios separately, during 1957-60, for the 1954 respondents and the 1957 respondents. The results for smokers of cigarettes are as follows : 1954 I957 NOll- respondents respondents respondents (68 percent) (17 percent) (1.5 percent) Current cigarettes only------------- 1.87 1.71 ? Current cigarettes and other-------- 1.56 1.33 ? Those who did not respond in 1954 but did respond in 1957 show lower mortality ratios than the original set of men giving usable replies. By making guesses about the mortality ratios in the 15 percent of non-responders, one can compare the resulting mortality ratio in the whole population with that found in the original 68 percent. To consider how much of an over- estimate the ratios of 1.87 and 1.56 might be, we might suppose, to illustrate the method, that the mortality ratio is unity for the non-respondents. The mortality ratio for the whole population then turns out to be 1.71 for cig- arettes only and 1.44 for cigarettes and other. Thus, with a non-response rate of 30 percent, the computed mortality ratio might overestimate by 0.1 or 0.2. Berkson (1) produced a set of assumptions under which, with a mortality ratio of 1 in the whole population and a response rate of 71 percent, the mortality ratio in the respondents is found to be 1.5. Non-respondents are assumed to be of two types. One group, destined to have a high death rate, refuses because they don't feel well. This group has a high refusal rate (50 percent) for both smokers and non-smokers, since the reason for refusal is illness and not smoking. In the remainder of the non-respondents, the refusal rate is higher among smokers than non-smokers. Qualitatively, these assumptions are not unreasonable and agree in direction with the results quoted previously for the British doctors and U.S. veterans' studies. Korteweg (15) worked further examples of Berkson's model as applied to individual causes of death in the first report of the study of men in nine states. He concluded that the response bias in the mortality ratio might be as high as 0.3. Both Berkson and Korteweg, had, of course, to make some arbitrary assumptions about the sizes of biases from different sources. Further discussion of the non-response bias and computations as to its magnitude are given in Appendix I. The computations indicate that re- ported mortality ratios lying between 1 and 2 might overestimate by as much as 0.3, a mortality ratio of 5.0 might overestimate by 1.0, and one of 10.0 might overestimate by 3.0. Thus, under assumptions that are rather extreme, although consistent with the available data about non-respondents, 97 the mortality ratios of cigarette smokers would still remain substantial+ higher than unity after adjustments for these amounts of over-estimation. MEASUREMENT OF SMOKING HISTORY Measurement of the type and amount of smoking, being based on a single mail questionnaire, was admittedly crude. Consider men recorded as cur- rent smokers of cigarettes only. Subsequent to enrollment, some of these presumably stopped smoking, at least temporarily, and some took up other forms, with or without cigarettes. Similarly, some men recorded as non-smokers may have begun to smoke cigarettes subsequently. Consequently, the group designated as "current smokers of cigarettes only" presumably contained men who were, for some period of time "ex-smokers" or "cigarette and other" ,aokers, while men designated as "non-smokers" contained some who smoked cigarettes for a time. It seems likely that this dilution of the contrast between the two groups would make the mortality ratio of cigarette smokers, as reported in previous tables, underestimate the mortality ratio of unchanging cigarette smokers relative to unchanging non-smokers, particularly when we note that the groups labeled "ex-smokers of cigarettes" and "cigarette and other" smokers both had mortality ratios lower than the group labeled "current smokers of cigarettes only". As regards number of cigarettes per day, two types of errors of measure. ment may occur. There will be "random" errors of measurement (some men overestimate the amount and others underestimate it) that tend to cancel out over all men in the study. The effect of such errors is that the reported data underestimate the increase in the mortality ratio per additional cigarette smoked daily, the computed increase being an estimate of B/ (1 + h) , where B is the true increase and h is the ratio of the variance due to errors of measurement in the amount smoked to its total variance, Yates (17). There may also, however, be systematic errors in reporting the amount smoked. Heavy smokers may tend to underestimate the amount smoked. If this happens, the reported increase in mortality ratio per additional cigarette smoked will be an overestimate of the true increase, although the upward trend of mortality ratio with increasing amount smoked will remain. On balance, we are inclined to agree with the opinion expressed by the authors of several of the studies to the effect that the general result of errors in reporting smoking history is to depress the mortality ratios of smokers relative to non-smokers, so that reported ratios will tend to be underestimates so far as this source of error is concerned. STABILITY OF THE MORTALITY RATIO The sampling distribution of the mortality ratio has not to our knowledge been at all thoroughly investigated and appears to be complicated. As a rough approximation (Appendix II), the ratio of smoker deaths to smoker 98 plus non-smoker deaths may be regarded as a binomial proportion with mean AR/ ( 1 + AR) where R is the true mortality ratio, A is the ratio of the expected smoker deaths to the observed non-smoker deaths and the sample size is the number of smoker plus non-smoker deaths. From this approxima- tion, confidence limits for R may be derived. This approximation requires that (1) the age distributions of smokers and non-smokers do not differ greatly and (2) all age-specific death rates are small. An alternative normal approximation that avoids assumption (1) is also given in Appendix II. The sampling variation of the estimate of R is seldom of major import in this part of the report, since the ratios for total mortality are mostly based on relatively large numbers of deaths. The estimate has a positive mathe- matical bias, negligible with large but not with small numbers of deaths. In another sense the particular mortality ratio used in this report has a different kind of bias. Since the standard age-distribution used in this ratio is the age-distribution of the smokers, who are somewhat younger than the non-smokers, the mortality ratios apply to populations slightly younger than the combined population of the study. This is not in our opinion a seri- ous objection, but may sometimes be relevant in questions of interpretation. OTHER VARIABLES RELATED TO DEATH RATES As mentioned previously, the smokers and non-smokers in these studies may differ with respect to other variables that might influence the death rate. Except in the new 25State study, no attempt was made to measure these variables apart from urban-rural residence, and previous reports on these studies give little discussion of this problem. For urban-rural residence, Doll and Hill (5) found that the proportions of smokers of different amounts in the study population were about the same in rural areas, small cities and large cities. In th ree studies the mortality ratios of cigarette smokers were computed separately by size of city (6, 10, 11). In the study of men in 25 States, the data refer to men who smoked 20 or more cigarettes a day and said that they inhaled moderately or deeply. In all three studies the mortality ratios show little change with size of community (Table 17). In the 25State study, over 20 other variables that may be associated with death rates were recorded. The study population was broken down into subgroups for many of these variables separately: for instance, into smokers who have long-lived parents and grandparents and those whose parents and TABLE 17.-Mortality ratios for cigarette smokers by population-size of city Population-size Study &h'& i I$X& / ;$; 1 Rural ' hcludes towns of less than 10,ooO. grandparents were short-lived. Included among these variables were reh. gion, educational level, native or foreign birth, residence by size of town and occupational exposure, use of alcohol, use of fried food, amount of nervous tension, use of tranquilizers, and presence or absence of prior serious disease. For cigarette smokers who smoked more than a pack a day and inhaled moderately or deeply, the mortality ratio was computed within each subgroup. For example, the mortality ratio was 1.99 for men with long-lived parents and 2.30 for men with short-lived parents. In every subgroup the mortality ratio was well above unity, the lowest among 71 computed ratios being 1.57 (for men with a history of previous serious disease). These data provide information on the association of the other variables with mortality as well as on the association of smoking with mortality. For six of the most relevant variables, Table 18 gives age-adjusted death rates, using the combined populations of non-smokers and cigarette smokers ag the standard population. The death rates apply to a period of roughly 22-months follow-up. As already mentioned, the cigarette smokers (of more than a pack per day who inhaled moderately or deeply) have higher death rates than the non-smokers in every cell of Table 18. Since not all respondents answered these supplementary questions, the results may be subject to some additional non-response bias. As would be expected, death rates are relatively high for men with previ- ous serious disease and for men from short-lived families, and are sometihat TABLE I&-Age-adjusted death rates per 1,000 men (over approximately 22 months) for variables that may be related to mortality Long-lived Short-lived No pr+~us PIemus Type of smoking parents and parents and ?teornu; serious grandparents grandparents disease _____- None __._........_~.~...................~. 14.8 21. 1 11.5 42. 8 Cigarettes 1~ . . ..~-....................--.. 27.1 44.8 22.3 05.0 ___- Single Married Use tram Do not use quilizers tranquilizers -___ 18.9 29.1 182 33.0 52. 4 31.8 Educational level I / I Degree of exercise * NCIIR Slight Moderate HIBVY -~_- _-- Sone...........~..........~.~..~~~........ 23.8 14. 7 11.0 9.5 Cigarettes ~~~.-~..~............~---~-.....- 34. 1 25.5 20.8 19. i 1 Smokers of more than a pack per day who inhaled moderately or deeply. 2 Confined to men with no history of heart disease, stroke, high blood pressure or cancer (except skin) who were not sick at the time of entry. 100 higher for single than for married men. The size of the excess death rate for users of tranquilizers compared to men who do not use them is perhaps surprising 129.1 against 18.2 and 52.4 against 31.8). However, the tran- quilizers in question required a doctor's prescription, so that some men in this group are presumably under medical attention for illna. The group of users is small, comprising only about 10 percent of those who answered this question. Death rates tend to decrease slightly as the educational level increases; this association may represent some facet of the association of death rates with socio-economic level. Degree of exercise displays an inter- esting association with mortality, the death rate declining steadily with additional degrees of exercise. In particular, the two "no exercise" groups show marked elevations in death rates. These groups, however, amount to only 2 percent of the respondents to this question. From the same data, Ipsen and Pfaelzer (14) made a further analysis of seven variables that appeared to be related to mortality? in order to see whether any of the variables had a stronger association with mortality than did cigarette smoking. They concluded that apart from previous serious disease, none of the other variables examined had as high a correlation with mortality as smoking of cigarettes. Further, the correlation of any of these other variables with cigarette smoking was too weak to reduce markedly the correlation of cigarette smoking with mortality after adjustment for the other variable. In the analyses above, smoking was matched against each variable sep- arately. In addition, Hammond (11) carried out a "matched pair" analysis, in which pairs of cigarette smokers and non-smokers were matched on height, education, religion, drinking habits, urban-rural residence and occupational exposure. The percentage who had died in the 22 months was 1.64 for smokers and 0.88 for nonsmokers. These informative analyses are available, unfortunately, for only one of the studies. However, in order that the association of cigarette smoking with mortality should disappear when we adjust for another variable, the correlations of this variable with smoking and with the death rate must both be higher than the correlation between smoking and the death rate. Except for the breakdowns by longevity of parents and grandparents, the analyses throw little light, however, on the objection that a part of the differences in death rates may be constitutional, psychological or behavioral; i.e., that regular cigarette smokers are the kind of men who would have higher death rates even if they did not smoke. Further discussion of this Point appears in the next section. MORTALITY BY CAUSE OF DEATH In all seven studies the underlying cause of death, as specified in the Inter- national Statistical Classification of Diseases, Injuries and Causes of Death, Was abstracted from the death certificate. In the two American Cancer So- ciety studies, further confirmation of the cause of death, including histological evidence, was sought from the certifying physician for all cancer deaths; this 101 procedure w-as also followed in lthe British doctors' study for all certificates in which lung cancer was mentioned as a direct or contributory cause. With these exceptions the data presented here represent the results of routine death certification. For current smokers of cigarettes the total mortality, after adjustment for differences in age composition, was found previously (Table 2) to be about `70 percent higher than that of non-smokers in these studies. The primary objective in this section is to examine whether this percentage increase ap- pears to apply about equally to all principal causes of death, or whether the relative increase is concentrated in certain specific causes or groups of causes. RESULTS FOK CIGARETTE SMOKERS For 24 causes of death, plus the "all other causes" category, Table 19 shows summary data over all seven studies.* In four of the studies the data are those for current smokers of ciga.rettes only, but in the two California studies and the 25-State study the cause-of-death breakdown was available only for all cigarette smokers including "cigarette and other" smokers and current and ex-smokers. For each listed cause, Table 19 shows the total numbers of expected and observed deaths of cigarette smokers summed over all seven studies, and TABLE 19.-Total numbers of expected and observed deaths and mortality ratios for smokers of cigarettes only 1 in seven prospective studies Underlying cause of death Expected Observed - ---__ Cancer of lung (162-3) _............_. ~- ._.. Bronchitis and emphysema (502. 527.1) *..- Cancer of larynx (161)~ . . . . . .._.._....... Cancer of oral cavity (140-S) .- . . .._..___ -_ Cancer of esophaeus (1.50) ._~ . .._.... --. Stomach and duodenal ulcers (540-l) _ _ _ Other circulatory diseases (451468) _....... Cirrhosis of liver (5811... . . .._. . .._.... -._ Cancer of bladder (181) __.. _.._..__ Coronary artery disease (420) _ _.-.-_. Other heart diseases (421-2, 43a-41.. _...._. Hypertensive heart disease (44W3) General arteriosclerosis (450) . . . ..___ Canwrofkidney cls0) ~... ..__. -__ All other cancer.. ._._._... . . . . .._....... Cancer of stomach (151). . . . . . . .._ __.... -. Influenza. wwumonia (486-493) .-_. ____ 170.3 89. 5 14.0 E:`: 105.1 254.0 169.2 111.6 6.430.7 526.0 % ; 79.0 1.061.4 285.2 303.2 1,%x3.7 1.461.8 253.0 1,063.2 156.4 290.6 207. 8 422.6 15,653.Q Allothercauses-......_....-..-.-........- Cerebral vascular lesions (33~~4) .._._ ..-__ Canwr or prostate (177) ~~.._. . . .._.__..___. .4ccidents. suicides, violence (KGQ99~ _ _ _ Nephritis (592-4) ..__ -._- _.__... _..._ Rheumatic heart disease (400-416). .._..._. Cancerofrectum (154~~~ ..__.... .._____. Cancer of intestines (1.52~31.. _....._____.. All causes. _ ___.____._.__. --- ___.____...... I,=3 546 2; 113 El 379 216 11,177 E 310 120 1,524 413 415 1,946 1,844 318 1,310 173 ii 395 26,223 - I -- - Mortality ratio 10.8 6. 1 5. 4 4.1 3.4 2.8 2. 6 2. 2 1.9 1. 7 1. 7 1. 5 1. 5 1.5 1.4 1.4 1.4 1.3 1.3 1.3 1.2 1.1 1. 1 1.0 0.9 1.68 11.7 7.5 5.8 3.9 3.3 5.0 2.3 2. 1 2.2 1.7 1.5 1.5 1.7 1. 4 1. 4 1.3 ::3" 1.3 1.0 1.3 1.5 1.1 0.9 0.9 1.65 1 Current cigarettes only lor four studies: all cigarettes (current and ex-) for the two California studies and the study of men in 25 States. 1 "Bronchitis and emphysema" includes "olher bronchopulmonary diseases" for men in nine States and Canadian veterans. Median mortality ratio *The individual results for the seven studies are shown for reference purposes in Table 26. 