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 yielded 152 cases of oral cavity cancer associated with cigarette smoking, with an adjusted expectancy of 37.0 cases giving a weighted mean mortality ratio of 4.1. This is the third highest mor- tality ratio of cigarette smokers to non-smokers among the several specific types of cancer deaths and the fourth highest among all causes of death as- sociated with cigarette smoking. The mortality ratios ranged from 1.0 in the Dunn, Linden, Breslow occupational study (96)) in which only seven cases have thus far been observed, to 9.2 in the current Hammond study (157). (See Table 1 of this chapter.) For cigar and pipe smokers, oral cancer has the highest mortality ratio, 3.3, of all causes of death, exceeding cancer of the esophagus, larynx and lung. Recently calculated data from six of the prospective studies (excluding the current Hammond study) show a slight gradient in the mean mortality ratios for cigarette smokers of more than a pack a day as compared to smok- ers of one pack or less. Estimates of gradients by amount of smoking of pipes and/or cigars, by duration of smoking and by discontinuance are not yet available, because of the relatively smaller number of deaths from oral cancer. Inasmuch as the incidence of female oral cancer is markedly lower than in males, data on these variables for the female, to be derived from the cur- rent Hammond study, will require an inordinately prolonged observation period. Carcinogenesis Cigarette smoke and cigarette smoke condensates have failed to produce cancer when applied to the oral cavity of mice (75, 177, 240 I and rabbits (312) or to the palate of hamsters (194, 303). Exposure of the hamster cheek pouch to cigarette tar, snuff, or tobacco also failed to induce cancer 202 (95, 194, 243, 244, 245, 246, 271, 272, 303, 303a). Leukoplakia was re- ported to have been induced by the injection of tobacco smoke condensates into the gingiva of rabbits (296). The oral mucosa appears to be resistant in general to cancer induction even when highly active carcinogens such as benzo(a )pyrene (95, 194, 209, 243,244.245,246,271,272.2%, 303) are applied. Mechanical factors, such as secretion of saliva, interfere with the retention of carcinogenic agents. Saliva may also play a chemical role in modifying the action of carcinogenic agents on the tissues of the oral cavity and the pharynx. The only positive results with carcinogens have been obtained with benzoiaipyrene, 20.methyl- cholanthrene, and 9,10-dimethyl-1,2-benzanthracene applied to the cheek pouch of the hamster (244, 303, 343). The cheek pouch, however, lacks salivary glands, and its structure and function differ from those of the oral mucosa. Pathology There is a strong clinical impression linking the occurrence of leukoplakia of the mouth with the use of tobacco in its various forms (201). However, in almost all the studies, the diagnosis of leukoplakia was made without his- topathologic examination. It is difficult to distinguish clinically between hyperplasia of the surface epithelium with keratinization (termed pachydermn or&) and "true" ZeukopEakia, which resembles microscopically senile kera- tosis, a preneoplastic lesion of the skin, showing atypical changes and mitotic figures, in addition to hyperplasia. In a study of the tissue changes in the palate of women in a part of India where the burning end of a cigar is held inside the mouth, Reddy and Rao (284) found ulceration, increased pigmentation of the epithelium of the palate and leukoplakia. Many of these women develop cancer at the same site. The carcinomas found are epidermoid and are frequently surrounded by an area of leukoplakia which sometimes shows changes characteristic of carcinoma-in-situ. Leukoplakia is a common finding in patients with multiple oral carcinomas, the majority of whom use tobacco (241). A histopathologic study of lesions in the oral mucosa in betel nut-tobacco chewers in Malaya showed frequent epithelial hyperplasia with atypical changes and papilloma formation (233). These lesions were considered to be frequent sites for the subsequent development of cancer. An association between leukoplakia and oral cancer has been noted by other investigators in studies on individuals with the habit of dipping snuff (179, 200). nlthough these results do not warrant any conclusion by themselves, they are consistent with the suggestion that oral cancer is frequently pre- ceded by characteristic premalignant changes and that these have a relation- ship to the use of tobacco. Evaluation, Because of the diversity of sites involved in the category oral cancer and the need to delineate forms of tobacco use in each of them, the number of retrospective studies is inadequate to furnish sufficient material for a 203 judgment of consisted of the association except for cancer of the lip ad pipe smoking. Inasmuch as only one retrospective study (301) had large enough numbers of cases to derive the relative risks for specific site associations, reliance for strength of the association must be placed on the prospective studies. Since, in turn, the numbers of deaths from cancer of these sites so far have been small, only a combination of such sites could be analyzed for relative risk determinations. Five of the seven studies show reasonably high rela- tive risk ratios for cigarette smokers and for cigar and pipe smokers. Specificity of the association cannot be said to be as high as that noted for lung cancer. The prospective studies provide no information as to specific localizations within the oral cavity. Sadowsky et al. (301) showed an association of pipe smoking with cancer of the lip and of pipe and cigar smoking with cancer of the tongue. Data are presently inadequate for a reliable assessment of the coherence of the association. However, it should be noted that the prospective studies provide a definite suggestion that a gradient of risk by amount smoked does exist for oral cancer and that in one large retrospective study (301) prevalence rates for every specific age group of smokers was consistently in excess over non-smokers. It has been noted that during the past 30 years cancer of the oral cavity and pharynx has declined, primarily because of a decrease in lip cancer among males (130). Cancer of the lip has never been an important localiza- tion for females and the rates in females have remained fairly constant. In males pipe smoking has decreased markedly in the United States during the past 30 years, so that the decline in lip cancer among males is not neces- sarily incompatible with a strong association between cancer of the lip and pipe smoking. Furthermore, other probable factors in the production of oral cavity cancer such as mouth hygiene, nutrition, and particularly alcohol consumption have not remained stable. In two studies (314, 378) alcohol consumption is clearly also associated with oral cancer and in one (378) evidence is presented for independent operation of this factor. The problem of heat from burning tobacco has not been investigated, as far as could be determined. It is of interest that cancer of the palate has been associated with smoking of cigars with the lighted end in the mouth (186). The heat factor should be kept in mind with respect to the excess of lip cancers among the cigar and pipe smokers. Although cancer of the oral cavity has not been produced experimentally by the exposure of animals to tobacco smoke, it has occurred following repeated applications of henzo(a)pyrene and other hydrocarbons to the cheek pouch of the hamster. The relationship of leukoplakia to tobacco use has been described earlier Conclusions 1. The causal relationship of the smoking of pipes to the development 0' cancer of the lip appears to be established. 204 2. 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.. LARYNGEAL CANCER Epidemiologic Euidencp RETROSPECTIVE STUDIES The possible association between tobacco smoking and laryngeal cancer received some attention in studies as early as 1937 ( 1. 185). Ahlbom noted a marked association between cigar and cigarette smoking and cancers of the pharynx. larynx and esophagus, but because of the small sample size, the three sites as defined were grouped together i I). The Kerrnaways calculated standardized mortality ratios for various occupational Froups (against the age-specific mortality rates for the general population of England and Wales for 1921-32`1 and found barmen, cellarmen. and tobacconists to have sig- nificantly higher ratios (185). This latter study was repeated in 1947 and again the tobacconists and their assistants were noted to have an excess mor- tality for cancer of the larynx (184). It is difficult to attach much impor- tance to these studies though they contain clues which should be investigated. The earliest controlled study, retrospective in approach, was that of Schrek and co-workers (311) in 1950. Their very carefully analyzed data showed an association between smoking and cancer of the larynx but the evidence is not firm, for the association was found in only one out of four age groups, perhaps because of the small number of cases in the study sample. There then followed nine additional retrospective studies, two more in the United States (301, 376) and one each in Czechoslovakia (353), Germany (30), France (3141, Sweden (385), Cuba (388), India (loo), and Poland (327) (Table 11 I. These were stimulated in part by the retrospective studies of lung cancer and the general prospective studies. Most of the studies (30, 100, 301, 311, 314, 327, 376, 385, 3881 show a stronger association between cigarette smoking and laryngeal cancer than for other forms of tobacco use but one of the studies shows a borderline relation- ship with cigar smoking (385). Wynder et al. (376) also distinguished be- tween intrinsic and extrinsic primary laryngeal cancers. It is of further interest that an excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal cancer group. One study disclosed a relationship between laryngeal cancer and the combined smoking of cigarettes, pipes and cigars, as well as with cigarette smoking alone (301). In another (376) there is an impression that cigar and pipe smoking is more closely associated with cancers of the larynx than with cancer of the lung. A gradient of risk with amount smoked was demon- strated in two studies (301, 376) and suggested in four others (30, 311, 314, 327). In the study by Sadowsky et al., this gradient was noted not only for cigarette smokers but for pipe smokers and combination smokers as Well. 205 TABLE 1 I.--Outline of retrospective studies of tobacco USC and cancer of the larynx i cases Coun try . _- -_ U.S.A. ._ , .- Cl.ChO SlOW -- ,- .kia. -- U.S.A. -- -- w -- Qerma U.6.A - M - M - M kf- er- nu? - :311) sex __ M M-F I- N I _- "Ill leer - 73 G 273 - 241 oe - Schrek et al. 1950 Valko 1962 Sadowsky et al. (1953) Bliimlein 1955 Wynder et al. 1956 Collection of data NIlIll- her 622 108 Method of selection Method of selection Referrals from V.A. hospitals in "entire mldwest" to V.A. Can. cer Center, Nines, Illinois, dur- ing 1942-44: patients with larynx- % hsrynr tumors clinically or lstologicelly diagnosed. 13.7% non-smokers 79.5% cigarettes 3.7% cigars 6.8% pipes From same set of referrals, patients with tumors other than lip, lung, larynx-pharynx. Random sample of 5003 admissions; questionnaires from Hines re- fermls for 1942-S; records ln- eluded smoking history. 23.9% non-smokers 59.2% cigarettes 10.0% cigars 11.5% pipes Clinic patients with cancer of the Clinic patients of same age group with other diagnoses. Medical history and questionnaire in clinic. 22.2% non-smokers litrym. 83.2% cigarettes 4.4% cigars 10.6% pipes 7.5% non-smokers Admissions to hospitals in N.Y.C. Missouri. New Orleans, Chica- go: patients with diagnosed laryngeal tumors, 1933-1943. 4.0% non-smokers EQ.l% cigarettes only 2.2% cigars only 4.3% Pipe only 23.9% some combination .- From same set of admlssions: patients with illnesses other Sample of 2605 out of 2347 inter- than cnocer. views (including smoking hls- tory) by trained lay interviewers. 615 13.2% non-smokers 53.3y0 cigarettes only 3.4oJ, cigars only 7.0% pipe only 23.1% some combination ml 203 Patients with no laryngeal disease. Personal history taken in clinic. 13.0% non-smokers 4.3% heavy smokers 17.0% inbalers Clinic patients with cancer of the larynx. 0.8% non-smokers 79.3% heavy smokers 95.0% inhalers Inpatients Memorial Cancer Re. search Center during 1952 to 1954, with be&-n or malignant epldermold tumors of larynx. 0.5% non-smokers 36.0% cigeiettes 7.5?& cigars 5.0% pipes Patients with other than e lder- mold cancer, indlvl ually 2 matched controls in same instl- tutions. 10.5% non-smokers 73.7% cigarettes 10.17~ cigars f.t,C pipe .i..._-,..i_ Trained lay interviewers. M - M M-F F" 132 Laryngeal cancer petlents at Tata Memorial Hospital, 1952-1954. 13.60/o non-smokers 78.8% bidis 5.3% cigarettes 1.5% hooksh 0.8% chilum Controls individually matctwl as for TJ.S.A. data abow. 30.3% non-smokers S2.1% bidis 4.5% cigarettes 0.8% hookah 2.39; chilum India Sweden 132 Interviews for smoking and medi- cal histories. -- -- _. -- -- , -- -- -- -- Schwartz et al. 1957. 121 -ii Patients hospitalized from 1954 through 1956 with laryngeal can- cer, in Paris and other large cities. 9SYo smokers 58Yo inhalers 440/, roll their own cigarettes 242 .-- 271 lame time and sources; patients hospitalized for non-canremus conditions or trauma. 84% smokers 47% inhalers 31% roll their own rigarrttcs Cases and controls individually matched withtn institutions; each member of a set questioned tgt;?, same trained lay inter- Patients at Rsdiumhemrrxt with squamous-cell cancer of larynx, from 1952 through 195n5. Males: 5% non-smokers 47% cigarettes 17% ciears 15"iu p;pes 17% mixed Patients from same source and time, with cancer other than squamouscell of larynx. hfslrs: 24% non-smokers 36% cigarettes 9% cigars 16% pipes 137, mixed By trained lay interViewers in hospital. Wynder et al. 1957-e Wynder et al. 1958. Cuba --- India -- `2 Clinic patients in Havana during 1956, 57, with histologically di- agnosed epidermoid cancer of larynx. 