102 the resulting mortality ratios, arranged in order of decreasing ratios. The combination of the results of the seven studies in this way is open to criticism, since it gives more weight to the larger studies than may be thought advis- able, and since the true mortality ratios for specific causes presumably differ somewhat from study to study. However, for some causes of death that are of particular interest the numbers of deaths are small in all studies, so that some procedure for combining the results is highly desirable. As an alternative measure of the combined mortality ratio, the median of the >even mortality ratios (obtained by arranging the seven ratios in increasing order and selecting the middle one) is also shown for each cause in Table 19. The median, of course, gives equal weight to small and large studies. Although there are some changes in the ordering of the causes when medians are used instead of the ratios of the combined deaths, the general pattern in Table 19 is the same for both criteria. Table 19 also presents the total numbers of non-smoker deaths on which the combined mortality ratios are based. Lung cancer shows the highest mortality ratio in every one of the seven studies, the combined ratio being 10.8. Other causes that exhibit sub- stantially higher mortality ratios than the ratio 1.68 for all causes of death in Table 19 are bronchitis and emphysema, cancer of the larynx, cancer of the oral cavity and pharynx, cancer of the esophagus, stomach and duodenal ulcers, and a rather mixed category labeled "other circulatory diseases," which includes aortic aneurysm, phlebitis of the lower extremities, and pulmonary embolism. For three of these cause-cancer of the larynx, oral cancer and cancer of the esophagus-the numbers of non-smoker deaths are small, so that the over-all mortality ratio cannot be regarded as accurately determined. The U.S. veterans' study and the 25-State study provide an additional breakdown for two of the causes listed in Table 19. For the rubric 527.1 iemphysema without mention of bronchitis), these studies give mortality ratios of 13.1 and 7.5, respectively. For ulcer of the stomach they give 5.1 and 4.3, whereas for ulcer of the duodenum their mortality ratios are 2.3 and 1.1. Bronchitis and emphysema also show a high rate, 12.5, in the British doctors' study. There follows a list of 14~causes whose mortality ratios are not greatly different from the ratio of 1.68 for all causes in Table 19. These causes range from cirrhosis of the liver, with a ratio of 2.2, down to a ratio of 1.2 for the miscellaneous class which contains accidents, suicides and violent deaths. Th' 1s group includes the leading cause of death, coronary artery disease, with a ratio of 1.7, cerebral vascular lesions with a ratio of 1.3, and the "all other causes" group with a ratio of 1.3. For each of these 14 causes the mortality ratio differs from unity, by the approximate statistical test of significance. Finally, th ere are four causes-nephritis, rheumatic heart disease, cancer of the rectum and cancer of the intestines-whose mortality ratios are close to unity. For smokers of cigarettes and other, the data from four studies agree in general with the ordering of causes in Table 19, although the mortality ratios for most causes are slightly lower than with smokers of cigarettes 103 only. These and the corresponding data for ex-cigarette smokers are shown in Table 20. Data on ex-cigarette smokers can be obtained from four studies. & causes of death with mortality ratios of 2.0 or higher are, in decreasing order, bronchitis and emphysema (7.6)) cancer of the larynx (5.4)) cancer of the lung (4.8), stomach and duodenal ulcers (3.1)) oral cancer (2.0) and other circulatory diseases (2.0). 1 The group of 17 causes with mortality ratios below 2 in Table 19 requires discussion. If cancer of the bladder (mortality ratio 1.9) and coronary artery disease (mortality ratio l-.7) are omitted, since they receive detail4 consideration elsewhere in this report, the numbers of expected and observed deaths for this group as a whole are as follows: Expected Observed Mortality Ratio 8,241.3 1.0,789 1.31 If we exclude from this total the four causes at the foot of Table 19, for which the mortality ratios are 1 and smaller, the corresponding totals become: Expected Observed 7,164.0 9,699 Mortality Ratio 1.35 In either case the excess of observed over expected deaths is close to 2,500 or about 25 percent of the total excess in observed deaths in Table 19. Thus, although the mortality ratios for these groups are only moderately over 1, the group as a whole contributes substantially to the total number of excess ob. served deaths. The group consists mainly of a miscellaneous collection of chronic diseases. Several tentative explanations of this excess mortality ratio can be put for. ward. Part may be due to the sources of bias previously discussed. It was indicated in the section on "Non-Response Bias" that the bias arising from non-response might account for a mortality ratio of 1.3. Relatively hi& mortality ratios in certain causes of death that have not yet been examined individually may also be a contributor, although as these causes are likely to be rare, the contribution from this source can hardly be large. Part may be due to constitutional and genetic differences between cigarette smokers and non-smokers. Except for the breakdown mentioned previously by longevity of parents and grandparents in the men in 25 States study, there is no body of data available that provides a comparison of cigarette smokers and non-smokers on these factors as they affect longevity. But it is not un- reasonable to speculate that the kind of men who become regular cigarette smokers are, to a moderate degree, less inherently able to survive to a ripe old age than non-smokers. We know of no way to make a quantitative estimate of the difference in death rates that might be attributable to such constitu. tional and genetic factors. Studies reported in Chapters 1.4 and 15 indicate that some average differ- ences can be detected between smokers and non-smokers on behavioral, psychological and morphological characteristics. Nevertheless, the same corn. parisons show considerable overlap between the individual men in a group of smokers and a group of non-smokers. For what they are worth, these corn. 104 TABLE 20.-Expected and observed dea.ths and mortality ratios for current smokers of cigarettes and other (three studies) 1 and for ex-cigarette smokers (four studies) 2 Underlying cause of death - Cmeer of lung (162-3)..-.---.. Bronchitis and emphysema (502, 527.1) a... . . . . . . . ..____ Cancer of larynx (161) _.... Carver of oral cavity (14&E) _ Cancer of esophagus (150) Bt?maeh and duodenal ulcers WC-1) _..________ --_- ___._. Other circulatory diseases (451468) .~ _.___.________._. Cirrhosis of liver (581)L .____.. Cancer of bladder 081) ..____.. Coronary artery disease (420. Other heart diseases (421-2. 4). _ __ _ ___ _ _ _ _ _. _ _ _ _ _ _ _ _ _ _ _. Cancer of prostate (177) __._. Accidents, suicides, violance o3no-Qw) ___ _______________ Nephritis (5924) .._________ Rheumatic heart disease (400- - .- Cigarettes and other - Number of deaths Expected -L 3bserved 60.9 510 8.4 30. 4 145 4.8 53.2 191 3.6 17. 4 133 7.6 1. 6 20 12. 5 1.3 7 5.4 11. 1 42 3.8 5.9 12 2.0 13. 1 57 4. 4 5. 4 6 1.1 23.0 99 40 3. 1 99.0 57.3 58.2 2,335.0 227 85 3,z 4.3 2. 3 1. 5 1.3 1.4 1.4 1.2 1.4 1. 5 1.2 1.4 0.8 1.0 1.0 1. 2 1. 1 1.4 0.9 0.7 1. 1 45.8 22.4 29.8 1,245.0 93 z 1,731 2. 0 1.2 1.0 1.4 225. 9 321 124.1 178 1.4 144.4 106.8 25.0 272.9 101.0 199.2 769.3 174 146 3;: 139 % 93.0 63.7 13.9 199.3 51.4 55. 1 308.1 1.4 1.2 1.8 1. 2 1.3 1.0 1. 2 634.0 97. 1 28.7. 1 30.7 96.0 89.7 149.6 605 118 321 57 316 44 169.6 21. 7 86 1E 47.9 43.3 85.8 159 23 59 i; 1. 1 1. 1 0.9 1. 1 1.2 0.9 1. 1 1.4 / 3,045. 5 1 4,107 1.35 I Mntish doctors, U.S. veterans and Canadian veterans. * British doctors. men in nine States, U.S. veterans, and Canadian veterans. ' "Bronchitis and emphysema" includes "other bronchopulmonary diseases" for men in nine States and Canadian veterans. Mortality ratio Ea.cigarette Expected _- 3hserved Mortality ratio parisons suggest by analogy that the differences in death rates from constitu- tional or genetic factors may be moderate or small rather than large.* Fur- ther, it seems unlikely that constitutional or genetic differences between cigar and pipe smokers and between these groups and non-smokers can have any substantial effect on their death rates, since the over-all death rates of these three groups differ only slightly. Finally, part of the difference may represent a general debilitating effect of cigarette smoking in addition to marked effects on a few diseases. Pearl's hypothesis that smoking increases the "rate of living" is of this type, though there are difficulties in making this hypothesis precise enough to be subject to medical investigation. Hammond (13) has suggested that the explana- tion might lie in the effect of cigarette smoking in decreasing the quantity of oxygen per unit volume of blood, but there are numerous medical objections to this hypothesis. This Committee has no information that would lead it to favor one or another of the possible explanations put forward above. `This question is discussed more fully in Chapter 9, p. 190. 105 h~oRT.amY RATIOS FOR CIGARETTE SMOKERS BY AMOUNT SMOKES For coronary artery disease and lung cancer, the mortality ratios are given by amount smoked in Tables 21 and 22 for current smokers of cigarettes only. In Table 21 an increasing trend with amount smoked appears in all five studies. The two California st-udies, in which the data are for all cigarette smokers (current and ex-smokers combined) show a less marked trend. TABLE 21.--Mortality ratios for coron.ury artery disease for smokers q cigarettes only by amount smoked Number of packs per da)- British Men in 9 U.S. doctors states veterans Canadian M;t",$a veterans -___ --- very heavy smokers 5.1 M 2.2 F 8.0 2.4 light smokers 34.1 heavy smokers 4. l1 pack/day 2.5<1 pack/day 10.8>1 pack/day lt has been pointed out that in retrospective studies the usual approach is to determine the frequency of an attribute among cases and controls. This measure does not provide estimates of the risks of developing the disease 161 among individuals with and without the attribute unless one makes assump. tions referred to above. The validity of such assumptions may at times be suspect, for the cases may not be representative of the total population with the disease nor the controls representative of the population without the disease. Thus, some retrospective studies may not truly assess the existent risks with reasonable accuracy. However, when aU the cases of a disease in an area and a representative sample of the population without the disease am included in a study, the estimates of risk bear high validity. Despite the criticisms leveled at the retrospective method in general and its obvious defects as practiced by some investigators, a number of the retro. spective studies on lung cancer have indeed overcome most of the criticisms of major import leveled at the method. These criticisms and their implica- tions will be treated specifically below in the section on an Evaluation of the Association Between Smoking and Lung Cancer. Suffice it to say at thfs point that certain shortcomings of the retrospective survey approach, some real and some exaggerated, led several courageous investigators to under. take the necessarily protracted, expensive, and difficult prospective approach. The first prospective study encompassing total and cause-specific mortality in a human population was initiated in October 1951 among British physi- cians by Doll and Hill (83, 8%). There then followed in rather rapid sue. cession, five additional independent studies in the United States and Canada (25,87,88,%, 97,157,162,163), all b u one of which continue to be active. t The earlier study, by Hammond and Horn, among 187,783 white males aged 50-69 years, initiated between January and May 1952, was terminated after 4+% months of follow-up (162, 163). This has been succeeded by the current Hammond study which broadened its age-base (35-89 years) and contains 1,085,OOO persons (in 25 states) of whom 447,831 are males ( 157). These studies have been described in detail, analyzed, and evaluated in Chapter 8 of this Report where a discussion of differences in total mortality between smokers and non-smokers has been presented, and are summarized in Table 1 of that chapter. All the prospective studies thus far have shown a remarkable consistency in the significantly elevated mortality ratios of smokers particularly among the "cigarettes only" smoking class. Of special interest is the fact that in a number of the studies the magnitude of the as- sociation between cigarette smoking and total death rates has increased as the studies have progressed. This has particularly been true for lung can- cer. The presently calculated total mortality ratios have been presented in Table 2 of Chapter 8 of this Report. With reference to the smoking and lung cancer relationship, each of the seven prospective studies has thus far revealed an impressively high lung cancer mortality ratio for smokers to non-smokers. Examination of Table 5, which presents in summary form the lung cancer mortality ratios for the seven studies by smoking type and amount, derived both from the published reports of these studies and current information from the investigators wherever available, reveals a range of ratios from 6.0 to 25.2 with a median value of 10.7 for all smokers irrespective of type or amount. For smokers currently using cigarettes only at the time of enrollment in the studies, the ratios range from 4.9 to 20.2 with a mean value of 10.4 as derived from a summation of observed and expected values of most recent data. 162 Several of the studies have fortunately provided data for a measure of the "dose of exposure" relationship (m, 88, 96, 157, 163). It can readily be seen from Table 5 that the mortality ratios increase progressively with amount of smoking. The pivot level appears to be 20 cigarettes per day. Cigar and/or pipe smokers (to the exclusion of cigarettes) manifest ratios lower than any of the cigarette smokin, m classes, including combinations of cigarettes with pipes and/or cigars (25, 84, 88, 157, 163 1. One study pro- vided data on occasional smokers (163), These have a ratio very close to that of non-smokers. Ex-smokers of cigarettes (83, 88, 163) fall into levels of risk ratios below those for current smokers of cigarettes depending upon the length of the interval since smoking was stopped. In the Doll and Hill study (831, the ex-smoker ratio was less than the current smoker ratio even when cessation had occurred less than 10 years before entry into the study. This, however, was not true for the first Hammond and Horn study 1163). In this latter study, if smoking had ceased more than 10 years before entry, the lung cancer mortality ratios were lower than for current smokers at the corresponding daily consumption levels, but if cessation of smoking had occurred less than 10 years before entry, the ratios were virtually identical to those for current cigarette smokers at the corresponding daily consumption levels. The Dorn material 187, 88), currently brought up to date (89), provides a measure of relative risk by amounts of smoking prior to stopping. The ratios thus elicited are again below those for cur- rent cigarette smokers of corresponding daily amounts. At this time it is difficult to assess the effect of other variables such as duration of smoking and starting age on lung cancer mortality since cross- classification by these variables, and amount smoked as well, leads to cells with small numbers of deaths. Most prospective studies have thus far con- fined themselves to analyzing the effect of these additional variables on deaths from all causes, or in one case (157) from cardiovascular diseases. The current Hammond study is concerned with inhalation practices, but here also the total number of lung cancer deaths analyzed to date does not permit extensive classification by age, type of smoking, amount smoked daily, present smoking status, and age when smoking was begun. In the studies of total mortality ratios, duration of smoking, obviously immediately dependent upon the age of the individual, was in turn dependent upon age when smoking (cigarettes) was begun. Age when smoking began was also a determinant, not only of the number of cigarettes smoked daily, but of the degree of inhalation, with smokers starting at earlier ages very distinctly tending to smoke mere and inhale more deeply than those starting to smoke at older ages (157). According to Hammond, men who smoke more per day also tended to inhale more deeply than those who smoke fewer ciga- rettes per day. When inhalation and quantity smoked were held constant, the total mortality ratios also increased as age at start of smoking decreased. The stability of the lung cancer mortality ratios referred to in Table 5 is to a great extent dependent upon the number of observed lung cancer deaths among non-smokers from which the expected values for the several smoker classes are calculated. Referring again to Table 5, in at least two of the studies (83, 96), calculation of the expected deaths among smoker classes had to be based on extremely small numbers of non-smokers. However, 163 I P - - the other studies have now yielded significantly greater numbers of non- smoker lung cancer deaths and in at least three of them (88, 157, 163) these are now appreciable. Experimental Pulmonary Carcinogenesis A'ITEMPTS TO INDUCE LUNG CANCER WITH TOBACCO AND TOBACCO SMOKE Few attempts have been made to produce bronchogenic carcinoma in experimental animals with tobacco extracts, smoke, or smoke condensates. With one possible exception (289), none has been successful i 331) . Mice rarely develop spontaneous bronchogenic. oral, esophageal. gastric, prostatic, laryngeal, or vesical carcinomas, but certain inbred strains have a high incidence of spontaneous pulmonary adenomas (6 1. The adminis- tration, by any route, of carcinogenic polycyclic hydrocarbons, including some found in tobacco tar, increases the incidence and decreases the time of occurrence of pulmonary adenomas. These tumors are usually regarded as benign, and probably arise from the alveolar epithelium I 4, 5,6, 131, 330) rather than the bronchial wall. They have no resemblance to most human bronchogenic carcinomas. Essenberg (106) and Miihlbock (248) exposed mice to cigarette smoke, but their reported results are equivocal. Lorenz et al. (224) and Leuchten- berger et al. (206) did not observe an increase in pulmonary adenomas in mice that inhaled cigarette smoke. Leuchtenberger et al. (205a.) described a sequence of microscopic changes in lungs of mice exposed to cigarette smoke resembling somewhat those found by Auerbach et al. in the lungs of human smokers. No dose-response effect was reported. The morphologic findings consisted of bronchitis with proliferation of the epithelium. Some areas of hyperplasia showed atypical changes. However, the changes were reversible when exposure to smoke was stopped. The production of bronchogenic carcinomas has not been reported by any investigator exposing experimental animals to tobacco smoke. Most experiments in which tobacco tars were brought into direct contact with the lung and tracheobronchial tree of experimental animals have yielded negative results (273, 274, 275). Blacklock (29) found one car- cinoma when tar from cigarette filters was placed in olive oil together with killed tubercle bacilli and injected into the hilum of a small number of rats. Rockey et al. (289) painted tobacco tar three to five times each week on the trachea of dogs with a tracheocutaneous fistula. Hyperplastic changes with squamous metaplasia of the bronchial epithelium were seen in seven dogs that survived 178 to 320 days. Carcinoma-in-situ was reported to occur in three, and invasive carcinoma in one out of 137 dogs, but this work has not yet been confirmed. SUMMARY.