1% non-smokers, M; 13% F 62% cigarettes, M; 72% F 20% cigars, M; 6% F 1% pipes. M 16% nixed, M; 9% F M22-3 F 214 Intxrview of patients in ctintc. Same source and time; apparently patients with cancers other than larynx, lung, or oral cavity, matched for age. 18% non-smokers, M; 6670 1' 45% cigarettes, M; 27% F 22% cigars, M; 6% F 1% pipes, M lG% mirad, M; 0% F -~_ Not specified. - - --___- Tobacco histories obtained during 1951-54, apparently by interview. Dutta-Choudhuri et al. 1959. M-F 582 - Patients in Calcutta cancer hos- pital during 195(t54, with laryn- geal tumor diagnosed and con- firn cd by biopsy or smear. 14.1% non-users 77.8% cigarettes or bidi 3.1% chew 5.0% both 41.7% non-users SZ.lY, cigarettes or bldi 3.8% chew 2.4% both -___.~ - TABLE ll.--Out&ne of retrospective studies of tobacco we and cancer of the larynx-Continued I I I I Ref- Investi@xx and year er- ems co"ntry sex Num her -- Stasrawski 1960. w7) Polmd F 207 13 cases Controls Method of selection Num- her Method of selection Patients admitted to chronic die.- M 912 Patients admitted during 1957 & ease hospital during 1957 & F 1813 1958 to chronic disease center 1968 with histologfeally eon- for cmce~ous and non-caucerous 5rmed squamous-cell carcinoma conditions presumably not re- of the larynx. 0.6% non-smokers lated to tobaoco consumption. 17.3% nonanokers 87.9% cigarettes only @4X5% cigarettes only 1.9% pipes and/or cigars 88.4%"hesvy smokers" 11.1% pipes and/or cigars 49.0%" heavy smokers" 96.1% inhalers 66.80/, inhalers 30.8% smoke, F 8.4% smoke, F I Collection of data Author interviewed patients SW petted of lung cancer for smoking history and backgtound. A combination group of lung and laryngeal cancer cases was also included by Wynder et al. (376) and relative risks for lung cancer as well as laryngeal cancer among the several smoking categories were calculated. It is of inter- est that the risks attending the several categories of amounts of cigarettes smoked were similar for both lung and laryngeal cancer, but the risk of laryngeal cancer among cigar and pipe smokers was 2.5 times that for lung cancer. Four of the retrospective studies concerned themselves with inhalation practices and a significant association between inhalation of cigarette smoke and laryngeal cancer was noted in three of them (30, 314. 327). The fourth study by Wynder et al. (376) f ound an association with inhalation among light cigarette smokers and among pipe and cigar smokers. For both whites and non-whites the male-to-female age-adjusted sex ratios in laryngeal cancer are higher than for any other site common to both sexes (130). Despite the fact that the female case material is exceedingly sparse, at least two studies concerned themselves with laryngeal cancer in the female (377,388). The material in one study was adequate to establish an associa- tion with cigarette smoking (388) whereas in the other only a suggestion was elicited in view of the paucity of the material (377). Wynder and co-workers (387) in their study of Seventh Day Adventists noted that cancer of the larynx was an extremely uncommon reason for ad- mission to a hospital and that this type of cancer was very infrequent among all cancer admissions. Smoking and drinking among adherents of this religious sect are uncommon. PROSPECTIVE STUDIES In the seven prospective studies previously described, laryngeal cancer has in each one of them been observed among smokers in frequencies in excess of the expected. Although in four of these studies (25, 84, 96, 97) the number of observed cases is so small as to weaken the stability of any calcu- lable ratios, in the three major studies, the number of observed cases among cigarette smokers is reasonably large and yields ratios of 3.7 [current Ham- mond study (157) 1, 5.8 [Dorn (88) 1, and 13.1 [Hammond and Horn (163) 1. A summation of all seven studies yields a mean mortality ratio of 5.4 (Table 1) for cigarette smokers. For five studies in which laryngeal cancer cases were associated with cigar and pipe smoking, the mean mor- tality ratio was 2.8. However, this was calculated from only nine cases observed and 3.2 expected (Table 24, Chapter 8). None of the studies currently in progress has yielded a sufficient number of cases of laryngeal cancer to permit analysis of smoking class categories by inhalation practices, duration of smoking, and age started smoking. However, the recently calculated material from six prospective studies (Table 23, Chapter 8) shows a gradient of risk ratios from 5.3 for smokers of one pack or less of cigarettes per day to 7.5 for smokers of more than a pack per day. Because of the relatively low yield of cancers of this site. the current prospective studies (25, 84, 88, 96, 97, 157) will have to continue for a considerable length of time to provide answers to the other components of the problem. 209 Carcinogenesis So far as known, no attempts to induce carcinoma of the larynx. by to. bacco smoke or smoke condensates have been reported. Pathology For information about histological changes in the larynx of smokers, see Chapter 10, Non-Neoplastic Respiratory Diseases. Evaluation of the Evidence The 10 retrospective studies have a high degree of consistency despite the weakness of the control selections in one or two of them. A sufficient number of these studies have an adequate sample size for categorization of type of smoking and these all show consistency in designating cigarette smoking as the significant associative class. The fact that each of the prospective studies yielded an excess of cases among cigarette smokere over the number expected from the incidence among non-smokers adds to the level of consistency noted. Th e calculations for cigarette smoking alone. as well as for the combination of cigarettes, pipes, and cigars, were almost identical to those in the prospective studies. The relative strength of the association as measured by the specific mor- tality ratio (as an average of combined experiences) is admittedly not as high as that noted for lung cancer, but two of the three major prospective studies with adequate case loads indicate that the real value of the relative risk may approach that for lung cancer. As has been discussed in the sec- tion on lung cancer, the implication of a lower relative risk is that other factors of etiologic significance may be independently associated with the disease. That this may be true for laryngeal cancer, as it seems to be for oral cancer, is reasonable because alcohol consumption, though frequently associated with heavy smoking, appears to be associated with laryngeal cancer independently from smoking (376, 377). As with lung cancer a dose-effect of smoking is also demonstrable. The majority of the retrospective studies have shown a greater association with heavy smoking and in two of them gradients with increasing amounts of tobacco consumed have been elicited. The prospective studies (Chapter 8. Table 21) also suggest a gradient although the numbers of deaths are small. Inhalation, a crude indicator of exposure, has also been noted as being asssoci- ated with laryngeal cancer in each of the studies in which such analyses were attempted. The parallelism with lung cancer, though not as complete be- cause of a smaller amount of material, is remarkable. In an assessment of the coherence of the association between smoking and laryngeal cancer with the facts of the natural history and biology of the disease an approach similar to that utilized in the lung cancer analysis can be helpful. TIME TRENDS Although laryngeal cancer mortality has increased somewhat over the past three decades, the increase has been much less than that for lung cancer 210 mortality. In this regard it has also been mentioned that in at least one de- tailed study (376) the laryngeal cancer risk for cigarette smokers, irrespective of amount smoked, seems to be equal to that for pipe and cigar smokers i as a combined group i . Furthermore, while the per capita consumption of cigarettes has risen, the consumption of pipe and cigar tobacco has declined. In addition, there is no evidence or reason to assume that the susceptibility of the larynx for cancer is equal to that of the bronchus. Finally, evidence has also been presented (stemming from the implications of lower mortality ratios of smokers to non-smokers) that othe; factors may play a significant role in the production of laryngeal cancer, such as alcohol and inadequate nutrition (376 1. Thus a diminution of such other factors in time could well have counterbalanced. in great part. a rise which could have attended increased cigarette consumption. Tobacco chewing has also declined to such a great extent in this country that adequate case material among chewers is not available for analysis. However, evidence derived from studies amonp betel nut chewers in India indicates that even among smokers of cigarettes. cigars, pipes or bidis o the addition of tobacco to the material chetied is associated with an even greater risk of laryngeal cancer ( 100. 376). The evidence from the retro- spective and prospective studies is compatible with the small rise in laryngeal c'ancer incidence observed. SEX DIFFERENTIAL IN MORTALITY As has been noted in the discussion of lung cancer, the much later advent of cigarette smoking among females wzould be compatible with their lower laryngeal cancer mortality rates. Furthermore. the negligible degree of pipe and cigar smoking and tobacco chewing among females would not only be compatible with a significantly lower risk of cancer of the larynx among them today as compared to males IWM: WF-- 10.8) but also with a lower sex ratio 30 years ago IWM: WF=6.3) (130). Assuming a reasonable induction period, the mortality rates 30 k-ears ago could have been a reflec- tion of the much lower consumption of iobacco even among males between 19OO-1910 (239). One cannot overlook the role of alcohol consumption in this differential. The greater alcohol consumption among males and a strong association be- tween laryngeal cancer and alcohol consumption (376, 377) must be con- sidered as contributing to the excess ratio of male to female laryngeal cancer mortality. The role of inherent sex differences (e.g.. hormonal, laryngeal anatomy) as determinants in the difference in mortality related to smoking cannot he fully evaluated from the limited information available. LOCALIZATION OF LESIONS TWO studies have dealt analytically with laryngeal cancer from the stand- point of specific localization, i.e., extrinsic vs. intrinsic laryngeal cancer 1327, 376). (Most laryngeal cancers designated as extrinsic arise in the larynx proper; about 30 percent designated as extrinsic arise in adjacent `Bidi (variant of biri)-a locally made cigarette of tobacco flakes rolled in the dried leaf of a variety of bauhinia (306). 211 structures such as the epiglottis, its valleculae and on the arytenoid folds.) In only one of these studies (376) were the data analyzed in sufficient detail to permit tentative interpretation. It should first be noted that intrinsic laryngeal cancer was more often associated with cigarette smoking, whereas a higher percentage of pipe and/or cigar smokers was found among extrinsic than among intrinsic cancers. Secondly, in both the United States and the Indian data referred to by Wynder, chewing of tobacco seems to be associated with a higher risk for the extrinsic type, implying that tobacco juice makes contact readily with such extrinsic structures as the epiglottis (37.6 percent of the extrinsic cancers were in this location). Finally, males predominate in intrinsic cancers of the larynx, whereas the ratio for extrinsic cancers, though lower, still shows an excess for the male. Thus far, the tobacco smoking and chewing patterns of males vs. females are compatible with the data on localization differences between the sexes. Extrinsic laryngeal cancer is relatively more common among rural than urban females. This evidence was presented by Wynder as indicating that some other factor which does not influence intrinsic lesions is operating. From some sugges- tive data he proposed dietary deficiency as a plausible explanation and cited the Swedish experience (385) as indicating the possibility of an iron-vitamin B complex deficiency. This remains to be adequately tested. In any event, the male excess of cigarette smoking and the inhalation factor are compatible with the male preponderance of the intrinsic type of laryngeal cancer. Pipe and cigar smoking is also not devoid of some uncon- scious inhaling, at least to the level of the larynx. Furthermore, the more common findings of pipe and cigar smoking among cases of extrinsic laryngeal cancer are compatible with exposure to tobacco juice from this form of smoking. And, finally, the obvious exposure to such juice from tobacco chewing is compatible with the preponderance of extrinsic types among such users of tobacco. Conclusion Evaluation of the evidence leads to the judgment that cigarette smoking is a significant factor in the causation of laryngeal cancer in the male. ESOPHAGEAL CANCER Epidemiologic Evidence RETROSPECTIVE STUDIF,S As with cancers of other sites, clinical impressions of an association be- tween smoking and esophageal cancer led to more or less controlled studies of the two variables as early as in 1937. Ahlbom (1) studied a group of patients with cancers of the pharynx, larynx, and esophagus and found an excess frequency of cigarette and cigar smokers among the combined group. The first controlled retrospective study directed specifically to the esopha- gus was by Sadowsky et al. (301) published in 1953, the data for which were collected in the period 1938-43. These investigators found associa- 212 tions with cigarette and with cigar smoking but only the cigarette smoking relationship was noted to be statistically significant. Since then there have been six other retrospective studies (306, 315, 325, 329, 374, 385) (Tables 12 and 13). It should be noted, however, that one of these (3291 is an autopsy series with no reliable data on smoking his- tories. Among the five remaining studies with better data collection meth- ods. significantly excess frequencies of tobacco smoking among esophageal cancer cases were noted in two (315, 325) excess frequencies of cigarette smoking were noted in two others ( 374, 385) but in only one of these (374) was the excess statistically significant. Cigar smoking and pipe smoking were implicated separately in these same two studies but again the excesses for each were statistically significant in only one study (374). In this latter study a significant association with tobacco chewing was also found. A por- tion of this same study was devoted to analyses of data collected in India. The Indian data should not be given the same weight as the others, since only 10 percent of the male cases and 4 percent of the female cases were histologically confirmed. It is of interest, however, that an association be- tween tobacco smoking and esophageal cancer was observed. The remaining study in this group is that of Sanghvi et al. (306) who found no significant associations with tobacco chewing alone and with cig- arette and bidi smoking alone, but found a significant association for the combination of smoking and tobacco chewing. Several of the studies were concerned with the amounts of tobacco smoked. The Swedish study by Wynder and co-workers (385) which had demon- etrated excess frequencies of cigarette and cigar smokers among the esopha- geal cancer cases not to be statistically significant, showed a significant excess of amount of tobacco smoked among the cancer cases. A later study by Wynder and Bross (374) found significant excesses of heavy smokers among both male and female esophageal cancer cases. Staszewski (325) found a highly significant excess of heavy smokers among the cases in his Polish study. Schwartz and his co-workers (315) in the most extensive study of all, found significantlv more smokers among cases than among controls. However, the differen'ce in daily amount of cigarettes smoked was not significant. A refinement of the data in two studies (301, 374) by classes of number of cigarettes smoked daily showed a gradient of increasing risks for esophageal cancer in both. Inhalation practices were explored in two of the retrospective studies (315, 325). In neither of them was a significant difference found in percentage of inhalers between cases and controls. Relative risk ratios were calculated from the data available in each of the retrospective studies (Table 13). The relative risks for all smokers in these studies ranged from 2.1 to 4.0 for American males and 2.0 to 4.1 for Ameri- can females. Data were available for calculation of relative risks with regard to heavy smoking in only two of the studies (32.5, 374). The Polish data revealed a relative risk ratio of 16:l for heavy smokers as compared with non-smokers, whereas the latest Wynder study revealed ratios paradoxically lower for heavy smokers than for the category "all smokers." In view of previous studies which had revealed an association between esophageal cancer and alcohol consumption, Wynder and Brass (374) tested 213 N TABLE 12.~-Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus Controls Investigator, yew, and rcferfxlce CaSeS Collection of data ;`ountrv sex - M - N -- -- -- -- -- `urn her - 104 Method of selection Method of wlrotion White patients admitted during 1938-43 to selected hospitals in N.Y. City Missouri, New Or. leans, and Chicago. ber 615 (1) 288 (2) 107 464 115 912 _- _- _~ _- .- White patients with illnesses other than cancer admitted to same group of hospitals during same period. (1) Obtained by 4 especially trained lay interviewers. (2) 242 records out of a total of 2,847 excluded because of incomplete or questionable smoking histories. Sadowsky et al. 1953 (301) U.S.A. Sanghvi et al. 1955 (306) India -- -- -- -- , , -- _- M 73 Consecutive cllulc admissions to Tata Memorial Eospital, Bom- bay. Consecutive cllnlc admissions of patients without cancer. Consecutive admissions of patients with cancers other than intraoral By meaus of `detailed questionary'. No other details given. U.S.A. or esophagus. Btelner 1958 (329) "F+ M 116 Consecutive cases studied at au- topsy In University of Chicago Dept. of Pathology during lSOl- 1954. Autopsy cases comprising: 116stomach cancer 116 lung caner 116 mallguant lymphatic dis. ll;e;z&;ithout any malignant Matched by sge, sex. race and year of autopsy. Not clear how smoking histories were obtained-from hospital records, probably, which indicates they may be inadequate. Wynder et al. 1957 (365) Sweden 39 - 24 - 362 Patients admitted to Radlumhem- met, Stockholm during 1952-1955. Patients admitted to same hospital with cancer of skin, and head and neck region other than squamous cell cancer, leukemia, colon, other sites. No matchinn. No details given on method of data collection. No age adjustment or matching. Avcmge age of ranter patients=60.5 and of wntrols=53. M M Patients admitted to Oncologlcal Institute during 1957-59. Other patients sent to Institute with symptoms probably not etiologi- tally connected either with smok- ing or with diseases of esophagus, stomach or duodenum. Staszewskl1960 (326,327) Poland Schwartzet al. 1961 (315) France 362 ---- Interviewed by team of special inter- viewers who iuterviewrd the largest proportion possible of al: caucer patients. Cases and matched controls inturviwved by same per.wn. Realthy individuals admitted to same hospital because of work or traffic accidents--matched by 5 yr. age group and time of admis- sion. Admisions to hospitals in Paris and a few large provincial cities since 1954. 215 - - - - - -c d, i - - - 216 this independent variable. Since a relationship between alcohol consumption and tobacco use is known to exist, these investigators analyzed the relation- ship between tobacco consumption and esophageal cancer after adjusting for alcohol intake. Of extreme interest is their observation that in the absence of alcohol consumption there was no association with tobacco consumption, but in the presence of alcohol consumption an increasing relative risk with increasing number of cigarettes smoked was apparent. In the presence of alcohol consumption, a high association between esophageal cancer and cigar and pipe smoking was also noted. PROSPECTIVE STUDIES In the seven prospective studies (Table 1 of this Chapter I some deaths from esophageal cancer have been accumulated to date. The mortality ratios range from 0.7 in the California Occupational study to 6.6 in the Dorn study. Combining the observed deaths from this cause for all seven studies yields a total mortality ratio of 3.4. The stability of the ratios for three of the studies (84, 96, 97) is of low order, for they are based on only 7, 4 and 9 cases respectively. The mean mortality ratio for cancer of the esophagus in cigar and pipe smokers is 3.2, second only to that for cancer of the oral cavity, 3.4 (Table 24, Chapter 8). This ratio is based on 33 cases of esoph- ageal cancer in cigar and pipe smokers in five studies. Recently calculated data from six prospective studies (Table 23, Chapter 8) reveal a gradient of risk ratios from 3.0 for smokers of one pack or less of cigarettes per day to 4.9 for smokers of more than a pack per day. It is obvious that with so few cases to date, further cross-classification by duration of smoking, inhalation practices, and discontinued smoking is not feasible at the present time. Carcinogenesis So far as known, no attempts to induce carcinoma of the esophagus by tobacco smoke or smoke condensates have been reported. A further note, indicative of needed research, is in order. In the recent Wynder and Bross study (374) these authors report that injection of ethyl alcohol into or painting of ethyl alcohol on the skin of mice promotes the carcinogenic activity of cigarette smoke condensate when applied to the skin. No data are presented in evidence. Evaluation of Evidence Five of the seven retrospective and six of the seven prospective studies show significant associations between esophageal cancer and tobacco con- sumption. One prospective study showed a mortality ratio less than unity (%) but this is based on only four observed cases among smokers. Al- though two of the seven retrospective studies investigating esophageal cancer did not find the smoker-excess among cases statistically significant, all showed such excesses. Furthermore, it is noteworthy that despite the variations in the quality of the control groups the calculated relative risks in the retro- spective studies fall within the same range of mortality ratios as in the prospective studies. Th is eve o consistency is not to be ignored although 1 1 f few of the studies revealed increasing gradients of risk with amount smoked. 217 Here, only two studies (301, 374) and possibly a third retrospective study I 385) show such a gradient. Whether this subclass inconsistency is due to inadequacy of data because of small sample size cannot be determined at the present time. The prospective studies have, however, revealed such a gradient for amount of cigarette smoking when the data of six studies were combined. Although not as marked a gradient as in the lung cancer group, the increase in risk for esophageal cancer among smokers of more than a pack a day is greater than for laryngeal and oral cancer. Inhalation data are extremely sparse but in the two studies in which the data were analyzed (315, 325), no correlation could be found. This is com- patible with an hypothesis that postulates an action on esophageal mucosa by swallowing of tobacco condensates or tars. Evidence for this is lacking, but the associations between esophageal cancer and several` forms of tobacco use, viz., cigarette, cigar and pipe smoking and tcibacco chewing, would support such an hypothesis. It is also supported by the fact that the mortality ratio for cigar and pipe smokers, though based on a relatively small number of cases, is approximately equal to the ratio for cigarette smokers (3.3 vs. 3.0). Mortality from esophageal cancer in the United States has shown a tend- ency to rise slightly among whites in the last 30 years; non-whites show a greater rise, but this is usually attributed to improvement and increased availability of diagnostic facilities. The smallness of the rise does not negate the significance of an association with tobacco use, some forms of which have been concurrently rising. This has b een discussed earlier but it should be emphasized that declines in other environmental factors may counterbalance the otherwise rising influence of the variable under study. Since neither prospective nor retrospective studies were executed in the decades of 1910- 1930, conjectures on such an hypothesis are speculative. Inasmuch as the interaction between alcohol and tobacco use is documented in only one study, it would at the present time be unwise to attempt any more detailed evaluation of the relationship of tobacco use to trends in the incidence and mortality of esophageal cancer. Suffice it to say that, if the component of tobacco use involves the swallowing of tobacco juice, then the time trends in types of tobacco use over the past 50 years are relevant and not incompatible with the hypothesis. Conclusion The evidence on the tobacco-esophageal cancer relationship supports the belief that an association exists. However, the data are not adequate to decide whether the relationship is causal. URINARY BLADDER CANCER Epidemiologic Evidence RETROSPECTIVE STUDIES The experimental work of Holsti and Ermala (177) in 1955 prompted the first retrospective study of the relationship between smoking of tobacco 218 and cancer of the urinary bladder. After the lips and oral mucosa of albino mice of a "mixed known strain" were painted with tobacco tar daily for five months, 10 percent of the animals developed malignant papillary carcinomas of the urinary bladder. No carcinomatous change was observed in the oral cavity. The report of this work led Lilienfeld (215) to undertake a study of bladder cancer cases admitted between 1945 and 1955 at Roswell Park Memorial Institute. Before being seen by clinicians for diagnosis, all patients at this institution are interviewed regarding smoking histories. Lil- ienfeld found a significant association between cigarette smoking and urinary bladder cancer among males but not among females. This study, though carefully controlled, was done before much knowledge of cigarette smoking relationships to other diseases had accumulated and before the results of the earliest prospective study had revealed a relationship of smok- ing to urinary bladder cancer. Thus, information on amount smoked. age at onset of smoking, duration of smoking, and inhalation was either not collected or not analyzed. Only three additional retrospective studies (220, 315, 389 ) have appeared since Lilienfeld's publication in 1956. The methodology and results of these studies are presented in Tables 14 and 15. All of these investigators found a significant association between cigarette smoking and urinary bladder cancer in males. Three of these studies (215. 