--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. 165 SUSCEPTIBILITY OF LUNG OF LABORATORY ANIMALS n, CARCINOGENS POLYCYCLIC AROMATIC HYnnoCARnoNs.--Epidermoid carcinoma has been induced in mice by Andervont by the transfixion of the lungs or bronchi with a thread coated with a carcinogen (5) and by Kotin and Wiseley (191) by treatment with an aerosol of ozonized gasoline plus mouse-adapted influenza viruses. Kuschner et al. (197, 197a) induced epidermoid carcinomas in the lungs of rats by the local application of polycyclic aromatic hydrocarbons, either by thread transfixation or pellet implantation. Distant metastases occurred from some of the carcinomas. Th e c anges in the bronchial tree at different h times prior to the appearance of cancer included hyperplasia, metaplasia and anaplasia of the surface epithelium as well as of the subjacent glands. These changes resembled those described by Auerbach in the tracheo- bronchial tree of human smokers (9). Stanton and Blackwell (324) induced epidermoid carcinoma in the lungs of rats that had received 3-methylcholanthrene intravenously. The car- cinogen was deposited in areas of pulmonary infarction. Saffiotti et al. (302) produced squamous cell bronchogenic carcinomas in hamsters by weekly intubation and insufflation of benzoia) pyrene (4 per- cent) ground with iron oxide (96 percent) resulting in a dust with particles smaller than 1.0 micron. A proliferative response followed by metaplasia pre- ceded the appearance of the carcinomas, but was not an invariable antecedent. VIttusEs.-Bronchogenic carcinoma has been induced in animals inocu- lated with polyoma virus by Rabson et al. (282). Carcinogens enhance the effect of viruses known to cause cancer in animals (99) and localize the neoplastic lesions at the site of inoculation of the virus (98). However, no evidence has been forthcoming to date implicating a virus in the etiology of cancer in man. POSSIBLE INDUSTRIAL CARCINoGE!6.-Vorwald reported that exposure of rats to beryllium sulfate aerosol resulted in carcinomas of the lung; 12 per- cent were epidermoid but most were adenocarcinomas. The tumors usually arose from the alveolar or bronchiolar epithelium. He also produced broncho- genie carcinomas in two out of ten rhesus monkeys injected with beryllium oxide and in three out of ten exposed to beryllium oxide by inhalation (357). Lisco and Finkel in 1949 (217) reported the production of epidermoid cancer of the lung in rats with radioactive cerium. Subsequently many other investigators have succeeded in producing carcinomas of the lung, predominantly of the epidermoid type, in a high percentage of rats and mice with other radioactive substances. The various modes of exposure included inhalation, intratracheal injection, or insufflation and implantation of wire or cylinder. These experiments were reviewed by Gates and Warren in 1961 (125). Hueper exposed rats and guinea pigs to nickel dust and found metaplastic and anaplastic changes in the bronchi (180). Following up earlier work in which squamous metaplasia of the bronchial epithelium was found in rats exposed to nickel carbonyl (341), S un erman and Sunderman (342) in- d duced bronchogenic carcinoma in rats by exposure to this compound. This 166 group also found 1.59 to 3.07 pg. of nickel per cigarette in the ash and in the smoke in several different brands. About three-fourths was contained in the ash. Although Hueper and Payne (182, 183) and Payne (270) have demonstrated that pure chromium compounds will produce both sarcomas and carcinomas in several tissues in rats and mice, bronchogenic carcinomas have not been produced by inhalation of chromium compounds in experi- mental animals. Experiments designed to test the carcinogenicity of ar- senical compounds have been either negative or inconclusive. Asbestosis can be produced without difficulty in experimental animals by inhalation of asbestos fibers (359), but efforts to produce bronchogenic carcinoma have been unsuccessful (129, 181, 227, 358). SUMMARY.-The lungs of mice, rats, hamsters, and primates have been found to be susceptible to the induction of bronchogenic carcinoma by the administration of polycyclic aromatic hydrocarbons, certain metals, radio- active substances, and oncogenic viruses. The histopathologic characteristics of the tumors produced are similar to those observed in man and are fre- quently of the squamous variety. ROLE OF GENETIC FACTORS IN PULMONARY ADENOMAS IN MICE Genetic factors exert a determining influence on the spontaneous develop- ment and induction of lung tumors in mice. Early studies of Murphy and Sturm (251) and of Lynch (225, 226) demonstrated the development of pulmonary tumors in mice after the skin was painted with coal tar, and Lynch (225) indicated the existence of genetic factors in the development of these tumors. Later investigations of Heston (169, 170) on the effect of intravenous injection of dibenzanthracene and the studies of several other investigators (3, 4, 27, 47, 320) utilizing different techniques gave addi- tional evidence of the operation of genetic factors in induced tumors. Link- age between multiple genes for susceptibility to spontaneous and induced tumors in mice and specific chromosomes has also been established (47, 168) and transplantation experiments (171, 173) indicate that the genetic susceptibility resides within the pulmonary parenchyma. A number of in- vestigators (36, 47, 124, 131) demonstrated conclusively that these tumors usually arise distal to the bronchus and are probably alveogenic. Metastases rarely occur. The relative importance of genes for susceptibility to these tumors of the lung is indicated by an incidence ranging from a few tumors to over 90 percent, depending on the inbred strain examined. Spontaneous tumors of the lungs are rare in species of laboratory animals other than mice, and the genetics of these neoplasms in other species has heen investigated only superficially. SUMMARY.PenetiC susceptibility plays a significant role in the develop ment of pulmonary adenomas in mice. Pathology-Morphology RELATIONSHIP OF SMOKING TO HISTOPATHOLOGICAL CHANGES IN THE TRACHEOBRONCHIAL TREE . In an extensive and controlled blind study of the tracheobronchial tree of 402 male patients, Auerbach et al. (11, 13, 15) observed that several 167 kinds of changes of the epithelium were much more common in the trachea and bronchi of cigarette smokers and subjects with lung cancer than of non-smokers and of patients without lung cancer (Table 6). The epithelial changes observed were (a) loss of cilia, ib) basal cell hyperplasia (more than two layers of basal cells), and (c) presence of atypical cells. The atypical cells had hyperchromatic nuclei which varied in size and shape. The arrangement of such cells was frequently disorderly (see illustrationa below). Hyperplastic changes were also seen in the bronchial glands. TABLE 6.-Percent of slides with selected lesions,' by smoking status aad presence of lung cancer NUITlber slides 3,324 3,436 l,R24 3,016 7,062 1,787 2.764 Percent of slides with cilia absent and averaging 4 or more cell rows in depth No cells Somecells All cells Total atypical atypical atypical 2 -- 1.0 0.03 ._~ ___.... 1. 1 3. 5 0.4 0.2 4.1 0. 2 4.2 0.3 4.7 7.1 0.8 7.9 12.6 4.3 169 .___.-__-. 26.2 11.4 37. 5 _ 12.5 14.3 26.8 I In some sections. two or more lesions were found. In such instances. all of the lesions were oounb d and are included in both individual columns and in the total column of the table. an ulcer were excluded. Lesions found at the edge of f These lesions may be called carcinoma-in-situ. a Of the 63 who died of lung cancer. 55 regularly smoked cigarettes up to the time of diagnosis, 5 regularly smoked cigarettes but stopped before diagnosis. 1 smoked cigars. 1 smoked pipe and cigars, 1 was an -. sional cigar smoker. Each of the three kinds of epithelial changes was found to increase with the number of cigarettes smoked (Table 6). In smokers who had no cancers, frequency and intensity of these changes correlated with the number of EXAMPLES OF NORMAL AND ABNORMAL BRONCHIAL EPITHELIUM . 1. Normal 168 2. Basal-cell hyperplasia-replacement of ciliary epilhelium with a thick layer of cells resembling stratified squamous epithelium. 3. Extensive basal-cell hyperphasia with numerous atypical cells. Source: Auerbach, Oscar. Special communication to the Surgeon General's Advisory Committee on Smoking and Health. cigarettes smoked. Among non-smokers, lesions composed entirely of atypi- cal cells with loss of cilia were uniformly absent, although a few could be seen with more than two rows of basal cells containing some atypical cells. In contrast, atypical cells were found in all lesions seen in the tracheobron- chial tree of patients who smoked two or more packs of cigarettes a day, irrespective of the presence of hyperplasia and/or cilia loss or whether the patients died of lung cancer. Th e most severe lesion, aside from invasive carcinoma, consisted of loss of cilia, and hyperplasia up to five or more cell TOWS composed entirely of atypical cells. This lesion was never found among men who did not smoke regularly and was found only rarely among light smokers. However, it was found in 4.3 percent of sections from men 169 who smoked one to two packs a day, in 11.4 percent of sections from those who smoked two or more packs a day, and in 14.3 percent of sections from smokers who died of lung cancer (15). While epithelial changes were found in all portions of the tracheobronchial tree, quantitative differences were found between the changes in the trachea and those in the bronchi; hyperplastic lesions consisting entirely of atypical cells without cilia were found in all regions of the bronchial mucosa but only rarely in the trachea. It is notable that cancer rarely occurs in the trachea. In 35 children less than 15 years of age, Auerbach et al. (16) found the same percent of epithelial changes in the tracheobronchial tree as in the same number of adults who had never smoked regularly (16.6 percent of children and 16.8 percent of adults). No hyperplasia with atypical cells was seen in any section. Later, Auerbach et al. (15a.) studied the morphology of the tracheobron- chial tree from 302 women and 456 men with respect to additional variables- sex, age, pneumonia, and amount smoked. One or more epithelial lesions were found in 68.2 percent of sections from men smokers and 68.6 percent from women smokers when matched groups were examined. However, on further study, hyperplastic lesions composed entirely of atypical cells were found in 6.9 percent of the sections from the male group and in 2.5 percent of those from females. Matched groups of male cigarette smokers of two age groups (averages of 37 and 67 years) were compared. Many more lesions, characterized by a large number of cells with atypical nuclei, were observed in the older than in the younger group. In a parallel study of women who did not smoke (average ages of 46 and 76 years), no difference in the number or type of lesions was noted. Few changes in the bronchial epithelium were found in sections from 27 women non-smokers over 85 years of age. Occasional atypical changes were found in women non-smokers (a) who died of pneumonia, (b) who died of various other causes but had pneumonia at the time of death, and (c) who died with no evidence of pneumonia. However, basal cell hyperplasia, loss of cilia, and ulceration were found more frequently in sections from women who died with pneumonia than from women who had no evidence of pneumonia. These observations are in agreement with those of other investigators who found metaplasia of the Lronchial epithelium to be more frequent in patients with various non- neoplastic pulmonary diseases than in controls without such disease (256, 305,352,366). Far fewer epithelial lesions were found in non-smokers than in pipe, cigar, or cigarette smokers (15a.), the difference being particularly evident in the occurrence of atypical cells. However, sections from pipe and cigar smokers showed fewer epithelial lesions than did sections from cigarette smokers. Cells with atypical nuclei were found far more frequently in cigarette smokers than in cigar or pipe smokers (Table 7). In 72 male ex-cigarette smokers who had smoked for at least ten years and had not smoked for at least five years prior to the time of death, there were less hyperplasia, less loss of cilia, and fewer atypical cells than in sections from current cigarette smokers (14). An interesting by-product of this study was the finding of "cells with disintegrating nuclei" in the 170 TABLE 7.--Changes in bronchial epithelium in matched triads of male non-smokers and smokers of different types of tobacc0.l Qroup Numbe of sub. jects 7th set (none vs. pipe vs. cigarette)3 Non-smokers ___ ___..__.___________ 20 Pipe smokers.. ____ .___.__ _________._ Ciearette smoker/s.. ___-_- ________. 8th set (none vs. pipe vs. cigarette) Non-smokers. _ _ _ .._- .._________ -._ Pipe smokers.-...-_-.-......-..--... Cigarette srnokers-~~~-.....--.-..~-.- 9th set (nom vs. cigar vs. cigarette) Non-smokers __________.___...__. __ Pipe smokers. __._...._._.___..______ Cigarette smokers.~ .~ __.__________ -__ - `r s w t - Total Sections with 1 ectlons or more epithelial -ith epi- ISfOIlS helium -I Number Percent -- Number Percent 985 214 21.7 110 11.2 924 3% 1 914 ii2 65. 5 352 96.6 810 88.6 1,246 22. 9 1, 164 fi8. 7 1, 126 96.3 1,706 467 27.4 1,733 I 1.573 i 90.8 1. 526 1.511 99.0 3+wll rows with cilia present Cilia absent 167 451 999 216 1% 13.4 38. 7 88.7 12. 7 40.0 92. 7 101 10.3 117 12.7 116 12. 7 132 10. 6 172 14. R ml 21. 1 ii: 42R - r 1 I- Percent 16. 5 14.3 28.0 t. _- - I Atypical cells Atypical cells present with cilir present absent - Jumber Pcroent Numbe --~-- 3: 37. 2.6 0 3 870 95. 2 1: 44: 38. 0. 7 2 1 1,008 89. 5 2% 14 0. R 3 1,275 73. 6 1,493 97. a 2; -___ - r -. Entirely atypical c&s with cilia absent 2 qumber Percent --- 0 _ _ _ _ _ _ _ _ 0 --_-_____ 35 3.8 0 __.._. -._ 0 - _. -. ___ 70 6.2 0 __.._-___ d 0.3 12.8 1 Modlfled table from Auerbach et al. (15a). 1 Carcinoma in situ. 3 Triads were matched for age, occupation, residency and (for smokers) by amount of tobacco used. bronchial epithelium of 43 out of 72 ex-smokers. These cells were not found in the bronchial epithelium of current cigarette smokers or non. smokers. They `were considered by Auerbach et al. to be pathognomonic of the ex-smoker. Many of the histopathologic findings observe-d by Auerbach et al. in the bronchial epithelium of smokers have been confirmed by other investigators 164, 155, 189, 304). The significance of the hyperplastic changes in the bronchial epithelium for the pathogenesis of lung cancer in smokers is not fully understood. The establishment of a link between the hyperplastic changes and the subsequent development of lung cancer would relate smoking causally to lung cancer. However, the non-specificity of hyperplasia of the bronchial epithelium is universally recognized. Furthermore, similar changes are known to be reversible. On the other hand, evidence from both human and experimental observa. tions points strongly to the conclusion that some hyperplastic changes of the bronchial epithelium, especially those with many atypical alterations, are probably premalignant. It is well documented that the bronchial trees of patients with lung cancer have areas, sometimes very widespread, of epithelial hyperplasia containing many atypical and bizarre cells. This was reported by Lindberg in 1935 (216) and by many other investigators (10, 12, 28, 52, 134, 265, 285, 349, 370). Black and Ackerman (28) have carried out an extensive study of the relationship between metaplasia and anaplasia and lung cancer in human lungs and have presented strong circumstantial evidence for the opin- ion that the basal cell hyperplasia with advanced atypical changes and loss of cilia (the so-called carcinoma in-situ) represent a stage in the devel- opment of lung cancer. They also emphasized, as has Auerbach et al. (12), the frequent occurrence of atypical basal cell hyperplasia at multiple sites in the bronchial tree considerably removed from the site of the lung cancer. They have pointed out the similarities between the atypical hyperplasias in the tracheobronchial tree and carcinoma in-situ in ather sites, such as the cervix, skin, and larynx. Lung cancer was induced in animals by radioactive substances (198,217)) chemical carcinogens ( 198, 34O), and air pollutants plus influenza virus (191). These studies have demonstrated the occurrence of extensive atop ical hyperplastic changes in the bronchial epithelium of experimental animals preceding the appearance of lung cancer. The changes described are, on the whole, similar to those seen by Auerbach et al. in the bronchial epithelium of heavy cigarette smokers and by others in patients with lung cancer. The hyperplastic lesions in animals do not invariably develop into cancer. This appears to be the case also in man (14). In view of these observations, it seems probable that some of the lesions found in the tracheobronchial tree in cigarette smokers are capable of de- veloping into lung cancer. Thus, these lesions may be a link in the patho- genesis of lung cancer in smokers. SuMMA,ttY.