220, 389) concerned themselves with the study of female cases as well. Two of them found no relationship between smoking and urinary bladder cancer in females, but one study (3891 found the relationship to be significant. Three of the studies examined other forms of smoking. Schwartz et al. (3151, in France where cigar smoking is negligible, separated pipe smokers and mixed smokers from cigarette smokers and found only a suggestion of an association with pipe smoking, but the number of cases in this cate- gory were too few for meaningful inferences. Lockwood (220) found sig- nificant associations between both pipe and cigar smoking and urinary bladder cancer in the male. Wynder and co-workers i389) found no excess frequencies of pipe-only and cigar-only smokers among the urinary bladder cases. Here, too, the number of such smokers was even smaller than in the Danish study by Lockwood. Only two studies (220, 389) are concerned with amount oj smoking. In each, a significant excess of heavy smokers was noted among male patients with urinary bladder cancer. In the Danish study, female cases and con- trols had equal proportions of heavy smokers but Wynder found only a suggestion of an excess of heavy smokers among the cases (Table 15). ln?dztion was examined in two studies, the French and the Danish (220, 315). Schwartz et al. (315) found a profound effect of inhalation on the association between smoking and urinary bladder cancer. When compari- sons between cases and controls were made in each of the classes of amount smoked, the bladder cancer cases showed a greater frequency of inhalers in each class. When inhalation was controlled, the effect of amount of cigarette smoking disappeared. Thus the implication is clear that the essen- tial relationship is between inhalation of either cigarette or pipe smoke with urinary bladder cancer. Lockwood (220) found statistically signifi- 219 TABLE 14-S wnmury of methods used in retrospective studies of smoking and cancer of the bladder Lilienfeld et al., 1956 (215). sc;l15ytc et al., 1931 Lockwood leSl(220). W ynder 1963 (389). (To be published). - .- I .- .- .- 1 - lJ.6.A. Denmark U.S.A. &x M F - M - F" - M F M F - i - N _- -- - `urn. ber - 321 116 - 214 - % - 200 60 100 20 - . .- -- _- _- - CaSeS I controls Method of selectlou Number Method of selection AdmIssions to Roswell Park Memorial Institute. 1945-55 over 45 yrs. of age. 337 No-diseese patients. 287 Prostate cancer. &me as males Admissions to hospitals in Paris and * few large provincisl cities since 1954. 109 Benign bladder mndltions. 317 Nodisease patients. 763 Breast cancer -- 214 Healthy individuals admitted to same hospital because of work or traffic accident-matched by 5 yr. age group. & admitted during same time to same hospital as I I case8. All bladder tumors reported to Danish Cancar Roglster during 1942-1956 and living at time of interview in and Fredericksburg. Copenhagen 282 A. From election rolls matched with 37 ca8es according to sex, age, marital status, occupation and residence. 33. Another control group obtained from sample of Danish Morbidity Survey (1952-53 & 54) compared with respect to smoking histories. First Phase Admission to several hospitals In N.Y.C. during January, 1957- 200 Admission to same hospitals (ex- December, 1960. 60 ;plu" cancer of respiratory sys- upper alimentary, tract, mydcardial infarction). Matched second Phase by sex and nge. A&nssion to same hospital during 100 &me 85 above. 20 - Collection of data _- Interview of pallents by groups of interviewers at time of 1st visit to Institute hefore seen and diagnosed by physicians. Cases-59 c8.m interviewed b Clemmesen and 310 hy Lockw rxxf Election Roll Controls-2 inter: viewed by Clemmesen and 367 by Lockwood. Trained Interviewers. TABLE 15.~Summary of results of retrospective studies uf smoking (irrespective oj type) and cancer of the bladder Percent non-smokers Percent heavy smokers Percent inhalers among Relative risk: ratio to smokers non-smokers Investigator, year, and reference sex CaSeS Controls CaSeS controls CWZS control3 All smokers Heavy smokers ____ Lillenfeldet al., 19% (215) ____________ -.__ _____..____ {f 29 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ _ _ - i! 2.3 ._._....______ 83 .___________._ . .._..._..__.. ..~_~ . . . . . ..__ ._..______.... 1.4 .._____...___- -- -- ~__- ___-- -~--__-.-- Schwartz, 1961 (315) ._____.__...._______---.-----.-.- M 11 20 ___- . .._...... ._.__.._..---- 54 37 2.0 __..._..._____ -- -- -___ Lockwood, 1961 (nO)-- ___.._._..._..._.___..-------- {F 30 15 33 9 2. 1 2.4 4 . . . .._........ ~__......_.... iM G zi 4 1. 5 1.0 Cancer cases .____ __..__...___________---.. _.__. g 11 ______ ___._._ _________...._ . ..__......-.- 24 _ _ _ _ _ _ _ _ . _ _. _ . _ _ _ _ - 69 _______ __..__ .__________.__ __________.... 14 ..~ . . .._._.... . . .._____ ____ ______... ---__ PapillomaCases~-~...................~~~---~..~ F 8 ._.___________ . . . ..-.__....- ._ .-.-- ------- 31 ._............ ..~ .._... .~... . . . . . .._______ 55 ____._____..__ __._._______.. . . . . . .._ . . . . . 14 .____.._._.._. __......._.... ...~.._...---- -- p-p__--__------- -- Wynderet al., 1963 (389) (Phase A and B combined). {F 47 23 . . . _ _ _ _ _ _. . 2.9 3.0 6: ii 6 0 -. _ . . _ . . _ _ _ 3.9 __.__. ..___.. cant relationships with inhalation also but, unfortunately, he did not attempt cross-classification of inhalation with amount and type of tobacco smoked. Schwartz analyzed this even though his numbers were smaller and his sample more heterogenous in tobacco habits than Lockwood's. Only one study analyzed data on age at onset of smoking. Lockwood (220) found that his patients began smoking larger amounts of tobacco at an earlier age than did his controls. Other variables were examined in three studies, not only as a check on possible biases and influence of confounding variables on the association (220, 315) but also as a means of eliciting other environmental factors (389). In the latter study by Wynder, which included analysis of occupation, an excess of leather workers and shoe repairers was noted among the urin- ary bladder cancer cases although their numbers were small. It is possible that exposure to aniline dyes also occurred. Relative risk ratios were calculated from the data contained in the origi- nal papers, and are presented in Table 15 and 15A. For male smokers these ratios varied from 2.0 to 2.9. 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A preliminary report on differences in incidence between Seventh-Day Adventists, and others. Calif Med 89: 267-72, 1958. 387. Wynder, E. L., Lemon, F. R., Brass, I. J. Cancer and coronary artery disease among Seventh-Day Adventists. Cancer 12: 1016-28, 1959. 388. Wynder, E. L., Navarrette, A., Arostegui, G. E., Llambes, J. L. Study of environmental factors in cancer of the respiratory tract in Cuba. J Nat Cancer Inst 20 : 665573,1958. 389. Wynder, E., Onderdonk, J., Mantel, Iv. An epidemiologic investiga- tion of cancer of the bladder. Cancer 16: 13881407,1963. 390. Wynder, E. L., Wright, G. A study- of tobacco carcinogenesis. I. The primary fractions. Cancer 10: 255-71,1957. 391. Wynder, E. L., Wright, G. Studies on the identification of carcino- gens in-cigarette tar. [Abstract] Proc Amer Ass Cancer Res 2: 159, 1956. 392. Wynder, E. L., Wright, G., Lam, J. A study of tobacco carcinogenesis. V. The role of pyrolysis Cancer 11: 1140-8, 1958. 257 Chapter 10 Non-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pulmonary Emphysema Contents Page ALTERATIONS IN THE RESPIRATORY TRACT AND IN PULMONARY PARENCHYMA INDUCED BY TOBACCO SMOKE ........................ Characteristics of the Exposure ............. Composition of Tobacco Smoke ............ Regional Deposition or Retention of Tobacco Smoke ... Mouth Retention of Tobacco Smoke ......... Retention of Particles by the Trachea, Bronchi, and Pulmonary Tissue ................ Retention of Gases by the Trachea, Bronchi, and Pul- monary Parenchyma ............... Metabolism and Toxicity of Specific Components in Tobacco Smoke .................. Clearance of Smoke Deposits ............. Effects of Tobacco Smoke on Defense Mechanisms of the Respiratory System ................. Pulmonary Hygiene and Ciliary Activity ....... Mucus Secretion. ................. Alveolar Lining .................. Phagocytosis ................... Other Mechanisms. ................ Histopathologic Alterations ............... RELATION OF SMOKING TO DISEASES OF THE RESPI- RATORY SYSTEM. .................. Effects of Smoking on the Nose, Mouth, and Throat .... Smoking and Asthma ................. Relation of Smoking and Infectious Diseases ....... Chronic Bronchopulmonary Diseases ........... Chronic Bronchitis and Emphysema .......... Definitions .................... Diagnosis ..................... Relationship Between Chronic Bronchitis and Em- Ph Y sema .................... 260 263 263 263 263 264 264 265 265 267 267 267 268 269 269 270 270 275 275 275 276 277 278 278 278 279 RELATION OF SMOKING TO DISEASES OF TllE Rl*:S- PIRATORY SYSTEM-Continued Chronic Bronchopulmonary Diseases-Continued Evidence Relating Smoking to Chronic Bronchitis and Emphysema. ................... Epidemiological Evidence ............. Prevalence Studies ............... (1.) Smoking and Respirator!- Sjmptomd .... (a.) Chronic Cough ........... (I).) Sputum .............. (c.) Cough and .Sputum ......... (cl.) Breathlessness. ........... (e.) Smoking and Chest lllnehs ...... (f.) Combinations of S?.mptoms. ..... (g.) Relationship Betw-een Svmptornh or Signs and Amount SmokEtl ..... (h.) Relationship Between 5) mptoms and Signs and _\lethod of Smoking. ... (i.) Ventilatory Function. ........ Prospective Studies .............. Clinical Evidence ................ Relationship of Smoking, Environmental Factors. and Chronic Respiratory Disease ............ Atmospheric Pollution .............. Basis for Interrelationship and Relative Magnitude of Exposure. ................ (1.) Experimental Evidence. ........ (2.) Relative Magnitude of the Exposure ... Epidemiological Evidence ............ Occupational Factors. .............. SUMMARY ....................... CONCLUSIONS ..................... REFERENCES. ..................... Figure FIGURE l.-Black pigment and emphysema in lungs of 83 patients . . . . . . . . . . . . . . . . . . . List of Tables TABLE l.-Summary of reports on the prevalence of cough in relation to smoking . . . . . . . . . . . . . . TABLE 2.-Summary of reports on the prevalence of sputum in relation to smoking . . . . . . . . . . . . . . QBLE 3.--Summary of reports on the prevalence of cough and sputum in relation to smoking . . . . . . . . . TABLE J.--Summary of reports on the prevalence of breathless- ness in relation to smoking . . . . . . . . . . TABLE S.-Summary of reports on history of chest illness in the past three years in relation to smoking . . . . . TABLE 6.--Summarv of reports on the prevalence of combinations of certain symptoms in relation to smoking . . . . 281 283 284 285 287 288 Pa@! 280 280 280 280 280 283 283 286 287 388 289 289 289 293 294 295 295 295 295 296 297 298 300 302 302 273 Chapter 10 This chapter presents the evidence on smoking in relation to the develop- ment and progression of the non-neoplastic respiratory diseases. The c hf onic bronchopulmonary diseases pose a health problem of substantial and steadily growing importance. Bronchitis and emphysema, in particular, severely disable large numbers of men of workin g age, and have a considerable effect upon mortality as a direct or contributory cause of death. Because of the importance of these diseases to public health, they receive the most attention in this chapter, in accord with the fundamental purpose of the Committee's Report. The design of this chapter is to consider first the experimental and patho- logical data, then the clinical and epidemiological data. ALTERATIONS IN THE RESPIRATORY TRACT AND IN PULMONARY PARENCHYMA INDUCED BY TOBACCO SMOKE CHARACTERISTICS OF THE EXPOSURE Composition of Tobacco Smoke Although the material under this subtitle is dealt with in greater detail in Chapter 6, Chemical and Physical Characteristics of Tobacco and To- bacco Smoke, it is considered here because particle size and other properties of tobacco smoke constituents are of prime importance in the relation be- tween smoking and respiratory diseases. Tobacco smoke is a heterogeneous mixture of a large number of com- pounds with gaseous and particulate phases. As it enters the mouth, ciga- rette smoke is an extremely concentrated aerosol with several hundred million to several hundred billion liquid particles in each cubic centimeter (lO'i, 116, 122). Measurements of the median particle size range from about 0.5 to 1.5 microns; the majority of the measurements have a median closer to 0.5 microns (2). Some of the major classes of compounds which con- stitute the particulate phase of cigarette smoke and notation of their toxic action on the lung (2) are presented in Table 1 of Chapter 6. Nine of the gases present in cigarette smoke are considered irritant to the lung (2) ; Table 2 in Chapter 6 lists some of the known constituents of the gas phase. Regional Deposition or Retention of Tobacco Smoke Little is known about the exact composition of cigarette smoke in the respiratory tract after it leaves the mouth. Inhalation of cigarette smoke undoubtedly exposes the airways and pulmonary parenchyma to smoke with 263 substantially different characteristics from the smoke that first enters the mouth. Insufficient direct evidence is available to characterize this exposure, and existing information is deriv,ed largely from s&stances with analogous physical and chemical features. The retention or deposition of smoke constituents in the several regions of the respiratory system varies because many factors alter the characteristics of the smoke and probably result in losses as the constituents are drawn deeper into the respiratory system. Included among such factors are the amount and composition of the constituents immediately after burning the tobacco, the method of smoking, the depth of inhalation. and the temperature and humidity of inhaled smoke. The physical laws which govern deposition of particles and absorption of gases and the anatomic structure ultimately determine the pattern of regional retention (2). When cigarette smoke is inhaled, total retention of particles in the mouth, respiratory tract, and pulmonary parenchvma is about 80-90 percent, even when the smoke is held in the lung for a relatively short period, two-to-five seconds. When deliberately held for periods as long as 30 seconds, retention of particles is almost complete (135). MOUTH RETENTION OF TOBACCO SMOKE Removai of tobacco smoke constituents while in the mouth has been studied incompletely. When cigarette smoke is drawn into the mouth and promptly expelled without inhalation, the analyzed weight or fluorescence of the re- tained tars ranges from 33 percent to 66 percent (18, 71,135). Experiments utilizing a model of the mouth and airways, but without the deeper portions of the lung, have demonstrated differential regional deposition of certain tar distillation fractions. A cigarette tar fraction distilling at less than 120" C. was deposited in concentrations three times greater in the simulated bronchi than in the mouth; a high-boiling fraction, however, was deposited equally in the mouth and bronchi (57). The available information suggests that removal of smoke constituents in the mouth may be an important defense mechanism that prevents delivery of certain noxious agents to the tracheobronchial tree and lung parenchyma, hut such information is not sufficient to determine which substance may be removed while tobacco smoke components are in the mouth. RETENTION OF PARTICLES BY THE TRACHEA, BRONCHI, AND PULMONARY TISSUE Most information pertaining to retention of smoke constituents by the tracheobronchial tree and pulmonary tissue is based on knowledge of physical factors M hirh determine retention of inhaled aerosol particles and on analo- gies drawn from physiologic studies of aerosol retention in man. In gen- eral: the particles of greater size and density are less able to traverse the twisting course of the airways and tend to be removed high in the tracheo- bronchial tree. Smaller particles penetrate more deeply into the lung and are deposited through gravitational settling or inertial impingement. except for verv fine particles which diffuse onto the surface. The size of virtually all the individual particles in inhaled smoke is probably less than two microns. Data from a number of laboratories indi- cate that particles smaller than two microns are deposited in the lower respiratory tract during normal breathing under rest conditions. Deep breathing shifts deposition of larger particles into the lower respiratory tract also (2, 83). The lowest proportion of deposition occurs for particles between 0.25-0.50 microns. D'ff I usion increases for particles below 0.25 microns, and extremely fine particles, approaching molecular size, diffuse so rapidly that many probably remain on the upper bronchial tree. The importance of such minute particles in tobacco smoke. even if present initially, probably is not great since they act as nuclei for vapor condensa- tion and would be expected to grow rapidly (2, 3). Data on sites of intra- pulmonary deposition derived from phy-siological studies indicate that even for particles smaller than two microns, only about five percent are deposited along the bronchial tree. Radioactive tracers in smoke have been used to stud\- site deposition in animals, Deposition in a diffuse llattern was obtained in dogs inhaling smoke from cigarettes impregnated with K 42. Na 23. and As 76 I 192). A similar experiment using I 131 as the tracer demonstrated substantial bronchial deposition but the physical state of the tracer. whether vapor or particulate, remains uncertain (191 I. In rabbits. cigarettes impregnated with As 76 produced deposition on the lark-nx, carina. and major bronchi but this deposition contributed only a small fraction of the total activity retained by the smaller bronchi, bronchioles, and pulmonary tissue ( 100). From indirect data, therefore, it is most probable that the vast majority of cigarette smoke particles penetrate deeply into the respiratory tract and are deposited on the surface of the terminal bronchioles, respiratory bronchioles, and pulmonary parenchyma. RETENTION OF GASES BY THE TRACHEA. BRONCHI, .4ND PULMO- NARY PARENCHYMA Insufficient data are available on the intrapulmonary fate of gases of cigarette smoke to warrant detailed consideration at present. Thorough re- view of the available information and the known physical characteristics of gas absorption suggest that the speed and depth of inhalation may affect both the amount and site of gas retention; moreover, while the distribution pattern may be diffuse, it seems possible, although not yet demonstrated, that a substantial portion of inhaled tobacco gas and vapor will deposit along the upper bronchial tree (2). In view of the ability of certain of these gases to interfere with normal function of the cleansing mechanisms of the respiratory system (e.g.: ciliary motility ) : such deposition could be of significance in production or augmentation of diseases of the bronchi. Jfetabolism and Toxicity of Specific Components in Tobacco Smoke Little is known about the metabolism of most compounds in tobacco smoke. The fragmentary data have been thoroughly reviewed ( 2 i . Hydrogen cyanide is present in cigarette smoke in concentrations that would be fatal for man were it not for a number of factors which accrue to Prevent such a lethal consequence of smoking (2, 60 ) . Among these factors are dilution of the small smoke volume, discontinuous exposure, rapid de- 265 toxification, and absence of cumulative effect. The cyanide ion is capable of stopping cellular respiration abruptly through inactivation of cytochrome oxidase. In sublethal exposures, the cyanide ion is gradually released from its combination with the ferric ion of cytochrome oxidase, converted to thiocyanate ion (SCN) , and excreted in the urine. Thiocyanate blood levels in smokers are three times higher than in non-smokers and differences in relative urinary excretion are even more pronounced (46: 127). It seems quite likely, therefore, that cyanide derived from cigarette smoke is metabo- lized rapidly in the body, and harmful effects have not been detected. The principal oxides of nitrogen, nitric oxide and nitrogen dioxide, are present in cigarette smoke in total concentrations varying from 145 to 665 ppm (23). Oxides of nitrogen are partially absorbed in the mouth; absorp- tion after inhalation, however: is almost complete i 23, 81) . ?Gtric oxide. one principal oxide of nitrogen in cigarette smoke, is mainly an asphyxiant and is only about one-fifth as toxic as nitrogen dioxide. There is no docu- mented instance of human poisoning due to nitric oxide. Nitrogen dioxide, however, is a primary lung irritant, presumably as a result of its hydration into nitrous and nitric acids which are subsequently converted to nitrites. Exposure to relatively high concentrations of nitro- gen dioxide produces injury sufficient in the human lung to result in pul- monary edema (187). Obliterating fibrosis of the bronchioles has also been observed in man follow-ing moderately high exposures (126). In physiologic studies, changes which resemble those of pulmonary obstructive disease have been observed in men who are occupationally exposed to high concentrations of nitrogen oxides (19). Experimental studies indicate that nitrogen dioxide is capable also of. producing pulmonary damage (24, 74, 76). A severe, but reversible, inflammatory reaction in the respiratory bronchioles of rats, rabbits and guinea pigs occurs after a single two-hour exposure to 8&100 ppm. of nitrogen dioxide. Five daily exposures at 15-25 ppm. for two-hour periods produce similar but less severe results (109). It seems clear from environmental exposures of man to nitrogen dioxide that definite pulmonary damage may result from such exposures. Whether nitrogen dioxide alone, in inhaled cigarette smoke, is capable of producing such damage in man is less certain. Equal amounts of nitric oxide and nitrogen dioxide in cigarette smoke have been reported (81)) but rebent work indicates that the proportion of nitrogen dioxide is much lower (108`1. These divergent results and the uncertainty as to the level of nitrogen dioxide exposure necessary to produce pulmonary damage make it very difficult to assess the role of nitrogen dioxide in cigarette smoke. Formaldehyde gas is present in cigarette smoke in concentrations of 30 ppm. Chronic exposure to 50 ppm. of formaldehyde gas produces an irritant cellular response in mice similar to that produced by tobacco smoke. These changes are found mostly in the trachea; higher levels of exposure are asso- ciated with more severe reactions and extension of the involvement to the major but not the smaller bronchi (102). E xposure of guinea pigs to low concentrations of acrolein, which is also present in cigarette smoke, caused an increase in total respiratory llow re- sistance accompanied by decreased respiratory rates and increased tidal 266 volumes ( 143) . It has been found also that acrolein is a potent ciliary depressant (80). Inhaled vapors of phenol are readily absorbed into the pulmonary circu- lation and, at 30 to 60 ppm., have produced an organizing pneumonia, the effects being most marked in guinea pigs, less severe in rabbits. and wholly absent in rats (42: 43). Data concerning the metabolism and toxic proper- ties of other constituents of tobacco, such as the polycyclic hydrocarbons, do not suggest that they have a significant role in the development of non- neoplastic respiratory disease in man. Clearance of Smoke Deposits Little direct evidence pertaining to clearance mechanisms for smoke de- posits is available. There is little reason to believe, however, that smoke deposits are cleared through routes different from the normal self-cleansing mechanism of the lung described in the section on "Pulmonary Hygiene and Ciliary Activity" of this chapter. EFFECTS OF TOBACCO SMOKE ON DEFENSE MEcHtZNIshls OF THE RESPIRATORY SYSTEM Pulmonary Hygiene and Ciliary Activity The cleansing mechanism of the mammalian respiratory system is depend- ent upon the efficient, integrated functioning of a complex system. From the nose to the terminal bronchioles, a mucous layer in which impacted particles and dissolved materials reside is propelled over the surface and removed from the respiratory tract by the rapid, rhythmic, and purposeful beat of cilia. The mucus is supplied by deep glands in the walls of the airways and by goblet cells. Clearance distal to the terminal bronchioles has be- come more clearly understood in recent years. Fine particles and gases de- posited in the lining of the acinus are removed by several mechanisms. Even relatively insoluble particles dissolve in the lung because of the large surface area-mass ratio of small particles and the high reactivity of body fluids (2). After solution, absorption into the blood stream or lymphatics may result in removal. Remaining particles may undergo phagocytosis or remain free. Some phagocytes enter the alveolar lumen, become laden with foreign material, and are transported to the ciliated air passages to be ex- pelled intact. Some disintegrate along the w-ay and deposit their products on the surface lining. Still other phagocytes may enter interstitial tissues and become sequestrated or be removed to regional lymph nodes. Foreign material which remains free in the fluid lining of the alveolus is transported onto ciliated mucosa by a relatively slow process. The transport results from effects in the fluid lining produced by the mechanics of respiration and re- plenishment of the alveolar fluid lining. Inhibition of ciliary motility following exposure to tobacco tars. cigarette smoke, or its constituents has been demonstrated frequently with experi- mental use of respiratory epithelium from a wide variety of animal species (17, 22, 39, 59, 79, 80, 96, 97, 98, 111, 112, 131, 147, 157, 158, 167, 178). 267 Similar results have been obtained with ciliated human respiratory epi. tbelium i 17, 22 I. Although all investigations have bpen conducted in vitro, the uniformity of the inhibitor)- effects in a number of different experimental models is impressive. Positive ions are present in cigarette smoke. Each cigarette >ields about 10'" positive ions: negatively charged rjarticles are also present ( 1211. These thermally produced gaseous ions have considerable energ>- and may produce effects in cells ( 190). In air free of cigarette smoke, positive ions decrease or abolish ciliary activitv. The reduction in ciliary motility which occurs after exposure to cigareite smoke is augmented and sustained by additional exposureto positive ions ( 112). Sicotine in high concentrations inhibits ciliary motility although con- centrations of nicotine similar to those in tobacco smoke do not affect rahbit. chicken, or human ciliary function (22, 121 i. In addition, tobacco smoke from low-nicotine cigarettes produced no significant difference in ciliarv response from that obtained with cigarettes whose nicotine content had not been altered (121). Hydrogen cyanide, ammonia. acrolein. formaldehy-de. nitrogen dioxide, all components of cigarette smoke, possess potent inhibi- tory activity (48 t . There seems to be little doubt that cigarette smoke is capable of producing significant functional alterations of ciliary activity in vitro. Such alterations could interfere markedly with the self-cleansing mechanism of the respira- tory tract. These in vitro results cannot be fully extrapolated to the effects of cigarette smoke on ciliated respiratory tissue of man because of the many variables present in the c.omplex experimental methods, including dosage of the I'articular agent. Ciliarv depressant activity in the environment of man is not limited to the components of tobacco smoke; agents such as ozone and sulfur dioxide. which are important air pollutants but are not found in sig- nificant amounts in tobacco smoke. are also potent ciliary depressants. Morphologic alteration of cilia of smokers has been described (31. 