---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 172 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. Hyperplasia without atypical changes was seen in the bronchial tree of children under 15 years of age and in women non-smokers at all ages who died with pneumonia. Women cigarette smokers, in general, have the same epithelial changes as do men smokers. However, at given levels of cigarette use, women appear to show fewer atypical cells than do men. Older men smokers have many more atypical cells than do younger men smokers. Men who smoke pipes or cigars have more epithelial changes than do non-smokers, but have fewer changes than do cigarette smokers consuming approximately the same amount of tobacco. Male ex-cigarette smokers have less hyperplasia and fewer atypical cells than do current cigarette smokers. CONCLUSION.--It may be concluded on the basis of human and experimental evidence that some of the advanced epithelial hyperplastic lesions with many atypical cells, seen in the bronchi of some cigarette smokers, are probably premalignant. TYPING OF LUNG TUMORS Historical aspects of the typing of lung tumors in relation to possible etiological agents are reviewed in the section on Retrospective Studies, His- tologic Types. Kreyberg (195, 196i noted that the increase of lung cancer in recent dec- ades seemed to occur for only certain types of lung cancers (his Group I), and that other types did not increase (his Group II). Kreyberg's classifica- tion is compared with the World Health Organization classification in Table 8. His Group I includes epidermoid carcinomas and small-cell ana- plastic carcinomas. His Group II includes adenocarcinomas and a few rare tP=. He postulated that a determination of the ratio between Groups I and II is a good index of the occurrence and magnitude of an increase in lung cancer in a given locality and his epidemiologic studies linked the increase almost entirely to the use of cigarettes. His thesis has been ac- cepted by many while disputed by others. The results of the study of lung cancer at Los Angeles County General Hospital (LACGH) by Herman and Crittenden (167) did not confirm Krey- berg's conclusions. These investigators, analyzing the autopsy data on lung cancer from 1927 to 1957 at LACGH, b o served a marked increase in the number of lung cancer cases as had been noted by many other investigators. However, the ratio of Kreyberg's Group I to Group II had not changed per- ceptibly over this period and was notably lower than in other series studied. The Committee on Smoking and Health sponsored a workshop in which slides from coded cases of lung cancer from four different institutions in three areas of the United States were typed "blind" by Dr. Kreyberg and Pathologists from the cooperating institutions.' There was good agreement a~ to typing. Th e 1 ow ratio of Group I to Group II cancers at L:iCGH was confirmed. When typing of the reviewed cases was compared with smoking `Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963. 173 TABLE 8.-Relation between WHO and Kreyberg classifications of lung tumors WHO classification 1 Krwberg classiflea- tion 2 - -- Epidermoid cRrcinomas~~....~........-....~......~.....~~..................-.... 8. highly differentiated b. moderately differentiated c. slightly differentiated Group I 2. 3. 4. :: 7. x. 9. Small-cpllanaplasticcarcinom~ ..- ~~~ . . . . . . . . . ~~.-...~ . . . . . . . . . .._. ~... 8. with ovalcell structure ("oat-cell" carcinoma) Adenocnrcinomas~.~.....~~.~~~..........~.......~......~~.....~.~...~..~~.....~. a. acinar (with or without formation of mucus) h. papillary (with or without formation of mucus) c. tumors with a predominance of "large cells" some of which show forma- tion of glands and/or production 01 mucus. Large-rellundifferentiatedcarcinomas .~ . . . . . . . ~~~.~ ~~ ._._. ~~~ . . . .._. ~-._ Combined c idermoid and sdenocarcinomas. ~~.~ ~._ ..~ _......__.... Bronchiole-a 4 veolar cell carcinomas.. . . . . ~.~ . . . . . . . . . . . ..~ . ..__ ~~ -..... Carcinoid tumors (solid. trabecular, slveolar) .~ . . . . . . . . .~- . . .._. . . . . . . . . . _...~. Tumorsofmucous glands~~.......-..............~~~...........-........-.-.-...- a. cylindroma b. muco-epidermoid tumcz~ Papillomas of the surface epithelium . . . . . . . . . . . . . . ~~..-- ..-..... . . . .._. ~~.. a. epidermoid b. epidermoid with goblet cells Other ^ . p.. .~lCO~la8..~~...~.........~.~......~.~~.........~.........~......~.~.-...~~......~.....~ "tt,er C. Combined Tumors of Epthelial and Mesemhymal Celk .___... ~. . . . . . . _ ..~. ______ Other I). Mesothcliomas ofthe Meura..............................~........~.......~~...~.~.....~ Other 1. Localized 2. Diffuse E. Tumors Lklasriflcd 1 Committee on Cancer of the Lung, World Health Organization. 3 Kreyberg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor. wegian Universities Press, 1962. 3 Types marked "other" are not included in either of Kreyberg groups. histories, moreover, it became evident that both Group I and Group II were increased among heavy smokers. Several factors were recognized to influence Group I/Group II ratios: (a) source of material (for example, significant differences in the ratio were found between autopsy and surgical materials, and between surgical materials obtained by biopsy and by resection during operation for lung cancer) ; (b) failure to autopsy certain cases which were judged to be inoperable (the patient being sent home as incurable) ; (c) the fact that Group I (squamous and oval-cell) carcinomas are more likely to be among the operable cases and among those accessible to bronchoscopy, and (d) variations in selection of patients in different institutions. An independent review of the histopathology of 1,146 lung cancer cases from the U.S. veterans study (policyholders) by Dom, Herrold and Haens- zel (Table 9) (89) showed high mortality ratios for both Group I and Group 11 cancers in current heavy smokers (over 20 cigarettes/day), al- though Group I bad a higher mortality ratio (31.2) than Group' II (7.2). Another study of Haenszel on white females (152), as well as studies of female patients at Massachusetts General Hospital (54)) Roswell Park Memorial Institute (133), Presbyterian Hospital (323)) and Washington Iiniversity (2601, indicated that adenocarcinoma is also contributing to the increment of lung cancer in women. CONCLLISION~--(a) The histological typing of lung cancer is reliable. However, the use of the ratio of Group I and Group II is an index to the mag nitude of increase in lung cancer is of limited value. 174 TABLE 9.-Mortality ratios for cancer of the lung by smoking class and by type of tumor, .!l.S. veterans study oroup I Oroup II 1.0 1.0 22 0. R 15. 4 s. 1 IP. 9 .s. R 12.9 5. 1 31.2 1 7. 2 8.4 1 3.7 1'; : 2. 7 6 5 ' Inrludes occasional smokers. ? Include men who were using pipe and/or cigars in addition to ricawttrs. Source. Darn, H. F., Haenszel, W. and Herrold. K. (89) (sre Chapter 8 alsol. (bl Squamous and oval-cell carcinomas (Group 1) comprise the pre- dominant types associated with the increase-of lung cancer in both males and females. In several studies, adenocarcinomas (Group II I hare also increased in both sexes although to a lesser degree. Evaluation of the Association between Smoking and Lung Cancer It is not practical to attempt an experiment in man to test whether a causal relationship exists between smoking of tobacco and lung cancer. Such an experiment would imply the random selection of very young subjects living under environmental conditions as nearly identical as possible, and random selection of those who were to be smokers and those who were to be the non-smoker controls. Their smoking and other habits would need to be held constant for many years. Because of the relatively low incidence of lung cancer in the human population, both the test and the control groups would have to be very large. As such an experiment in man is not feasible, the judgment of causality must he made on other grounds. The epidemiologic method, when coupled with clinical or laboratory observations, can provide the basis from which judgments of causality may be derived. INDIRECT MEASURE OF THE ASSOCIATION The crudest indicators of an association between lung cancer and smoking are certain indirect measures : (a) a correlative increase in lung cancer mortality rates and- in per capita tobacco consumption in a number of countries (76, 138, 211, 239, 255), and (b) disparities between male and female lung cancer mortality rates correlated with corresponding differences in smoking habits of men and women, both by amounts smoked and duration of smoking (65,151,344). Figure 9 shows a correlation of crude male death rates from lung cancer iu I1 countries in 1950 with the per capita consumption of cigarettes in these countries in 1930 as presented by Doll (76). Assuming a 20-year induction Period for the appearance of lung cancer, Doll found a significant correlation (0.73-CO.30) between the death rates and cigarette consumption. Since virtually all the tobacco consumption in 1930 was among men in the countries 714-422 O-M-13 175 500 400 300 200 100 0 CRUDE MALE DEATH RATE FOR LUNG CANCER IN 1950 AND PER CAPITA CONSUMPTION OF CIGARETTES IN 1930 IN VARIOUS COUNTRIES. I I GREAT BRITAIN GREAT BRITAIN # # SWITZERLAND SWITZERLAND # U.S.A. * NORWAY -* `t ICELAND CIGARETTE CONSUMPTION FIGURE 9. Source: Doll, R (76) represented (Great Britain, Finland, Switzerland, Holland, the United States, Australia, Denmark, Canada, Sweden, Norway, and Iceland), it seemed reasonable to compare the annual per capita consumption of each country with the crude, male lung cancer death rates. It will be noted in Figure 9 that the data from the United States show a relatively low death rate in relation to cigarette consumption. Doll sug- gested two explanations: the influence of a higher proportion of young 176 people in the U.S. population and the method of smoking, with the U.S. smokers consuming less of each cigarette than the British smokers. Since Doll's explanations of the discrepancy. additional information has become available. Studies on length of cigarette butts discarded have shown Amer- ican discards to be significantly longer than British discards; 30.9 mm (156) and 18.7 mm (85) respectively. Also, there is a significantly greater percentage of smokers in Great Britain than in the United States in the age groups in which lung cancer occurs at high rates (52.6 percent in 60+ year age group and 29.2 percent in 65+ year age group respectively). Strictly comparable data do not exist on inhalation practices for the two countries. Such information would aid in explaining this discrepancy as well as a similar disparity between Holland and Great Britain. In Holland I 156) the length of the cigarette butts was almost the same as in Great Britain (19.7 mm), but the crude male lung cancer death rate in Holland was significantly lower than in Great Britain. This correlates well, as shown in Figure 9, with the annual per capita consumption of cigarettes in Holland which has been much lower than in Great Britain. It should be mentioned that differences in intensity of air pollution and industrial exposures in these countries have not been taken into account. However, for reasons given below, these latter factors do not account for the magnitude of the difference in incidence of lung cancer nearly as well as the amount of each cigarette smoked and the degree of inhalation. Finally, the varying composition of the tobacco in the several countries was not considered in these studies. An elaboration of the disparities between male and female lung cancer mortality rates and their correlation with differences in smoking patterns is also in order, for the sex disparity has also been posed as contradictory to the smoking-lung cancer hypothesis. Although the opponents of the hypothesis, pointing to the sex disparity (116, 229), have minimized the differences in smoking habits, the fact remains that the magnitudes of the differences are quite large. In a representative cross-sectional survey of smoking habits coupled with the Current Population Survey of the Bureau of the Census in 1955, Haenszel, et al. (151) f ound the following disparities between male and female smoking patterns: 1. Whereas only 22.9 percent of males had never smoked, 67.5 percent of females had not. 2. Males showed relatively little variation among the component age groups in percentage not smoking, whereas females after age 25-38 showed a consistently increasing percentage of non-smokers in successively higher age groups (Figure 10). 3. Sixty-five percent of males smoked cigarettes as compared with 32 percent of females. 4. Cohort analyses revealed the adoption of cigarette smoking late in life for both males and females among cohorts born before 1890; but male cohorts born after 1900 successively began to smoke earlier in life. Large-scale adoption of cigarette smoking by women did not occur until the decades of the 1920's and 1930's. 177 PERCENTAGE OF PERSONS WHO HAVE NEVER SMOKE1 BY SEX AND AGE, UNITED STATES, 1955 Age (in years) 18-24 25-34 35-44 55-64 65 and over 45-54 PERCENT NEVER SMOKED = MALES g@gj FEMALES FICCHE 10. Source: Harnszel, W. M. et al. (151) 5. The median age at which males started smoking has remained fairly stable for the several age cohorts: from 19.3 years for ages 65 and over to 17.9 years for age 25-34; the median age that females started smoking has dropped dramatically from 39.9 years for the age group 65 and over to 20.0 years for age 25-34. 6. Males in all age groups smoked considerably more cigarettes per day than did females.. In ages 55 and over, 6.9 percent of the 178 males smoked more than a pack a day, compared with only 0.6 percent of the females. Although urban-rural and geographic re- gional differences were noted, significant disparities between male and female smoking were maintained throughout. Thus it can readily be deduced that these findings are consistent not only with the sex disparity in lung cancer mortality but also with the slower but nevertheless continuing rise in female lung cancer mortality. Rritish studies (344) also revealed that females, especially before World War II, consumed much less tobacco than did males. A correction for the marked disparity in smoking habits of males and females reduced the ob- ser\:ed 5-fold excess of male lung cancer deaths to a 1.4-fold excess as of 1953 1149). Supporting this finding are the data from two retrospective studies (147, 152) in which the age-adjusted lung cancer death rates in 195% 59 among male and female non-smokers were 12.5 and 9.4 respectively for a ratio of 1.33 (145). This residual ratio implies that there may be other factors operating to produce a portion of. the sex differential in mortality. DIRECT MEASURE OF THE ASSOCIATI0i-V For a direct measure of the association between lung cancer and smoking it is, of course, essential that both variables or attributes be measured in the same populations. The 29 retrospective studies, described earlier, consider smoking (usually kind, amount, and duration) and non-smoking among cases of lung cancer and individuals without lung cancer. The seven prospective studies consider the occurrence or lack of occurrence of lung cancer among smokers and non-smokers. ESTABLISHMENT OF ASSOCIATION.