32, 104). The length of cilia in the trachea and bronchial epithelium was meas- ured at autops! and found to be shorter than in non-smokers. In addition the percentage of cells remainin, u ciliated is loser in smokers than in non- smokers (9. 10. 1041. Mucus Sfw-etion Definitive studies on the effrct of cigarette smoking upon the quantit! and qualitv of human respiratory tract mucus have not been performed. Alteration .in the appearance of mucus after exposure to cigarette smoke has been noted several times. Following exposure to sulfur dioxide. a gas not present in cigarette smoke. c-hanges in the physical properties of mucu> have been observed t-%01. Whether such changes result after exposure to Fases present in cigarette smoke has not been estahlished. Morphological changes observed in the goblet cells and mucous glands at post-mortem examination. however. support the possibility that mucus produrtion ma!- have been altered during life. In essence. little has been contributed in this regard since the observation ahout 100 years ago that a marked increase in mucous secretions in the trachea and larger bronchi of the cat occurred after large doses of nicotine. 268 Atropinization blocked this effect, indicatin, m that this action of nicotine was mediated by stimulation of the mucous glands since goblet cells are not under nervous control (185 I_ An increase in mucus-secreting cells after exposure of rats to cigarette smoke has also been observed recently i 130). Alveolar Lining The alveolar surface is covered by a secretion which stabilizes the alveoli and is produced by the alveolar epithelium I T9, 151). Little is known of the influence of cigarette smoke on this alveolar lining. The application of cigarette smoke to rat lung extracts. considered to represent the alveolar lining, caused a decrease in surface tension and an increase in surface com- pressibility. Lung extracts prepared from rats exposed to cigarette smoke during life also showed lower surface tension and increase in surface com- pressibility. These findings differ markedly from results in non-exposed animals. Such changes during life would be expected to result in a de- crease in the efficacy of surface forces stabilizing the alveoli ( 131). Fur- ther interpretation of the results of this single study does not appear war- ranted; however, because of the great potential significance of the alteration described, further studies should be encouraged. Phngocytosis The importance of phagocytosis as a mechanism for clearance of deposits in the acinus has become more clearly established in recent years. The uptake of tobacco tars by phagocytes is well documented in experimental studies. On the basis of solubility, fluorescence, and pigment characteris- tics of the phagocytized material, and its resemblance to the fluorescence of tobacco smoke condensate: this phagocytized material would appear to con- tain polycyclic hydrocarbons. The accumulation of exogenous pigmented material in mice has been shown to be directly proportional to both the level and duration of cigarette smoke exposure (119, 121 j. Similar fluorescent material was observed in rats exposed to cigarette smoke (130) and in the respiratory lining of the white Pekin duck after application of tobacco smoke condensate (166). Impairment of the efficiency of the phagocytic clearance mechanism after long-term exposure to cigarette smoke apparently occurs in mice 1121). Early in the exposure period, the clearance mechanism of the lungs is ade- quate to the task of aggregating and removing pigmented material and pigment-laden phagocptes; in the final stages of the 2-year experiment, especially at the high dose levels, the phagocytic mechanism appears to be overwhelmed since large areas of parenchyma are flooded with pigment in the absence of phagocytes. A similar suppression of the effectiveness of the phagocytic clearance mechanism for the human lung has been described in pneumoconiosis (41) . Fluorescent histiocvtes have been found in the sputum of cigarette smokers but were not detected in the induced sputum of non-smokers ( 1%). The intensitv of fluorescence and the number of histiocvtes were in dirrct propor- tion to ;he number of cigarettes smoked. These fluorescent histiur! tes pre- 269 sumably represent the phagocytic cells of the acinus which are delivered intact to the sputum. Phagocytosis appears to serve an important function as a concentrating, localizing, and transport mechanism for redistribution of injurious constit- uents of cigarette smoke. The full significance of phagocytosis of cigarette smoke constituents in the pathogenesis of disease has not been clarified. Impairment of this function, however, cannot be dismissed since it might be expected to result in lung injury. Other Mech.anisms Little is known about the role of lymphatics in the removal of tobacco smoke deposits. The evaluation of the effects of smoking on pulmonary function tests will be considered in this Chapter in the section on "Chronic Bronchopulmonary Diseases." Because the several defense mechanisms of the respiratory system are af- fected in various ways by tobacco smoke, it may be useful to recapitulate the evidence presented in this section. Substantial experimental evidence indi- cates that tobacco smoke and certain of its components, like many other substances, can reduce or abolish ciliary motility, at least temporarily, and can slow mucus flow. Impairment of this mechanism in man has not been demonstrated under conditions of cigarette smoking, although it seems logi- cal to assume that alterations would occur. If the removal of noxious agents were slowed, the protracted contact might be expected to result in respira- tory tract damage. Decrease in the number of ciliated cells and shortening of remaining cilia have been described in post-mortem examinations of bronchi from smokers, with implied functional impairment. Alterations in bronchial mucus have been suggested by changes in goblet cells and mucous glands after cigarette- smoke exposure. Increased amount of secretions in the tracheobronchial tree is a frequent observation after exposure to cigarette smoke. Alteration of the fluid lining of the alveoli in rats as a consequence of ciga- rette smoke exposure has been reported in the only study of this aspect. The decrease in surface tension and the increase in surface compressibility ob- served in this study could have great potential significance in terms of human respiratory disease. That tobacco products are ingested by alveolar phagocytes of the experi- mental animal and of man seems fairly well documented. Experimental data from animals indicate that the phagocytic mechanism fails under stress of protracted high-level exposure. The potential implications of these observa- tions again appear to loom large for respiratory disease in man but further definition of these effects and quantitation will be necessary before their full significance can be understood. HISTOPAUIOLOGIC ALTFXATIONS Imucm IN TEIE RESPIRATORY TR-ICT CD IN PULMOSARY PARENCIIYBI.~ BY TOBACCO SM'OKE A variet!- of histopathologic studies from diverse points of Gew indirate clearIT that Fmoking is associated with abnormal changes in the structure of 270 both the surface epithelium and wall of the airways, including the mouth. Many of the studies are open to criticism because of inadequate numbers, lack of proper controls, and defects of experimental design. but specific criticisms are different for each study, and the sum of the evidence points unmistakably to the reality of deleterious consequences upon the respiratory tract from tobacco smoke. Several reports implicate smoking, in particular pipe smoking. as an im- portant etiolopic agent in the development of a condition of the hard palate, and less often the soft palate, known as stomatitis nicotina (34. 70, 172, 181). This condition is associated with excessive proliferation of the surface epi- thelium and overproduction of keratin : the hyperplasia frequently involves the stomas of the salivary gland s, leading to blockage and subsequent dilata- tion of the ducts. Epithelium lining the ducts commonly shows squamous metaplasia. This condition is believed to be very common in pipe smokers but usually disappears upon cessation of smoking. A somewhat similar morphologic change has been described in the lawnI- that correlates closelv with the cigarette smoking history (45. 170). Epi- thelial hyperplasia with hyperkeratosis and variable degrees of chronic in- flammation and squamous metaplasia are present in the true vocal cords, false cords, and the subglottic area. The trachea and bronchi show many morphological changes in the cigarette smoker as compared to the non-smoker (9. 10, 11, 31,33. 35,38, 171 I. Var- ious degrees of hyperplasia, with and without overt atypical change. and metaplasia of the surface epithelium have been described. Deviations from the normal have also been found in the goblet cells, cilia, and mucous glands of smokers. Significant increases in the number of goblet cells and in the degree of mucous distension of the goblet cells were present in whole mounts of bronchial epithelium of smokers (31). Hyperplasia and hvpertrophy of mucous glands and a higher proportion of cells with shorter cilia also were observed more frequently in smokers (33, 1711. The hypertrophy and hyperplasia of mucous glands from miners correlated much better with the degree of smoking than with exposure to silica (35). Even though the num- ber of non-smokers among the miners was small, the relationship between smoking and mucous gland alteration was very striking. The studies on goblet cells and mucous glands in smokers and non-smokers are especially important when considered in the light of current concepts vf the pathology of chronic bronchitis. It is now apparent that one of the commonest morphologic alterations in the bronchi in chronic bronchitis is an increase in goblet cells, and hypertrophy and hyperplasia of the mucous glands (69, 163, 164). Similar findings have been noted in examination of patients with chronic bronchitis in the U.S.A. (182, 183: 1831. Although many cases of chronic bronchitis show other morphologic signs of acute and chronic inflammation, these are not as constant as are the glandular changes. Provided further investigation of the pathologic anatomv of chronic bronchitis in other countries indicates that the disease is essentiallk identical pathologically, the few British studies on goblet cells and mucous glands in smokers offer the first anatomic support for the relationship between smoking and chronic bronchitis suggested by seTera epidemiologic reports. con- ceivably, one or more components of cigarette tobacco smoke have the prop- 714-422 o-64- 19 271 erty of stimulating mucous cell hypertrophy and hyperplasia in a manner similar to that of other unknown factors which appear to be important in the pathopenesis of chronic bronchitis I cf. 64). This mucous cell activity, accompanied by excessive mucus production, may increase the susceptibility of the tracheobronchial tree to secondary infection with various micro- organisms which in turn may lead to acute and chronic inflammation and their consequences. .!lthough this hypothesis (64) has many attractive features, especially in reconcilin g the epidemiologic and anatomic findings in regard to smoking and chronic bronchitis, it must be emphasized that the anatomic data relating to smoking are still essentially preliminary in nature and require confirmation by more extensive and thorough studies. Experimental studies on chronic cigarette smoke exposure in animals, al- though acutely massive compared to human exposures, confirm some of the above morphological findings in man (118, 119, 121). In mice exposed for long periods to cigarette smoke, changes observed in the bronchi and peribronchial tissues were characteristic of severe bronchitis; purulent bron- chiolitis severe enough in some instances to cause massive atelectasis, bron- rhiectasis with organization, and compensatory emphysema were also observed as a response to long-term cigarette smoke exposure. These changes are similar to those described in advanced cases of human bronchitis. In addition to the hypertrophy of mucus-secreting elements already men- tioned, scattered areas of purulent bronchiolitis, small abscess cavities, bronchiolar dilatations and alveolar changes also have been observed. The studies in animals therefore support a conclusion that cigarette smoke is irritating to the tracheobronchial tree and is capable of inducing severe acute and chronic bronchitis. It must be emphasized that the tracheobronchial tree makes only a lim- ited number of histopathologic responses to a large number of different types of injuries. This restriction, perhaps a reflection in part of our methodo- logic limitations, makes it difficult to identify with any certainty the basic nature of the etiologic agent in any given disease process. It is therefore important to be aware of this element of uncertainty when attempting to compare histopathologic findings in the respiratory system under different environmental conditions and in different species of animals. Recent studies indicate that changes in the pulmonary parenchyma are associated with cigarette smoking (12, 136). Formalin fume-fixed lungs from 83 patients over 40 years of age, from which coal miners were excluded, were examined in a preliminary analysis of a continuing study of the rela- tionship of smoking, parenchymal pigment, and emphysema (136). The causes of death included "cliff use obstructive bronchopulmonary disease." The quantity of "departitioning" ( i.e., emphysema) and the amount of black pigment were graded from zero to three. The pigment was not analyzed but was considered to be enthracotic. A close correlation was observed between the quantity of smocking, the quantity of pigment deposited, and the amount of departitioning. At this early phase of the study, the potential etiologic relationships, if any. between the anatomic changes and smoking have not been defined I Fi`guurc 1) . Histologic examination of peripheral lung sections has revealed changes in pulmonary parenchyma, the severity of which was proportional to the 272 + BLACK I I I I PIGMENT I I E I I E BLACK PIGMENT AND EMPHYSEMA IN LUNGS OF 83 PATIENTS DEPARTITIONING 0 AAAQ AAA AAA 0 AA :: A0 0= NON-SMOKERS I5 CIGARETTES PER DAY A= + I 1 I I A0 A o ?? ? ??? o moo A0 o ?? o ??? o ??? 