-A number of investigators, though ac- cepting the existence of an association, have questioned its significance in terms of a causal hypothesis (58, 102, 114, 115, 116, 117, 141, 178, 218, 219, 287, 288, 298, 299). Some of these doubts have been on the basis of a possible genetic underlay which might determine both smoking and lung cancer (114, 115, 116, 117). Some have followed contradictory obser- vations in the dissenter's own work (58, 102, 141), incorrectly assessed evi- dence of lung cancer mortality trends, or the belief that the causal hypothesis requires cigarette smoking to be the sole cause of lung cancer (178, 287, 288). Others believe that the lung cancer rise is spurious and can be at- tributed either to improvements in diagnosis and reporting, (218, 219, 287, 288, 298, 299) or to the aging of the population. In the latter explanation they ignore the fact that aging of the population does not affect age-specific mortality rates which, for lung cancer, are also rising with the passage of time. Still others express doubt on the basis of the lack of a concomitant rise in cancers of the oral cavity (178, 298) or of the skin of the fingers (178). Finally, some doubts have been based on supposed incongruencies between the cigarette-smoking hypothesis and urban-rural as well as sex dif- ferences in lung cancer mortality (116, 178, 229). There are a few investi- gators who maintain that the association may be spurious or that it has not heen proved (22,23, 24, 228,229, 230). A number of these objections have been assessed in earlier discussions in this section; others will be evaluated below. These latter criticisms have revolved about defects inherent in the retrospective or the prospective 179 methods of approach, biases of selection in either method, biases of non. response. the validity of the results in the early phases of a prospective study. and the misclassification of both variables: smoking habits and lung cancer. It should be noted that the Current Population Survey of 1955 yielded results highly consistent with data on tobacco production and taxation (151 I ; that classification errors in terms of amount of smoking were rela- tively minor in a reliability study by Finkner (113) ; and that, in at least three prospective studies, in which subjects were requestioned on smoking habits at intervals of at least two years, the replies were closely reproducible (87, 88, 157, 159, 162, 163) ? particularly if no illness had intervened (159). With regard to the retrospective studies, it has also been suggested that knowledge of the illness might have introduced bias in relation to histories of smoking habits (158, 229). In at least one retrospective study, both patient and interviewer were unaware of the diagnosis of lung cancer. the smoking histories having been obtained before the diagnosis was made (207). Furthermore. patients initially believed to have lung cancer who, after interview: were found .not to have the disease, reported smoking his- tories similar to the control groups and not the lung cancer groups (84). Finally, this bias cannot have influenced the findings of several studies in which a significantly greater proportion of cigarette smokers and heavy cigarette smokers were associated with epidermoid cancers than with adeno- carcinoma (86, 150, 163, 313, 375). Th e reliability of response to smoking history would thus appear to be markedly above the critical level for the firm establishment of an association by the retrospective method. In pro- spective studies, this factor is less of a problem. In retrospective studies the investigator can confine himself to cases with accurate diagnoses. In the prospective approach, accuracy of diagnosis may not always be attainable, but all cases must be included. In assessing the results of the prospective studies it must be kept in mind that all deaths from any cause were involved in the calculations, with the cigarette smoker rates higher than those for non-smokers and with a gradient by amount of smoking demonstrated in all of the studies. Evidence that the specific estimates of risk for lung cancer among smokers actually might have been underestimated has been presented by Hammond and Horn (162, 163), who found higher relative risk ratios among smokers for confirmed cases than for those with less well-established diagnoses. Most of the prospective studies yield relative risks of lung cancer by various smoking categories which approximate those found in the Doll and Hill physician study (83) where, obviously, diagnostic evidence would be more readily available than in the general population. It would thus appear that in the data from retro- spective and prospective studies, diagnostic accuracy was not a critical factor in the establishment of an association between smoking and lung cancer. The question of selection bias is, of course, a more complicated problem. Several criticisms have been leveled at both the retrospective and prospective methods. Although in retrospective studies the selection of a control group may pose a more serious problem, even the selection of the case material may interject difficulties. It has been claimed by Berkson 124) that the selection of hospitalized cases may lead to bias if smokers with lung cancer 180 were more often hospitalized than non-smokers with the disease. However, nearly all lung cancer cases are hospitalized, a point which, he concedes, would thus minimize this bias. Furthermore, several retrospective studies have surveyed all the cases in the area regardless of hospitalization (238, 335)) or all deaths regardless of cause or hospitalization 1379). Another criticism of patient selection in retrospective studies deals with the danger that, in studies highly cross-sectional in time. if smokers live longer than non-smokers, there would obviously be more smokers in the disease group, and thus a spurious association of disease with smoking would result (254). There is no evidence for this basic assumption. Furthermore. it is inapplicable because almost all the retrospective studies were actually hased on newly diagnosed cases collected serially- over an interval of time long enough to remove this bias. Control groups pose a problem in retrospectiv-e studies. In 2T of the 29 retrospective studies (exceptions are references 11'7 and 152 ) the controls were subjects without lung cancer, such as patients with other cancers. with diseases other than cancer. or so-called normals selected from the population. Analysis of the prospective studies proved that the biases interjected by the selection of sick controls in the retrospective studies actually operated to produce an underestimation of the association. for it has been shown that a number of other diseases are also associated with smoking. Furthermore, several studies have. in addition to controls with other diseases. selected a second set of random controls from the general population (82, 150. 222'1, only to find that the association utilizin g sick controls, significant tholrgh it proved to be, was intermediate to the association utilizing random population controls. The problem of selection bias in prospective studies is much more subtle, since there may be self-selection on the basis of illness existing at the time the study begins. This is essentially a problem of non-response which has been handled in detail in Chapter 8. The character of this non-response presents at least two nuances: a combination of self-selection and operator selection, as in the volunteer studies of Hammond and Horn ( 162) and Ham- mond (157) and the-response to questionnaires in a total population study such as Dorn's (88). Suffice it to say at this point that, regardless of whether there is over- representation of sick smokers or well non-smokers or both in a prospective study, with the passage of time more deaths of sick persons would occur (without regard to the independent variable of smoking). Thus the death rates of smokers would tend to approach the death rate of non-smokers, removing the original selection bias and providing greater confidence in the residual association of the death rate with smoking if it persisted. In two of the studies (157, 162, 163) exclusion of ill persons on entry did take place. Further, in the studies that provide this comparison, the high lung cancer mortality ratio of cigarette smokers was maintained with the passage of time. In the D orn study the mortality ratio was 9.9 after three years experience and 12.0 after six years experience; the Hammond study gave 9.0 after 10.5 months (157) and.9.6 after 22 months, while Doll and Hill (84) showed that the gradient `of increase in lung cancer death rate with increasing amount smoked appeared consistently in each of the first four years of their study. 181 This also weakens the criticism by Mainland and Herrera (230) of the uw of non-professional volunteer workers for subject selection. Thus it would appear that an association between cigarette smoking and lung cancer does indeed exist. CAUSAL SIGSIFICANCE OF ~1-1~ ASSOCIATION.-AS already stated, 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 cigarette smoking and lung cancer a number of criteria must be utilized, no one of which by itself is pathognomonic or a sine qua non for judgment. These criteria include: ia) 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. THE CONSISTENCY OF THE AssocrATIoN.-This criterion implies that di- verse methods of approach in the study of an association will provide similar conclusions. It is noteworthy that all 29 retrospective studies found an asso- ciation between cigarette smoking and lung cancer. The very nature of the criticisms leveled against these retrospective studies indicates a diver- sity of characteristics of approach and, for that matter, marked differences in shortcomings which have been discussed in detail above. It is indeed remarkable that no reasonably well designed restrospective study has found results to the contrary. Seven prospective studies have also revealed highly significant associations. Where relative risks could be calculated on the basis of some reasonable assumptions in some of the retrospective studies, a consistency not only among them (38, 82, 147, 152, 222, 283, 301, 313, 381) but also with the prospective studies could be demonstrated. Such a situation would prevail if the association were either causal, or spurious on the basis of an unknown source of bias. It is difficult to conceive of a universally acting bias in all the diverse approaches unless it be a consti- tutional genetic characteristic or one acquired early in life, which will be discussed later in the section, Constitutional Hypothesis+ Two studies of tobacco workers (58, 141) have been cited as inconsistent with the 29 retrospective and particularly the 7 prospective studies cited in detail in the early portions of this section. Both these studies can be dis- missed because of major defects in methodology and concept. The heavier smoking among the tobacco workers in these studies was considered, but no comparison of observed-to-expected rates was made on the basis of smoking classes within this population. Furthermore their conclusions are based on expectancies in the general population without regard to the fact that persons with acute, chronic, or disabling illness are initially excluded from employ ment and that those developing permanent illness are lost to employee rolls. THE STRENGTH OF THE AssocrATroN.-The most direct measure of the strength of the association between smoking and lung cancer is the ratio of lung cancer rates for smokers to the rates for non-smokers, provided these two rates have been adjusted for the age characteristics of each group. An- other way of expressing this is the ratio of the number of observed cases 182 in the smoker group to the expected number calculated by applying the non-smoker rate to the population of smokers. This provides us with a measure of relative risk which can yield a judgment on the sire of the e,fect of a factor on a disease and which, e\en in the presence of another agent without causal effect, but correlated with the causal agent. will not be obscured by the presence of the non-c.ausal agent. Cornfield et al. (62 1 have uot only provided us with a detailed anal! sis of the applic,atiotls of hoth absolute and relative measures of risk, but have also demonstrated the useful. ness of the relative risk measure in judgin, m causal and non-causal effects with mathematical proof of their statements. An absolute measure of difference in prevalence of a disease between populations with or without the agent I e.g., cigarette smoke`) _ where the agent may be causal in its effect on several diseases. can provide us with the means of appraising the public health significance of the disease. i.e. the size of the problem, in relation to other diseases. It is less effecti\-e for appraising the non-causal nature of agent5 having apparent effects. the importance of one agent with respect to other agents. or the effects of rrfine- ment of disease classification. This, Cornfield and his co-authors / 62 1 hare demonstrated. In essence, then: a relative risk ratio measurin g the strength of an aeoo- ciation provides for an evaluation of whether this factor is important in the production of a disease. In the data of the nine retrospective studies for which relative risks of lung canrer among smokers and non-smokers were calculated, the ratios were not only high in all of the studies but showed a remarkable similarity in magnitude. More important: in the se\`en pros- pective studies which inherently can reveal direct estimates of risks among smokers and non-smokers, the relative risk ratios for lung cancer were uni- formly high and. again, remarkably close in magnitude. Furthermorr, the retrospective and prospective studies yielded quite similar ratios. Important to the strength as well as to the coherence of the association is the dose-effect phenomenon. In every prospective study that provided this information, the dose-effect was apparent, with the relative risk ratio increas- ing as the amount of tobacco (84) or of cigarettes (25, 88, 96, 97, 163) smoked per day increased (Table 51. Even the retrospective studies for which relative risks were calculated by amount smoked (38. 147. 1.52: 222) showed similar increases in risks with amount smoked (Table 4i. It may be estimated from the data in the prospective studies that. in com- llarison with non-smokers, average smokers of cigarettes have a 9- to lo-fold risk of developin g lung cancer, and heavy smokers, at least a 20-fold risk. Thus it would appear that the strength of the association between cigarette smoking and lung cancer must be judged to be high. THE SPECIFICITY OF THE AssocI.~TIoN.-This concept cannot be entirely dissociated from the concept inherent in the strength of the association. It implies the precision with which one component of an associated pair can be utilized to predict the occurrence of the other, i.e., how frequently the presence of one variable (e.g.. lung cancer`) will predict. in the same indi- vidual, the presence of another (e.g.. cigarette smokillg) . In a discussion of the specificity of the relationship between any factor possibly causal in character and a disease it may produce, it must be rec- 183 opnized that rarely. if ever. in our biologic universe, does the presence of an agent invariably predict the occurrence of a disease. Second, but not less important. is our growing recognition that a given disease may have multiple causes. The ideal state in which smoking or smoking of cigarettes and every case of lung cancer was correlated one-to-one would pose much less difficulty in a judgment of causality, but the existence of lung cancer in non-smokers does indeed complicate matters somewhat. It is evident that the greater the number of causal agents producing a given disease the less strong and the less specific will be the association between any one of them and the total load of the disease. But this could not be posed as a contra- diction to a causal hypothesis for any one of them even though the predictive value of any one of them might be small. For example, the pathologist who examines a lung at autopsy and finds tubercle formation and caseation necrosis would almost invariably be able to predict the coexistence of tu- bercle bacilli. Experience has shown that the lesions are highly specific for Mycohacteriurn tuberculosis. On the other hand, a clinician may encounter a combination of signs and symptoms including stiff neck, stiff back, fever, nausea, vomiting, and lymphocytes in the spinal fluid. Experience has re- vealed that any one of a number of organisms may be associated with this syndrome: polio virus, ECHO viruses, Coxsackie viruses and Leptospirae, to name but a few-. The predictability of the coexistence of polio virus per se is rather low. In other words, the syndrome as noted is not very specific for polio virus. Th .: ic may well be the condition which prevails in coronary heart disease where the mortality ratio is between 1.6 and 1.8 or a 60 to 80 percent excess among smokers of cigarettes. If this ratio is appli- cable to the entire population from which the sample data are derived, another w-ay of expressing this relationship is that. of the total load of coronary heart disease mortality among males only 61 to 64 percent is associated with ciga- rette smoking. The large residual among non-cigarette smokers implies either other causes in addition to smoking or, as a somewhat greater possi- bility, factors actually causally related to coronary heart disease and fre- quently, but not invariably, associated with smoking. However, in lung cancer, we are dealing with relative risk ratios averaging 9.0 to 10.0 for cigarette smokers compared to non-smokers. This is an excess of 900 to 1,000 percent among smokers of cigarettes. Similarly, this means that of the total load of lung cancer in males about 90 percent is associated with cigarette smoking. In order to account for risk ratios of this magnitude as due to an association of smoking history with still another causative factor X t hormonal, constitutional: or other), a necessary con- dition would be that factor X be present at least nine times more frequently among smokers than non-smokers. No such factors with such high relative prevalence among smokers ha\,e yet been demonstrated. Another aspect of specificity requires some insight. Several cr%tics of the causal hypothesis have `questioned the significance of the association on the grounds that the existence of an association with such a wide variety of diseases, as elicited in the prospective studies, detracts from specificity for any one of them (22, 7). In a sense, this viewpoint is an exaggeration, for not all the specific disease mortality ratios in excess of 1.0 are large enough to warrant secure judgments of the strength of the association and of causal significance. A detailed discussion of this latter point has been presented in Chapter 8. The number of diseases in which the ratios remain significantly high, after consideration of the non-response bias, is not so great as to cast serious doubt on the causal hypothesis. Even if we were dealing with a single pure substance in the environment, the production of a number of disease entities does not contradict the hypothesis. It is well known that a single substance may have several modes of action on the several organ systems and that neither inhalation nor ingestion implies action restricted to the respiratory or digestive tracts, respectively. In tobacco we encounter a complex of substances whose additive and synergistic characteristics before and after combustion remain inadequately explored. It w-ould not be surprising to find that the diverse substances in tobacco smoke could produce more than a single disease. Actually, the finding that an excess risk for smokers does not occur for every one of the cauSes of death reinforces the specificity of the excess risk for those causes where the excess is significant. Thus, it is reasonable to conclude that the association between cigarette smoking and lung cancer has a high degree of specificity. TEMPORAL RELATIONSHIP OF ASSOCI.~TED VARIAm.Es.-In chronic diseases, insidious onset and ignorance of precise induction periods automatically present problems on which came first-the suspected agent or the disease. In any evaluation of the significance of an association, exposure to an agent presumed to be causal must precede, temporally, the onset of a dis- ease which it is purported to produce. The early exposure to tobacco smoke and late manifestation of lung cancer among smokers, seem, at least superficially, to fulfill this condition. This does not, however, preclude the possibility that such patient? who, many years after the initiation of smoking are diagnosed as having lung cancer, may have had the primitive cellular changes or anlage (as postulated by Cohnheim) before the advent of their smoking. However, no evidence has thus far been brought forth to indicate that the initiation of the carcinomatous process in a smoker who developed lung cancer antedated the onset of smoking. COHERENCE OF THE A~SOCMTION.-A final criterion for the appraisal of causal significance of an association is its coherence with known facts in the natural history and biology of the disease. In the lung cancer-cigarette smoking relationship the following should be noted : (1.) Rise in Lung Cancer Mortality.-The increases in per capita consump- tion of cigarettes (76, 138, 211, 239, 2551 and the age-cohort patterns of smoking among males and females (lS1) are highly compatible with a real increase in lung cancer mortality. (2.) Sex Differential in Mortality.-The current sex differences in tobacco use (151, 160), the pronuonced differences in ape-cohort patterns between males and females, particularly in the older age groups-over 55 (1.51) and over 50 (160) -and the more recent adoption of cigarette smoking by women (151, 344) are all compatible with the high male-to-female ratio of lung cancer mortality and also with the lower ratios of 30 years ago (130). Haenzel and Shimkin (149) developed a statistical model for determining whether the results of the retrospective and prospective studies 185 %ere compatible with the information on distribution of lung cancer and thus valid for generalization to larger populations." Applying their model of scheduled relative risks to data on cigarette consumption by age and sex derived from the Current Population Survey of 1955, their predicted male/ female ratio came quite close to the observed ratio in the general population. (3.1 Urban-Rural Differences in Lung Cancer Mortality.-A number of sources in this country (90, 136, 148, 175, 238, 252) and overseas (82, 199, 335 ) have firmly established this existence of an urban excess in lung cancer mortality. Because of the possible implication of an air pollution effect, this urban lung cancer mortality excess has been cited as either being incom- patible w-ith the smoking-lung cancer hypothesis (178, 229) or minimizing its significance I 69, 70, 71, 101., 190). The data of the studies of a number of authors have clearly shown, however, that although adjustment for smoking history does not equalize the urban-rural lung cancer mortality ratio (149). control on the urban-rural residence factor nevertheless leaves a large mortality risk difference between smokers and non-smokers. Haenszel has demonstrated this fact in his two population sample studies on males and females (147, 1521. Mills and Porter (238) demonstrated a much greater effect of smoking on lung cancer mortality than the urban-rural factor. Stocks (335) also demonstrated that though smoking is not the sole factor, as manifested by a rural-urban gradient among non-smokers, it represented a much more preponderant factor in accounting for the lung cancer mortality than did presumed air pollution or at least urbanization. He noted that his regression lines on amount smoked were parallel for the different areas in England and North Wales and that the urban-rural mor- tality ratios declined from 2.3 among non-smokers and 2.5 among light cigarette smokers to unitv among heavy smokers. The first prospective study of Hammond and Horn 1162) also showed higher lung cancer mor- tality rates irrespective of residence. In Dean's second study in South Africa (70), in which he corrected the critical defect in his first study of not studying the smoking habits of the test populations, he continued to emphasize urbanization or air pollution as the major factor in lung cancer. .A perusal of his data. however. shows that by controlling on smoking, the lung cancer mortality rates arv doubled by the factor of country of ori- gin: whereas. \+.ith country of origin controlled, the lung cancer risk increases from 3 to 20 times as the amount of cigarette smoking increases. After smoking patterns are controlled, the residuals in the urban over rural excess imply other factors, although the smoking factor preponderates in the urban- rural differences in lung cancer mortality in all of these studies. Thus the urban excess of lung cancer mortality is not incompatible with the smoking- lung cancer hypothesis. (4.) Socio-Economic Differentials in Lung Cancer Mortality.-Distinct socio-economic differentials have been demonstrated convincingly in the epidemiology of lung cancer. Cohart (57) found a 40-percent excess of lung cancer incidence among the lowest economic class (both sexes) in the New Haven population, and the morbidity survey by Dorn and Cutler (90) demonstrated a distinct gradient by income class among white males, with the highest rates among the lowest income groups. In Denmark, Clemmesen and Nielsen, utilizing data derived from the Danish Cancer Registry, aIs0 186 found a much higher incidence of lung cancer among males in the lower rental groups (55) . In relation to the contribution which smoking makes to this differential, there is evidence that cigarette smoking may be inversely related to socio-economic status. The components of socio-economic status are, at best, difficult to define, compartmentalize, and measure. Direct inquiries of family income are rare and, when made, are subject to con- siderable error. Studies based on rental values. as in the Danish studies. express more adequately socio-economic status. Another high correlate of income is educational achievement. which has been considered by Hammond in his current prospective study I 161) in relation to smoking habits. Among males, the highest proportion of ciga- rette smokers (past or present) and the highest proportion of those smoking 20 or more cigarettes per day (past or present) w-ere found in the group classified as "some high school education I but not high school graduates ) )" whereas the lowest proportion was found among college graduates. The highest proportion of ex-cigarette smokers (as of 1961-62) was among college graduates. Although the relation of smoking and educational le\-el in women is more complicated, the group which had been to college also had the highest proportion of ex-smokers. Finally. college graduates had the next to the lowest proportion of heavy cigarette smokers. NolIe of the female gradients was a sharp as those for the men. Occupation has also been utilized as a measure of socio-economic status, but this measure obviously has severe limitations. No definitive study has been reported in which lung cancer has been correlated with occupation and smoking class; the current Hammond I 1571 and Dorn 188) prospec- tive studies may ultimately yield definitive findings in this regard. However. some indirect evidence of a partial correlation between the observed higher lung cancer death rates in lower socio-economic groups may be found in Table 26 of the Survey of Tobacco Smoking Patterns in the United States I, 151). Keeping in mind that type of occupation is not a critical index of income, it will nevertheless be noted that the professional and farmer and farm manager groups had higher proportions of non-smokers among them than did the laborers and craftsmen. This finding is in the proper direc- tion for compatibility with the socio-economic differential in lung cancer mor- tality but the disparity does not appear to be sufficient to provide a satisfying correction. In fact, in this U.S. study, analyses by amount of cigarettes smoked tended to obscure the ordering by social class. In Great Britain, however, the inverse relationship of socio-economic class to heavy cigarette smoking remained apparent (174). In the U.S. study, classification by industry showed the highest proportions of non-smokers to be in the pro- fessional and agricultural groups and the lowest among industries. Thus, though the measures are admittedly crude. they are compatible with the socio-economic differential in lung cancer mortality. (5.) The Dose-Response Relationship.-If cigarette smoking is an im- portant factor in lung cancer, then the risk should be related to the amount smoked, amount inhaled, duration of smoking, age when started smoking, discontinuance of smoking, time since discontinuance, and amount smoked prior to discontinuance. Herein lies the.greatest coherence with the known facts of the disease. In almost every study for which data were adequate 187 and which was directed to amount of smoking, duration of smoking and age when smoking was begun, the associations or calculated relative risks (direct or indirect) revealed gradients in the direction of supporting a true dose effect. Where discontinuance, time since discontinuance, and amount smoked prior to discontinuance were considered in either retrospective studies or. with more detail, in prospective studies, these all showed lower risks for ex-smokers, still lower risks as the length of time since diseon- tinuance increased, and lower risks among ex-smokers if they had been light smokers. These findings have been described in detail in the section on Retrospective Studies. Some contradictory information has been presented in regard to inhalation of tobacco smoke. This is the lack of association between inhalation and lung cancer as noted by Doll and Hill (82) alluded to earlier. These authors have begun collecting data (iu their prospective study) on inhalation for the mortality experience since 1958. These data are not presently available (80) . However, until the current ongoing prospective studies will have yielded in- formation on this point in regard to lung cancer, four retrospective studies provide information on inhalation contrary to the Doll and Hill early nega- tive findings ( 38, 211, 222, 313). In two of these (222, 313) inhalation and amount of smoking were considered and led to the provocative finding that with increase in daily amounts of cigarettes smoked the differences in risks between inhalers and noninh,ders diminished. There is no immediate ex- planation for this apparent discrepancy. Hammond has studied the smoking habits of the men and women in his current prospective study quite intensively ( 160). He has observed that the majority of men (92.9 percent) who smoke cigarettes inhale, and of these the majority inhale "moderately" to "deeply." Pipe or cigar smokers inhale rarely. Combination smokers i i.e., cigarettes in combination with pipes and/' or cigars) inhale in proportions intermediate to these. These findings become compatible with the hypothesis that the degree of inhalation accounts for a gradient of lung cancer risks, high to low, for smokers of cigarettes only. combination smokers, and pipe or cigar smokers (Table 5). An explana- tion of the diminishing differences in risks between "inhalers" and "non- inhalers" with increase in amount smoked might be obtained if a more objective measure of inhalation were available. (6.) Localization of Cancer in Relation to Type of Smoking.-Although historically a relationship between cancer and smoking was suspected by Holland ( 176) and Soemmerring (322) with reference to the lower lip, it was not until the systematic, controlled study of lung, lip, pharynx, esophagus. colon and rectum cancers in relation to types of smoking by Levin in 1950 that significantly distinctive associations between localization of the cancer and type of smoking were ehcited (207). Levin noted that statistical sig- nificance was achieved for cigarette smoking and lung cancer and for pipe smoking and lip cancer and stated, "It is somewhat surprising that type of smoking is the associated factor, rather than the actual use of tobacco." Since then other studies have pointed up the relationship between type of smoking and localization of ca.ncer. Sadowsky I 301) in relative risk estima- tions of types of smoking and cancer site, also noted the highest significant values for cigarettes with lung, larynx and esophagus; for pipes with lip. 188 tongue and oral cavity; and for cigars with tongue and oral cavity. The complexities involved in a rational explanation for these phenomena are legion. especially since critics of the smoking-lung cancer hypothesis would point to no phenomenal rise of laryngeal cancer (onl?- a slight rise for whites between 1930 and 1955i in the face of increased cigarette consumption. Although among cigarette smokers, the relative risk of mortalit!- from lung cancer is presently greater than the relative risk for laryngeal cancer, the reverse seems to be true among cigar and pipe smokers I Chapter 8, Tables 19 and 24). Furthermore. the per capita riae in cigarette consumption has been accompanied by a concomitant decline in consumption of pipe and cigar tobacco, the smoke of which was not deeply inhaled. It is thus con- ceivable that the increase in cigarette consumption ( and decline in cigar and pipe smoking) could affect an increase in lung cancer more significantly than in laryngeal cancer. Finally. there is no reason to assume that the susreptibility of the larynx to cancer equals that of the bronchus. Thus. a reasonable explanation for the difference in localization and relative risk is apparent. especially when it is known that in certain industrial exposures in which the irritant is in- haled and lung cancer is associated with such inhalation ~chromatesi, laryngeal and tracheal cancer is rare. It is. on the other hand. easier to visualize a mode of action for pipe and cicar tobacco in production of lip and ton,- and other oral cavity cancers. Thus, none of these considerations de- tract from the coherence of the association between cigarette smoking and !ung cancer. HISTOPATHOLOGIC EVIDEIVCE In earlier -mtions of this Chapter it has been noted that the application of tobacco extracts, smoke or condensates to the lung or tracheobronchial tree of experimental animals has failed to produce bronchogenic carcinoma, except possibly in dogs ( 289 I . I n addition, no animal experiments have thus far been devised to duplicate precisely the act of smoking as it is practiced by man. However, that the lungs of experimental animals are susceptible to car- cinogens, particularly polycyclic aromatic hydrocarbons isolated from to- bacco smoke. has been demonstrated by a number of workers (5, 197, 302). Of immediate import to the smoking-lun g cancer relationship is the observa- tion that the histopathologic characteristics of the cancers thus produced are similar to those observed in man and are predominantly squatnous in type. Furthermore. certain bronchial epithelial changes, sequentially observed prior to the malignant changes in animals exposed to these carcinogens are similar to those in the bronchial epithelium of human smokers (9). In this latter extensive and well-controlled study, these changes were rarely seen among non-smokers, but increased in frequency and intensity with the number bf cigarettes smoked daily by individuals without lung cancer and were most frequent and intense in patients dying of lung cancer (Table 6 of this Chapter). Ex-cigarette smokers and pipe and cigar smokers yielded a higher frequency of such cellular changes than non-smokers but less than did current cigarette smokers. Thus. the histopathologic evidence derived from laboratory and clinical material supljort the cigarette smoking-lung cancer hypothesis. 189 CONSTITUTIONAL HYPOTHESIS GESETIC CoNsrDERATloPs.