0 o ? 0 o ?? ??? o ?? o ?? o ?? FIGURE 1. Source: Mitchell, R. S. (136) intensity of cigarette smoking as well as to its duration (12). One section from each of four major lobes of the lung was obtained at autopsy from 1,340 patients for whom a careful smoking history was available. Non- smokers were matched with various categories of smokers by age, race, and occupation and then placed in random order for microscopic examina- tion. The pulmonary ahnormalities, measured by arbitrary gradations, included the following: (a) fibrosis or thickening of alveolar septa, (b) rupture of alveolar septa, (c I thickening of the walls of small arteries and of arterioles, and (d) pad-like attachments to alveolar septa. The association of increased pulmonary fibrosis and cigarette smoking was apparent in all age groups (less than 45, 4549, 60-64, 65-69, 70-74, 75 + ) , even in those who smoked less than one pack per day. The increase in fibrosis was most marked in heavy smokers. Whereas the degree of fibrosis rose slightly with advancing age (60+ ) in the non-smokers, the rise was far more dramatic in smokers. The findings were similarly dra- matic for the degree of rupturing of alveolar septa, the most severe changes being detected in smokers in the older age groups. The same association was found for the degree of thickening of walls of arterioles and small arteries. Findings in matched pairs of subjects, who differed in respect to one fac- tor but who were alike in respect to another factor, were compared. The degree of pathological change was significantly greater in three categories (pulmonary fibrosis, rupture of alveolar septa, thickening of the walls of small arteries and arterioles) for the following groups: (1) The older cigarette smoker greater than the younger cigarette smoker ; (2) The one-two pack cigarette smoker greater than "never smoked"; (3) The one-half pack a day cigarette smoker greater than "never smoked" ; (4) The one-two pack smoker greater than one-half to one pack cigarette smoker ; (5) The current cigarette smoker greater than ex-cigarette smoker who had stopped 20 years. In addition, the degree of fibrosis (but not the other three indices) was significantly greater: (1) In one-half to one pack a day cigarette smokers than in less than one-half per day cigarette smokers; (2) In two pack per day cigarette smokers than one-two pack a da! cigarette smokers; I .3) In current cigarette smokers than in ex-cigarette smokers stopped 3-4 years. Degree of fibrosis, rupturing of alveolar septa, and thickening of walls of the small arteries (but not arterioles) was significantly greater in current cigarette smokers than in ex-cigarette smokers who had stopped 5-19 years. ,A11 the changes above were statistically significant at the five percent level. The degree of fibrosis among men over 60 years of age was studied further by relation to smoking habits in an "age standardized" percentage distribu- tion. Increased fibrosis over that found in non-smokers was striking for current cigarette smokers but some trends in this direction were also noted for current smokers of cigars: of pipes. and of cigars and pipes. 274 After review of the design of the study with the investigators and the micro- scopic sections on which judgments were made, some concern remains about two of the four pulmonary abnormalities. Increased thickness of the walls of arteries or arterioles is difficult to interpret on microscopic section, as contraction with decrease in lumen size may simulate an increase in wall thickness. The pad-like attachments are puzzling and the possibility of arti- fact has been discussed repeatedly. The conclusions drawn from this stud!- are based in large part upon the findings pertaining to fibrosis or thickening of alveolar septa and rupture of alveolar septa. In summary, histopathologic alterations in the mouth, larynx, tracheo- bronchial tree and pulmonary parenchyma, associated with smoking, have been documented in man. The alterations in the bronchi support the hypothesis that cigarette smoking is a cause of human chroni,c bronchitis. Whereas definite pathologic changes in the lung parenrhvma of man also are clearly associated with cigarette smoking, the abnormalities observed in the lung parenchyma cannot be related with certainty to recognized disease entities at the present time. RELATION OF SMOKING TO DISEASES OF THE RESPIRATORY SYSTEM EFFECTS OF SMOKIKG ON THE NOSE, MOUTH, AND THROAT Edema, vascular engorgement, dryness, excess mucus production and epithelial changes have been attributed to cigarette smoking on the basis of clinical observation. Rhinitis, angina, and laryngitis, also observed fre- quently in cigarette smokers, are reversible on cessation of smoking. -4ggravation and prolongation of sinusitis are also attributed to smoking. These observations have become clinical tradition, yet surprisingly little documentation of predictable changes in these tissues as a consequence of smoking is available (129). Changes in the palatal mucosa ("stomatitis nicotina") and in the laryngeal epithelium (45'1 closely associated with tobacco smoking have been con- sidered in the earlier discussion of histopathological alterations. Thus, evidence of progressive non-neoplastic disease in the upper res- piratory tract, induced by smoking, is lacking. Only in studies of "stomatitis nicotina" and of epithelial changes in the larynx has there been adequate pathological substantiation of the clinical opinion that alterations are induced by smoking. SIWOKING AND ASTHIVIMA The definition of asthma of the American Thoracic Society will be used for the purposes of this report (4j : "Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a wide- spread narrowing of the airways that changes in severity either spon- taneously or as a result of therapy. "The term asthma is not appropriate for the bronchial narrowing which results solely from widespread bronchial infection, e.g., acute or chronic bronchitis; from destructive diseases of the lung, e.g., pulmonary emphysema; or from cardiovascular disorders. Asthma, as here defined may occur in vascular diseases, but in these instances the airway obstruc. tion is not causally related to these diseases." In rare instances, allergy to tobacco products has been ascribed a causa- tive role in asthma (99, 105, 168, 169, 189). Support for this association comes largely from the presence of skin test reactions to tobacco products and passive transfer tests (168, 169). In the "Tokyo-Yokohama Asthma" studies, a severe asthma-like disease, presumed to be caused by air pollution, affected cigarette smokers predomi- nantly ( 155 J . The absence of smoking data on unaffected members of the same population leaves the question of an additive effect of cigarette smoking unanswered. One study suggests that non-smokers may have a slightly greater prevalence of asthma than smokers; the possibility of bias due to self-selection of the base population could not, however, be excluded in this study (84). Apart from the exceptions noted above, it is clear that cigarette smoking is of no importance as a cause of asthma. A hypothetical contraindication to cigarette smoking can be postulated for asthmatics on the basis of the physiologic alterations induced in the tracheobronchial tree by tobacco smoke. Nonetheless, substantiation of worsening from cigarette smoking in asthmatics has not been reported frequently. A cause-and-effect relation- ship between cigarette smoking and asthma, as defined above, is not supported by evidence available. RELATION OF SMOKING AND INFECTIOUS DISEASES The category, influenza and pneumonia (ISC 480-493)) contributed to the excess mortality of smokers observed in six of seven prospective studies ( Chapter 8, Tables 19 and 26). Details sufficient to warrant conclusions about the nature of this association are not presented in these studies, nor has the apparent association been evaluated further by careful epidemiolopi- cal research. Studies adequate for examination of this association are available for only two categories of infectious diseases, upper respiratory viral illness ,and tuberculosis I 30 I . Experiments on transmission of common colds failed to demonstrate increased susceptibility in volunteers with a history of ciga- rette smoking (50 J . Jloreover, common colds were detected among 5,500 employees over a P-year period with approximately the same frequency in smokers and non-smokers (110). In a study of illness in a group of families under close observation for several years, the frequency and severity of common respiratory diseases, such as the common cold, rhinitis, laryngitis, acute bronchitis, and nonbacterial pharyngitis, were the same in cigarette smokers and non-smokers (21). Similar results were obtained by ques- tionnaires in an analysis of the frequency of common colds in a group (Jf college graduates followed over a 20-year period (85). 276 A number of studies have suggested a substantial relationship between smoking and pulmonary tuberculosis (55, 125, 133, 175). The possibility that the relationship is not a direct one needs further careful examination. Certain social factors, important to epidemiological assessment in tubercu- losis, have not been considered in detail in these studies. Of particular interest in this regard is a study (29) in which both cigarette and alcohol consumption were found to be in excess in tuberculosis patients as compared to the matched controls. The number of cigarettes consumed in the two groups was the same, however, at each level of alcohol intake. Matching by cigarette consumption failed to weaken the association between alcohol con- sumption and tuberculosis (29). Thus, the relationship between tubercu- losis and smoking in this study was only an indirect one: the association was found to occur between smoking and alcohol consumption and between alcohol consumption and tuberculosis, rather than between smoking and tuberculosis. Thus the association between smoking and the infectious diseases is con- fined at present to a single cause-of-death category : Influenza and pneumonia contribute to the excess deaths in cigarette smokers, but the data are insuffi- cient to evaluate this observation. In the limited number of studies avail- able, cigarette smoking has not been shown to contribute to the incidence or severity of either naturally acquired or experimentally induced upper respir- atory viral infections. CHRONIC BRONCHOPULMONARY DISEASES Mortality for certain respiratory diseases (bronchitis, bronchiectasis: chronic pulmonary fibrosis, chronic interstitial pneumonia, and emphysema) increased in the decade 1949-1959 (48) and continues to show an upward trend (132, 141) . In 1955, cancer of the lung was certified as the under- lying cause of death in 27,133 persons and chronic bronchopulmonary dis- eases in 11,480 persons. A tabulation of all diagnoses, both contributing as well as underlying causes of death, however, showed that cancer of the lung was entered upon a total of 28,123 death certificates, whereas the chronic bronchopulmonary diseases were certified as contributing to 32,051 deaths (47). The possibility that mortality data, as presently recorded, may under- estimate the role of chronic bronchopulmonary diseases through incorrect listing by the physician as contributory rather than the principal cause has also been suggested (115). Social security records in 1960 show that chronic bronchopulmonary dis- eases, particularly emphysema, ranked high among the conditions for which disability benefits were allowed to male workers 50 years of age or older in the United States (186). Chronic bronchitis and emphysema are the chronic bronchopulmonary diseases of greatest public health importance in the United States. They contribute to the excess mortality of cigarette smokers. but there is little information about the effects of smoking on the other chronic broncho- Pulmonary diseases. The scope of the subsequent remarks is limited there- fore to the possible relationship of smoking to chronic bronchitis and 27; emphysema. Since dexriptions of both were published long before ciga. rette smoking became commonplace (13, 14, II4), it seems reasonable to suggest at the outset that cigarette smoking alone 1s not the only cause oI chronic bronchitis and emphysema. Chronic Bronchitis and Emphysema DEFINITIONS Many definitions of chronic bronchitis and emphysema have been sue. gested. For the purposes of this report the definitions proposed by the American Thoracic Society (4) will be used: "Chronic bronchitis is a clinical disorder characterized by excessive mucous secretion in the bronchial tree. It is manifested by chronic or recurrent productive cough. Arbitrarily, these manifestations should be present on most days for a minimum of three months in the year and for not less than two successive years. Many diseases of the lung, e.g., tuberculosis, abscess, and of the bronchial tree, e.g., tumors, bronchiec. tasis, as well as certain cardiac diseases, may cause identical symptoms: furthermore, patients with chronic bronchitis may have other pulmonary or cardiac diseases as well. Th us, the diagnosis of chronic bronchitis can be made only by excluding these other bronchopulmonary or cardiac disorders as the sole cause for the symptoms." Tb is . . definltlon and classification of chronic bronchitis later considers complications. listing three: infection, airway obstruction, and pulmonary emphysema : "Emphysema is an anatomic alteration of the lung characterized by an abnormal enlargement of the air space distal to the terminal, non- respiratory bronchiole, accompanied by destructive changes of the alveolar walls." DIAGNOSIS The diagnosis of chronic bronchitis is based essentially on descriptions of clinical manifestations and is achieved by exclusion. Recollection and interpretation on the part of the subject are necessary. There is, no simple sensitive pulmonarv function test that will indicate which person has chronic bronchitis. A clinical diagnosis of emphysema, based on the clinical syndrome and certain changes in pulmonary function, is even less exact. The clinical features usually encountered in emphysema tend to be very similar to those found in chronic bronchitis. Most of the symptoms and signs and many of the physiological changes usually thought to indicate the presence of emphysema may result from airway obstruction due to bronchitis (66, 180). There is no completely satisfactory method of detecting emphysema by pulmonaq function testin, - and no pulmonary function test is specific for the detection of pathologic lesions of emphysema (521. The clinical detec. tion of emphysema is therefore not a simple matter, especially in the presence of chronic bronchitis. 