--Thus far in the evaluation, the Committee has considered whether the al-ailable data are consistent with the hypothesis that smoking causes cancer of the lung. The analysis must consider with equal attention the alternative hypothesis that both the smoking of cigarettes and cancer of the lung hare a common cause which determines both that an individual shall become a smoker and also that he shall be predisposed to lung cancer. This h as often heen called the constitutional hypothesis. How- ever. one should distinguish between the morphologic and physiologic char- acteristics of any individual due to a given environment and those character- istics (phenotyie~ that are due to an interaction of hereditary susceptibility and the environment. The characteristics of individuals studied in relation to smoking have been numerous and varied. Some of them have been physical attributes such as physique or somatotype, height and weight and their ratios, masculinity, anthropometric variables, physiologic variables (heart rate, pulsk pressure, blood pressure, cholesterol le\-els), and physical activity; others have been psychosocial iincluding persoqalitv-i in character (Chapter 14). Cigarette smokers have been described as consuming more alcohol, drinking more black coffee. being more neurotic. engaging more often in athletics: and as being more likelv to have at ltaast one parent with hypertension or coronar!- dieeasr i 1.X. 214. 235). Many studies have been poorly designed and controlled. others have yielded contradictory findings: and still others. 1)~. admission of their authors. have included characteristics that could either have heen acquired or have heen produced by smoking. None of these constitutional attributes have been included in a prospective study of mor- tality front Lund cancer fulfilling satisfactory epidemiological criteiia. except for a breakdo\\n h! longeviti of parents.and grandparents in one study ( 1.59 I. Thr penrtics of the c%haracteristics themselves has not been deter- mined. and adequate anal!si; of common genetic determinants in relation to the hahit of smoking has not been attempted. No environmental deter- minant.< that ~vould uni\-rrsall7; induce smoking and also produce the char- acteristics are evident I 02 I or have been proposed. Fisher I 11:: I bar: hem forelnost in calling attention to the possibility that cancer of the lung and the habit of smoking may be due to a common geno- type. Selection of smokers then would automatically provide a population in I( hich I)uln~onarv canrer would appear on the basis of genetic suscepti- hilit)-. Studies on the concordance of smoking in twins (122. 127,281. 3561 were used to supl)ort the hvljothesis, since more monozypotic pairs haye similar smoking hahits than.do dizygotic pairs. Although the data on the smoking hahits of identical and fraternal twins raised apart are compatible with this h!-pothesis. the histor Y of cancer in twins whose smoking habits are knorin has ne\-er been documented sufficiently to be useful in helping to resolyp the question of whether the concept of the constitutional hypothesis is valid. Also information about the habits and medical history of other siblings. offspring. and parents is singularly scanty, and efforts to separate genetic factors from influences of the environment in such studies have been only rudimentary. 190 Although single genes may be involved in a few exceptional neoplastic and preneoplastic states such as retinoblastoma and precancerous colonic poly- posis, genes for susceptibility to human cancer are usually multiple (48). Whether multiple genes for susceptibility may also be operating in the instance of cancer of the lung has not been established. The linkage (in a genetic sense) between multiple genes related to a habit (smoking) and a disease (lung cancer) in an heterogeneous population would require numer- ous coincidences with small probabilities. Also, in order to adhere to a con- sistent argument in explainin g the reduced incidence of cancer of the lung in this group, it would be necessary to postulate another common genotype for those who smoke and subsequently terminate the habit. The argument becomes even more labored when multiple examples of identical genotypes for susceptibility to smoking and respective specific types of cancer are re- quired by the hypothesis to explain the multiple types of cancer associated writh smoking. Since cancer of the lung occurs in both men and women who do not smoke, susceptibility genes acting alone or in combination with extrinsic or additional intrinsic factors can be effective without exposure to tobacco smoke. The occurrence of the disease, therefore, is not invariably linked to hypothetical genes responsible for the habit of smoking. Since susceptibility to cancer may be due to multiple genes with variable penetrance, and since the expression of these genes may change with environmental conditions, a minor portion of the cases of pulmonary cancer can be explained as the expression of genetic susceptibility in an environment excluding the habit of smoking. Smoking then mav add an extrinsic determinant which can increase the incidence of cancer of the lung beyond that which would otherwise prevail in the same population. It should be emphasized that comparisons of lung cancer mortality in smokers, non-smokers and ex-smokers have been made on different popula- tions. Thus, in considering the fact that the incidence of lung cancer appears to decrease when smoking is discontinued, it must be remembered that the population which can stop or does stop smoking may differ from that which continues. It is possible that the ability to terminate the habit may also be determined genetically. In assessing the importance of a possible genetic influence in the etiology of lung cancer, it should be recalled that the great rise in lung cancer inci- dence in both men and women has occurred in recent decades. This points either to a change in the genie pool, or to the introduction of an agent into the environment, or a quantitative increase of an agent or agents capable of inducing this type of cancer. The genetic factors in man were evidently not strong enough to cause the development of many cases of lung cancer under environmental conditions which existed half a century ago. In terms of what is known about rates, pressures, and equilibria of human mutations the asumption that the genome of man could have changed gradually, simul- taneously and identically in many countries during this century is almost inconceivable. 714-422 O-64-14 191 Smoking may be placed more properly in the role of an environmental determinant than as part of the phenotype of the pluripotential gene or genes, interacting with the environment and resulting in cancer of the lung. Current evidence is compatible with the opinion that genetic factors play a minor role compared to thse contribution of the smoking habit in the etiology of lung cancer today. EPIDEMIOLOGICAL CoivsmER,\TIoi%-Although evidences for the consti- tutional hypothesis are, at present, either tenuous or actually lacking, the basic philosophical and logical prerequisites for this hypothesis are contra- dicted by a number of well-established observations (62) : ( 1.) Lung Cancer Mortality.-Lung cancer mortality has been increasing in the last SO years and much more in males than females. This in- crease could be due to either an environmental change or a mutation. Since an unchanging constitutional makeup cannot of itself explain the in- crease, we must postulate either that there are genetic differences which make some individuals sensitive to a new environmental factor (not tobacco), or that differences in constitution,al makeup ire not genetic but the result of differential exposure to some new factor that predisposes to lung cancer and creates the desire to smoke, or that the mutation has produced an increased susceptibility and a desire to smoke. For the first two postulates a new,en- vironmental factor, other than tobacco, is required. Such a factor, it must, be remembered, must be correlated with lung cancer as highly as are ciga- rettes and also highly correlated with cigarette consumption. None has yet been found. In order to account for the magnitude of the lung cancer mortality increase, the third postulate would require a mutation rate which far exceeds any observed. (2.) Tobacco Tars.-Tobacco tars have been found to be carcinogenic for experimental animals. AlthouiFh carcinogenicity of tobacco tars has not been demonstrated in man, the constitutional hypothesis would require that they are not, and that the association with lung cancer in man of substances found to be carcinogenic for experimental animals is a coincidence. (3.) Pipe and Cigar Smoking.-Pipe and cigar smoking appears to have a higher correlation with laryngeal and oral cancer than with lung cancer. The constitutional hypothesis would require that there shall be two consti- tutional makeups, one predispos.ing to cigarette smoking but not to pipe and cigar smoking and also to cancer of the lung; the other predisposing to to- bacco consumption in any form and to cancer of the larynx and oral cavity but not to cancer of the lung. The alternative within this hypothesis would require that the special constitut.ional makeup predisposes to cigarette smok- ing and lung cancer, but that tobacco smoke, whether from cigarettes, cigars or pipes, is carcinogenic for the larynx and oral cavity but not for the lung. These requirements are unrealistic. (4.) Ex-cigarette Smokers.-Ex-cigarette smokers have a lower lung-can- cer mortality and a gradient is noted by length of time smoking has been dis- continued and by the amount previously smoked. This would require complicated genetic interrelationships if the constitutional hypothesis were to be satisfied. A simpler hypothesis, which involves a causal relationship be- 192 tween smoking and lung cancer, but recognizes differences, defined or ill defined, between smokers and non-smokers may be stated as follows: There are factors in the individual acquired early (or genetic I which predispose to cigarette smoking, and cigarette smoking by direct action of smoke on the bronchial epithelium is a major factor in producing lung cancer in susceptible individuals. A detailed discussion of the significances of the data on psycho-social, constitutional, and physical characteristics of smokers and non-smokers is presented later in this report (Chapters 14 and 15). The role of the genetic factor in carcinogenesis has been discussed earlier in this Chapter. OTHER ETIOLOGIC FACTORS Ah'D CONFOUNDING F'ARIABLES Throughout this evaluation. it has been recognized that a causal hvpothesis for the cigarette smoking-lun g cancer relationship does not exclude other factors. This is attested to by the fact that a small but not insignificant percentage of cases of lung cancer does occur among non-smokers. Some estimates in retrospective studies and most of the prospective studies indi- cate that approximately 10 percent of the lung cancer cases are in non- smokers. Doll (78) h as p rovided a higher estimate of 20 percent. Further- more, the inability to account for the higher lung-cancer incidence in the lower economic classes entirely by disparities in smoking habits, which do exist, does imply other causal factors. Several other possible etiologic factors which have been explored merit discussion. These include occupational hazards, urbanization or industrial- ization and air pollution, and previous illness. (1.) Occupational Hazards.-In an extensive review of the literature on lung cancer in chromium and nickel workers and in uranium miners, Seltser (318j found the evidence for an excess of lung cancer mortality among chro- mate workers highly consistent. However, because of the smallness of the numbers involved, caution must be exercised in any calculation of the magni- tude of the risk. Furthermore no evidence has been presented either for or against an excess risk of lung cancer among workers exposed to other chromium products or chromium mining. The evidence for an excess risk among nickel processing workers in refineries was even more consistent than for chromate workers. The lung cancer risk was five times greater among nickel processing workers than in other occupational groups in the same area (the risk for nasal cancer was 150 times higher). Among uranium miners an excess risk is apparent (3601, and is greater than in certain other miners of similar ores without the high radioactivity component (361). Although the induction of lung cancer by radio nuclides is probable in man, the evi- dence is not as firm as in animals. In addition, Doll has found a significant excess of lung cancer deaths among coal gas workers i81) and asbestos workers (77 i . In another review article, Doll (79) has added arsenic and hematite as suspects to the list, with isopropyl oil, beryllium, copper. and printing ink as possible risks. The evidence for the possible role of arsenic as a factor in the etiology of lung cancer has been summarized by Hueper (178), and I{uechley (45) has 193 recently suggested that it merits epidemiological investigation. The chief points of evidence cited include 1) the universality of arsenic in many ores and in the atmospheres in and near smelters; 2) the widespread use of ar-s&c as an insecticide and rthe consequent exposure of workers in insecti- cide manufacture, agricultura.1 workers, and those handling or consuming crops with arsenic residues; and 3) reports of a relatively high incidence of lung cancers in people living around smelters processing arsenic-containing ores, and also in vineyard workers exposed to large amounts of arsenical pesticides and consuming large amounts of arsenic-contaminated beverages. It is noteworthy that for the nickel and chromate material the lung cancer mortality is referrable to a high exposure period in the respective industries, a situation which probably does not prevail today. Of greater importance is the regrettable fact that in none of these occupational hazard studies were smoking histories obtained. Thus the contribution which smoking, as a contributory or etiologic factor, may have made to the lung cancer picture in these risk situations is unknown. However, the series of cases in non- smoking chromate workers is large enough to exclude the possibility that cancers of the lung in chromate workers develop only in those who smoke cigarettes. Nevertheless, it must be emphasized quite strongly that the popu- lation exposed to industrial carcinogens is relatively small and that these agents cannot account for th'e increasing lung cancer risk in the general population. (2.) Urbanization. Industrialization, and Air Pollution.-The urban-rural differences in lung cancer mortality risk, though small and accounted for in part by differences in smoking habits (see section entitled Coherence of Association) ) nevertheless may have a residual which implies other etiolopic factors in an urban environment. This has been the explanation offered in the studies by Stocks and Campbell (337) and Stocks (335) who noted a gradient among non-smokers, light cigarette smokers and pipe smokers by density of population but who found no gradient among heavy smokers. Less direct evidence was derived by Eastcott (101) and Dean (69, 71 j who found higher lung cancer rates among migrants from Great Britain to New Zealand. South Africa and Australia, respectively. Their inferences were that these immigrants had had significant exposure to air pollution in Eng- land prior to coming to the Commonwealth countries. Unfortunately, these interpretations were untenable for there was no individual case-control in- formation on tobacco consumption. A correction of method by Dean in a later study (70) did elicit smoking histories and revealed a marked influence of cigarette smoking but a significant though lesser factor of urbanization. Doll's study of non-smoking lung cancer cases (78) revealed no differences in risk among men and women and in residents of areas of different popula- tion density. His findings cannot be considered to be conclusive of a nega- tive result. for density of population need not necessarily be highly correlated with pollution. In a more recent, as yet unpublished, paper by Stocks* a *Stocks. P.: A Study of Tobacco Smoking, Air Pollution. Residential and Occupa- tional Histories and Mortality from Cancer of the Lung in Two Cities. Inter-regional Symposium on Criteria for Air Quality and Methods of Measurement, W.H.O., Geneva, Switzerland, August 6-12, 1963. 194 mathematical model embodying amount of smoking, age, air pollution measurements by specific carcinogenic constituents, proportion of life spent in country and town, and lung cancer mortality was applied to the data de- rived from Belfast and Dublin. The lung cancer death rates were found to be compatible with an hypothesis that in Belfast about two-thirds of the deaths of men resulted from cigarette smoking and one-third from air pollution by smoke and, in Dublin, 75 percent from cigarette smoking and 25 percent from air pollution. These data are not offered as proof but represent the ap- proaches necessary for future research in the area of proportional contribu- tions to lung cancer mortality. Such appl t ica ions may be useful in determin- ing the role of air pollution in such disparate lung cancer mortality rates between, for example, the United States and Great Britain when adjustments in smoking habits still do not eliminate the difference completely. Two studies (147, 152 ) have also indicated that migration of rural people into urban areas subjects them to lun g cancer risks greater than for life- time urban residents. This effect is noted among non-smokers as well. The least that can be said is that the intensity of urbanization or industrializa- tion may have a residual influence on lung cancer mortality. (3.) Previous Respiratory Infections.-Relatively few soundly designed studies have tested the effect of prior respiratory disease, particularly infec- tions, on the development of lung cancer. Winternitz (371) called attention in 1920 to proliferative changes in cases of post-influenza] pneumonia similar to those seen in invasive, malignant neoplasms of the lung but this report stimulated relatively few epidemiologic observations. In the retrospective study of the smoking-lung cancer rela- tionship by Doll and Hill (82) inquiry into a history of previous respiratory infections led to finding a significant excess of antecedent chronic bronchitis and pneumonia among lung cancer patients even when smoking class was controlled. However, because a collateral comparison with another control group of patients, for whom a lung cancer diagnosis was subsequently found to be in error, failed to reveal a difference, Doll and Hill concluded that either "chronic bronchitis and pneumonia predispose to a whole group of respiratory disorders . . . or that patients with respiratory disorders recall previous chronic bronchitis and pneumonia more readily than do patients with diseases with other symptoms." However, almost simultaneously Beebe (20) investigated the relationship between mustard gas exposure, chronic bronchitis, pneumonia and influenza and lung cancer, and Case and Lea (53) between mustard gas exposure and/or chronic bronchitis and lung cancer. Smoking histories were controlled in these studies. Beebe found no evidence of an increased lung cancer risk with an antecedent history of influenza] pneumonia and primary pneumonia but there did appear a highly suggestive association between mustard gas exposure and lung cancer. No relationship between chronic bronchitis and lung cancer was noted. Case and Lea, however, interpreted their findings to mean a sequential relation-. ship between mustard gas exposure, chronic bronchitis, and lung cancer. The lung cancer risk was doubled by pre-existing chronic bronchitis. Doll, 195 in a later review (76), however, indicated that since the smoking-lung cancer relationship is stronger than the chronic bronchitis-lung cancer relationship, chronic bronchitis is not a necessary intermediate pathogenetic process. The failure of the Beebk study to affirm the Case and Lea findings in regard to chronic bronchitis may lie in the problem of differences in British and American diagnoses of chronic bronchitis. In an epidemiologic approach to other factors in lung cancer risks, Denoix et al. (72) studied 160 characteristics. Among other factors, much less strongly associated with lun,g cancer than smoking of cigarettes, they found a history of exposure to war gas and chronic bronchitis to predispose to lung cancer. The war gas component was strong enough to double the risk of lung cancer even with control on smoking class. Thus, the observations on previous respiratory illness are too few in number to place any degree of assurance on a relationship, but the studies hy Case and Lea and by Denoix et al. remain interesting. (4.) Other Factors.-Numerous other factors, such as coffee drinking, alcohol consumption, nutritional status, and beer drinking, have been studied and some associations with lung cancer have been found, but none of them does more than double the risk (and sometimes these are noted to be as- sociated with lung cancer via the smoking component') as compared to the 9- to lo-fold risk in average cigarette smokers and the 20 + fold risk in heavy smokers. Conclusions 1. Cigarette smoking is carnally related to lung cancer in men; the mag- nitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. 2. 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. 3. 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 in non-smokers, but much less than for cigarette smokers. The data are in- sufficient to warrant a conclusion for each group individually. ORAL CANCER Epidemiologic& Evidence The suspicion of an association between use of tobacco and oral cancer dates back to the early 18th Century when Holland ( 176) first noted cancer of the lip among users of toba.cco. In 1795, Soemmering (322) made the same observation. In the pre;ent era. additional clinical observations have been recorded. The investigators noted the proportions of users of the 1% various forms of tobacco among the various cases of oral cancer and found clues to a relationship. These observations lacked controls. Notable among these reports are the review by Haase (142) emphasizing location of the cancer of the lip and mouth according to where the pipe was held; the analysis by Ahlbom (1) by specific type of tobacco use in relation to site; and the work of Potter and Tully (280) which indicated an increase in risk of oral cancer with increax in smoking. From the first two studies mentioned (1, 142)) it is immediately apparent that any reasonably meaningful study of the relationship between tobacco and oral cancer must take into account ndt only the specific sites (lip, cheek. gingiva, tongue, oropharynx, etc.) hut also the precise form of tobacco u-se (pipes, cigars, cigarettes, chewing tobacco. snuff, etc.). Of additional interest is the specialized use of tobacco as a component of hetel nut quids in certain areas of the world: several observations suggest an association with oral cancer (66, 67. 269. 319). In contrast. observations of populations using betel nut quid s without tobacco (104. 234. 367) in certain other areas of the world show no association of betel nut with oral cavity cancer. More formalized case-control or retrospective studies varying in spe- cific approach, in suitability of controls and in sample size have appeared between 1920 and the present (26,41,103,202,207,221,237,245,272.301, 306, 314, 326, 355, 369, 385, 387, 388: 398 I. These studies are described in Table 10 which includes general smoking data, for the most part, on com- binations of specific sites of orat cancer. A number of these investigations either did not separate the several sites of the oral cavity because of the small number of cases for each site or. upon separation into such sites, found the smoking classes too numerous for testing of significance (26,221, 237, 388). Since associations with form of tobacco use varied according to smoking classes and, wherever possible, to specific sites (Table lOA), in this sum- mary table, a statistically significant positive association is designated by a plus sign, whereas the lack of such an association is designated by a minus sign. A plus-minus sign indicates that there was some evidence of an asso- ciation which was not, however, statistically significant. It will immediately be noted that in 10 of 17 studies all oral sites were combined in an attempt to elicit an association with forms of tobacco-use (26, 202, 221, 237, 245, 272, 306, 314, 326, 388). Although eight of these showed positive association, they were so scattered among the several forms of tobacco use that little can be derived from them. Furthermore, distinctly specific site associations may be masked by such combinations. In examin- ing the data for specific site localizations and forms of tobacco use, several associations become clarified. It would appear that pipe smokin g is associated with lip cancer in all six studies in which this site and form of tobacco use was analyzed (41,103,207, 301,378,385). In one additional study (237) an association with pipe and cigars com- 197 TABLE lo.--Outline of retrospective studies of tobacco use and cancer of the oral cavity T Co"trols __- Method of selectlo" Investlgetor and yen, Her- W"Cl Collection of data Numba 500 VU"llR 526 II .__ 217 Method of selcctio" ,' -- `r -_ (41: ("21: Series of elimc patients without epithelion~n of the lip. 7s. 6% tobacco users 75.2% xnokers 44.4% rigarettes 13.4%, chew ZS.G% pipes 44.0% cigars Apparently by interview in the clinic. U.S.A. M F Series 01 rlinir patients with epi- thclioma of the lip. 80.6% tobacco users 75.1'% sl"okers 0.9% +arettes 24.0% chew 59.0% pipes 38.57, cigars Clinic patients with cancer of vsriou sites. Site breakdown md smoking data not rlpar. Lonlhanl and Doer- ing lW%. 217 Clinir pnticnts without cancer, "Wched by sex and age. Smok. in7 ,,?,+* .,,>* "I"". . ..* ""%.. ..1(1 \.Y`.L. Personal interview by investigators in clinics. 1J.S.A. M-F __ Bigelow and Lorrlbnrd, 1933. (27: (103) (? 439 33 143 Patients without ca"cer, in eom- parable "u"lbers. 26.5% "on-users 24.07:. excessive users (Table 111). -__-- Sweden M F ) Clinic and hospital patients, ap- parently several hundred. 14.2% "on-USXS. 36.4% exessive users (Table 111). -___ Clinic patients with cxncer of the tin Personal interview in hospitals and clinics. /- Not defined. 68.7% tobacco "sers. M 1 to 2 701 tobacco users, F 22.9% pipes, M 60.7% chew OT use snuff, M 32.5% cigars and cigarettes, M Ebenius 1943 _.,. 79.7% tobncro users, M 57.6% tobacco user+, F (all pipes) 61.8% pipes, M 47.4% chew OT "se snuff, M 12.9% rigars and cigarettes, M - Canrer institute patients with cancer of the lip. 84.5% smokers 45.3% cigarettes 48.1% pipes 26.5% cigars Levi" et al. 1950 m7) 1J.S.A. 1 M Rolltine clinic interview. Csnrer institute patients with non-cancer diseases of same site. 74.0% snlokers 43.00/, cigarettes 30.7% pipes 34.9% cigars Mills and Porter 1950 (237) M 124 185 Sn"lple of population of Colum- bus. Ohio, and in same proportion of valor, sex, and age as in CRSW. 32.4% cigarettes only `29i;~;sPipes, rlgers. or combina- From next of kin of deceased by rnsil questionnaire or by personal interview. Controls by house- to-house interview. Deaths from canrcr oi oral cavity ill Cincinnntl and Detroit, 1940- 45 and 1942-46, rcspectivcly. 35.5% eiearettes only 54i~~XXs"prs, clpirrs. or combina- _- - Moore et al. 1953 (245) U.S.A. M 112 Patients OYer M yrs. old since 1961 with ca"cer of oral cavity. 38 Patients of same age groups with 53.0% chew be"irn oral lesions or benign Personal IntervIew of contmls; fool cases, next-of-kin were visited or 42.0% pipes surgical amditions. 38.4% cigars and cigarettes 31.6% chew contacted by letter. 47.4% pipes 52.6% cigars and cigarettes ____^.____ Sadowsky et al., 1953 (301) IJ.9.A. Smghvl et al., 1955 -- (306) India M F 136 Hospital patients with oral and pharyngeal cancer, 193M& 42.3% cigarettes only 4.0% cigars only 6.57 31 17.3% pipes only 23.2'% mixed IIospibl patients with cancer of M oral cavity and pharynx. F 3~3.87~ smoke and chew, M; 3.7% F 46.7% smoke only, M; 6.2y0 F 11.7% chew only, M; 64.2% F 2.7y0 neither, M; 25.9% F (Smoking is of bidis among both cases and controls.) 615 Pntients with illrlrss other than Ily trained lay interviewers, cmccr. 53.3% cigarettes only 3.4% cigars only 7.0% pipes ouly 23.1% mixed Hospital patients witb disetlses other thxn cancer. 24.0% smoke and chew, M; 0% F 50.0% smoke only, M; 6.3% F 8.7% chrw only, M; 23.2% F 17.376 neither, M; 70.5% F Personal history interview in hos- pital. Ledermenn 1955 Wynder et al., 1957 (202) France M (373) U.9.A. y- 240 Patients with cancer of oral cavity 62 & pharynx. Patients with cancer of ski", bone, FIYlSCk. 4.6% non-smokers 17.2% "on-smokers 23.4%>20 cigarettes per day 18.6%>20 cigarettes per day 543 Patients with cancer of oral cavity M 207 Patients with cancer of other sites Personal Interviews tn hospltsl or 116 1 3% non-users, M; 4770 F 20% cigars, M 11% pipes, M 3% mixed, M 17% chew, M 57% cigarettes, M: 53% F 29%>35 cigarettes per day, 34%>16 cigarettes per day, W;;l$ns and Vogler (369) U.S.A. $f 37 Clinic ad hospital patients with NO"e 44 cancer of gingiva. 327' chew or chew and smoke, M 20?& smokers, M 52% use snuff, F 9% smokers, F and benlg" disexes. 10% non-users, M; 70% F 1~37~ cigars, M 6Y0 pipes, M 8% mixed. M Sal0 chrw, M clinic. 63% cigarettes, M: 307, F 17%>35 cigarvttcs per day, M 110/,>16 cigarettes per day, F Clinic and hospital histories. pt;tir;ts with "on-cancer Questioned about the swne time wcident CLLSCS, by the same interviewer. TABLE lO.-Outline of retrospective studies of tobacco use and cancer of the oral cavity-Continued Investigator and yea `le Ref- rem Country T sex F P i-i-- F M G- F CmS T C0*tr01s Nunbe] - I . . !r -- Method of xlectlon Collectlo" of data Method of selection Wynder et al. 1957 (388: , Cuba Hospital clinic patients with mncer of oral cavity and pharynx. Personal questiontng in clinic, all by 2 interviewers. 4% "on-smokers, M; 24y0 F 45% cigarettes predom., M; 62% F 33% cigars predom.. M; 12% F - -- -- Wynder et al. 1967 Sweden -- rumbe 178 34 115 140 ---ii al 383 Hospital patients with cancer of oral cavity and pharynx. -- -- -- _- _- M 116 F 166 Patients in same hospital with center of sites other than oral, pharynx, larynx, lung, esopha- gus and breast. 36% cigarettes, M 9% cigara, M 16% pipes, M 13% mixed, M Personal interview in hospital; and medical histories. 3&S?& cigarettes, M i3.0yo oijara, M 12.2% @pes, M 15.7% mixed. M Peacock et al. 191% m: __-- U.S.A. Hospital patients with oral cancer "F :: Persons1 interviews. 66.67o chewed or used snuff over 20 years. Patients in same hospital without oral wwer and 117 male and 100 female randomly selected outpatients. 32.6?0 of Arst nroup, 43.30/, of second group chewed or used snuff over 20 years. Staszewski ,880 (3271 Poland Male patients with oral cancer 912 -- -_ Male patients with other cancer a"d "on-cancerous conditions. 17.3% non-smokers 49.0% "heavy" smoking index aO..5% cigarettes only 11.1% pipes and/or cigars Personal interviews. 5.7% non-smokers 72.8% "heavy" smoking tnder 72.3% cigarettes only 12.3% pipes and/or cigars Vogler et al. IQ62 (35.51 J:S.A. 133 92 Clinic patients with cancer of lip and oral cavity. M 521 F 1,064 Patients of same clinic with other cancer or non-ma&want mndi- tions. 6.1% snuff dippers, F 2 5670 totwco users, M + F `erwnal interviews in clinic. 32.Wo chewers, M 2 22.9% excessive chewers, M 72.07, snuff dippers, F 41.3% excessive snuff dippers, F 905% tobacco users, M + F - ' Estimate of prevalence o "se. f Due to varying tabular treatment of the data, the percentages of tobacco wars are not all based on the same numbers of cases. Investigator and reference Cigarettes Broders (41). ..~ .~ . . . . . . Lombard and DoerIng wzl). Bigelow and Lombard (26) Ebenius (103) ____._.... ~.. Levin et al. (207).-..~ . . . . . Mills and Porter (237). (Lip)- *.. .~~.-.- ____._.. ~. (Lip)+ ____ ~.__~.._~ . . . .._.__ (Lip)- _.__..__._.. ~.~~~ . . . . . (Lip)+-...-- . . .._ _ ._._.... (Oral)*.. ~~.~...~ . . . . . .._.. ..__._._._._._....._ ~.~ . . . . . . (Lip, mouth)- z..- ~... (Lip, mouth)-.... -~_~ (Lip, tongue, other oral, (Lip, tongue, other oral)+.. pharynx)-. (Oropharynx)+ 3 ___._.._.... . . . . . . . . . . .._.__.___..... ~... (Oral)+. fhl, +F (Floor of mouth)-. (Each site except tongue)+. (Pharynx)+ ' . . . . . .._____... My2n;p+ (Oral and phnr- CO+)-. (LIP)+- .____.. ~~ ._..____.... y&afPnx)+, (Other ...-~.~.~~~ . . . . . ..-.......... Moore et 81. (245)m . . . .._ Sadowsky et al. (301)... Sarlghvi et al. (306) _______ Ledermarm (2w.. __~. Wynder et al. (378) ._____. Schwa&et al. (314)m.... Wyndrr et al. (338) . . . . . . Wynder et al. (385) ~~. ~~ Peacock et al. (272). _. Staszrwski (326). _..~-..~ Vogler et RI. (355) . . . .._.. TABLE lOA.-Smmry of results of retrospective studies of smoking by type and oral cancer of detailed sites ' Pipes cigars (Lip) - .___. ___ _. . -.. Chewing (Lip)+. - Miscellsneous --~-___ (Lip,oralcavity)+ __.. ~..~ . .._.............. . . . . . . -._ (UP)*. (Tongue, other oral)+. (Each site)+ . . . . . ..__... My+,`,)r`+ (oral and phar- (Tongue, gingiva, phsr- yox)t. :/- (Lip)-. ~~. 1 (All forms combined-oral)+ (Pipes and cigars combined- oral)+. (Lip, mouth)+ ______.... (SnuR-lip, mouth)+. (Or++ __..._......_.... (If smoke and chew-base of tongue, hypopharynx)+. ((+ingivs, lip)*. . .._ (Pipes, and cigars com- bined -tongue)+. (Or3l)f be-.-.- . . . . ..___ (s!lu~-oral)+.~ ..~. (Pipes and cigars combined- lip, oral cavity)*. ._._ (.411 terms combined)+, Ff (snuff -flip and buccal cavity in both cases). -I- lf=Significant association. - =Association ahsent or not signiflcaot. * = Association of doubtful qignlficsnce. * Cigarettes and cigars. 3 Hidis. 1 Includes cigarettes and other. 1 Only in individuals oi low economic status and over 60 years old. bined was noted. Among four studies of lip cancer the chewing of tobacco and/or snuff was found to be associated in two of them (41,245). There is some indication of an association of tongue cancer with cigar smoking in three studies (301, 378, 385) and in one of these (385) with pipe and cigar smoking combined. In two studies an association of gingival cancer with cigar smoking was demonstrated (378, 385) ; in one of these (378) an association also noted with pipe smoking, and a suggestion of an association with chewing of tobacco. Pharyngeal cancer was considered as a separate site in four studies (301, 306, 378, 385). An association with cigarette smoking was noted in two out of three (306, 385) ; with cigars in two (378, 385) ; and with pipe in one (378). Among the better studies in which the sample sizes were large and con- trols adequate, one deserves special mention (301). In this investigation by Sadowsky and others, it was possible to establish gradients for lip cancer by number of pipefuls smoked a day, for tongue cancer by amount of to- bacco in pipes and cigars combined, and for other oral cavity cancers by number of pipefuls. I IVo gradient by amount smoked was noted for cigarettes. The seven prospective studies have yielde