27% The following, adapted from the American Thoracic Society-`s statement (4), epitomizes the situation for emphysema: Clinicopathologic correlations have demonstrated that certain per- sons who have this morphologic alteration at autopsy have symptoms of pulmonary insufficiency during life and die of this disease. Others show- ing qualitatively similar pathologic findings had no respiratory symp- toms during life and died of unrelated causes. In some persons, em- physema may be strongly suggested by the patient's symptoms and its existence predicted on clinical grounds with considerable accuracy. On the other hand, clinical manifestations identical with those of patients with emphysema may occur in persons who are not found to have this disease at autopsy but who have some other lung disease. Emphysema may exist without any clinical manifestations, and its clinical and func- tional alterations are not unique but occur in other pathologic conditions. RELATIONSHIP BETWEEN CHRONIC BRONCHITIS AND EMPHYSEMA Chronic bronchitis and emphysema frequently coexist, although one can be present without the other. A 1' ' c nucal continuum appears to extend from bronchitis at one end, through a mixture of the two conditions in the major- ity of cases, to emphysema at the other end (123). An alternative method of assessing the relationship is by study of patho- logical change. A 1 c ose relationship is found between chronic bronchitis and emphysema on purely morphologic grounds. Although emphysema occurred more frequently in patients with chronic bronchitis than could be accounted for by chance, the two conditions also occurred independently of one another (183). Three of the possible reasons why chronic bronchitis and emphysema are found in association more often than would be expected by chance are the presence of a common cause and causation each by the other. The protective mechanisms for the upper respiratory tract are cilia and a mucous sheath, and the lower respiratory tract mechanisms involve macrophages, the lymphatic system, and possibly the fluid lining of the alveoli. Although not yet proved, failure of the protective mechanisms of the upper respiratory tract might be expected to lead to chronic bronchitis and failure of the pro- tective mechanisms for the lower respiratory tract to emphysema, On this hypothetical basis, a common cause would not seem unlikely; noxious en- vironmental agents in gaseous or aerosol form would be likely to affect upper and lower respiratorv tracts simultaneously, perhaps with potentiation of the injury in the lower tract by particles. Several ways in which chronic bronchitis might cause or aggravate emphysema have been suggested: such as through trauma resulting from pressure changes induced in the thorax by cough (138) and by airway obstruction (114). Clinical evidence of bron- chitis preceded clinical evidence of emphysema in over 50 percent of cases in one continuing study (137). of chronic bron,chitis 153 I. Others suggest that emphysema may be a cause It seems likely that a common cause. causation of emphysema by chronic bronchitis, and causation of chronic bronchitis hy emphysema are all operatin g mechanisms, with varying importance in different populations and different individuals (123). 270 Evidence Relating Smoking to Chronic Bronchitis and Emphysema Experimental and pathological evidence bearing on the possible rela. tionship of smokin g to chronic bronchitis and emphysema has been pre- sented in an earlier section of this chapter. Epidemiological and clinical evidence relating smoking to these diseases will be considered here. EPIDEMIOLOGICAL EVIDENCE Chronic bronchitis and emphysema probably represent disorders of multi- ple causality. Such problems are particularly suited for analysis by the epidemiological method, especially with regard to the identification of causes and the disentanglement of their relations (140). Two types of studies, prevalence studies and prospective studies, will be considered. PREVALENCE STUDIES.-The most important epidemiological evidence available relating smoking to non-neoplastic respiratory diseases is found in the prevalence studies which concern the number of cases in a population at one point in time. The definitions and criteria for diagnosis of chronic bron- chitis and emphysema are not ideal for the purposes of these epidemiological surveys. The absence of standardized diagnostic methods in chronic bron- chitis and the non-specificity of clinical diagnostic criteria for emphysema have resulted in the use of prevalence of symptoms and signs of the respira- tory diseases under study as a basis for the surveys. Studies of the prevalence of chronic bronchitis and emphysema in the United Kingdom and in the United States over the last decade have developed highly reliable epidemiological methods. Because of the nature of the diseases in question, these surveys present results by the prevalence of specific symp- toms and signs, or combinations, rather than diagnostic labels of disease en- tities. Various levels or grades of severity of the symptoms or signs are defined and the data are obtained and handled in a standardized manner, permitting comparisons between different populations and communities; thus it becomes feasible to evaluate whether smoking is associated with cer- tain signs or symptoms to a greater extent than with other findings. ( 1. I Smoking and Respiratory Symptoms-( a.) Chronic Cough-The common phrase "smoker's cough" suggests that this symptom is popularly be- lieved to be associated with smoking. Several workers have investigated the relationship between smoking and cough; Table 1 lists surveys that tabulate the frequency of cough in smokers as compared with non-smokers. Several different types of populations have been surveyed; the purpose of presenting the findings together is to demonstrate the variation found among the differ- ent populations. The 1,456 mill workers studied by Balchum et al. ( 16) constituted the ran- dom sample of those who volunteered for chest X-rays and pulmonary func- tion tests. Of 1.198 smokers, 23.3 percent reported cough; of the 253 non- smokers, 10.2 percent reported cough. When the percentage of smokers re- porting cough is considered in each of several categories described by pack- years of smoking experience, a gradient was found for those reporting cough, ranging from 11 percent of those who smoked less than one pack-year of cigarettes up to 50 percent of the subjects with 60 or more pack-years of smoking experience. 280 TABLE I.-Summary of reports cm the predence of cough in relation to smoking Author I Year Numhrr of subjects Hrfrr- __- ence Smokers Non- ; smokers 23. R In. 2 31. 5 13. n n.6 4. 1 21. 2 78 20.6 1% 7 z 54. R qu 12 1 0 IR. 9 R. 3 64 IA 60 I 0 Boucot and others (251 considered the relationship in older men of smok- ing and chronic cough in a self-selected population 45 vears of age and older. Chronic cough was defined as cough existing for months or rears. Again. a considerably higher percentage of the smokers reported cough. and a clear- cut gradient was established according to amount of smoking. Bower (26) studied 172 men and women employed in a bank. This study is one of the few which included men and women working under similar con- ditions. Eighteen percent of 95 men and 17 percent of 77 women admitted to cough "more or less every day." Of the smokers, 27.6 percent admitted to daily cough (12 of 42 men, 9 of 34 women), whereas 4.1 percent of non- smokers admitted to this symptom (0 of 13 men, 2 of 36 women). Densen and others (44) presented findings in transit and postal employees. Persistent cough was reported by 21.2 percent of 2:530 smokers and 7.8 per- cent of 514 non-smokers. Fletcher and Tinker (67) studied male workers aged 30 to 59 in the British General Post Office and in the London Transport Executive. In the G.P.O., 18.7 percent of 166 smokers reported cough during the whole of the day in the winter, compared with none of 10 non-smokers. Among smokers of the L.T.E., 20.6 percent of 272 admitted to a comparable cough pattern whereas none of 30 non-smokers described such a cough pattern. Flick and Paton (68) in a study of patients excluding those with cardiac and respiratory disorders, found 55 percent of 157 smokers admitted to habitual cough compared with 10 percent of 51 non-smokers. After the first hundred patients, the admission to the study was weighted in the older age groups. The questioning was not as standardized as in some of the more recent surveys. Olsen and Gilson (148) ~ in their study comparing findings in population samples in Britain with those in Denmark, found cough in 32.1 percent of 162 British smokers and in 18.9 percent of 132 Danish smokers: the cor- responding figures for non-smokers was 0 percent of 11 and 8 percent of 24. Schoettlin (173) studied a group of veterans in a domiciliary and medi- cal-care center, mostly in the age group 45 to 74. The results for cough !"constantly present for two years or more") are presented in terms of 281 years of smoking. although the original figures were not published and are not included in Table 1. By recalculation, it appears that of those who smoked more than 10 years, 43.9 percent of 2,153 subjects had cough whereas 18.0 percent of 718 u-ho had smoked less than 10 years had cough. In the population samples quoted thus far. the percentage of smokers admitting to cough ranged from 17.3 percent to 55 percent, whereas the range for non-smokers was 0 percent to 13.0 percent. Two other studies show a considerably lower prevalence of cough both among smokers and non-smokers in two unusual types of population. Short and others I 176) reported the frequency with which unselected policyholders admitted to cough on periodic health examination, a time when they would be expected to minimize their symptoms. Of 1,292 smokers, 6.4 percent admitted to cough whereas 1.6 percent of non-smokers admitted to cough. In a study of a parachute brigade, Liebeschuetz (120) found 6.0 percent of 83 smokers and none of 52 non-smokers admitted to cough. The study of members of this unit with particularly high fitness standards was con- ducted at the time of discharge. Hammond ( 82) has presented the frequency of cough in smokers and has compared this with the frequency of cough among non-smokers. The subjects were asked to state whether they had a cough at the time of the questionnaire. They were also asked the question: "Have you had a cough over a period of many years?" They also were asked to estimate its severity as slight. moderate, or severe. The analysis of complaints has been reported so far for 43,068 questionnaires, 18,697 for men and 24,371 for women. For each age group and for both sexes, cough was significantly more common among those who smoked cigarettes. The percentage with cough (and the percentage with more than a slight cough ) increased rapidly with the num- her of cigarettes per day in both sexes and in all four age groups. Except for ex-smokers. the relationship between "chronic cough" and smoking habit was very much the same as the relationship between "present cough" and smoking habits. The proportion of male smokers with the complaint of cough \vas almost three times as ,areat as might have been expected on the basis of cough prevalence among non-smokers. For women: the ratio of observed-to-exl:ected smokers w-ith the complaint of cough was 2.5 to 1. The ratio of ohserved-to-expected numbers complaining of cough "more severe than slight" \\as 4.09 for males and 2.74 for females. The difference in frequent!- of the comf)laint of cough or of cough "more severe than slight" bet\\een smokers and non-smokers is statistically significant at the 0.001 level. The study sample was not a random sample of the population, but it pro\-idrs information about the relationship between smoking and various complaints for larger numbers of subjects than does any other study. The results again make it clear that a larger proportion of cigarette smokers are aware of couph than are non-smokers. In earh of the surve\s. smoking \cas found to be associated with the e\mptom of rough defined in a variety of ways. The studied populations varied considerably-from hospital patients. workers in dusty trades and clean offices. urban and rural population samples to members of a parachute brigade. Despite the diversity of these groups. it is surprising to note the consistency of the difference between smokers and non-smokers in regard 282 to cough. In each of the surveys, a larger proportion of the subjects ad- mitting to cough were smokers and about twice the proportion of smokers admitted to cough as non-smokers. (b.) Sputum.-Table 2 lists surveys in which the frequency of sputum pro- duction has been tabulated separately for smokers and non-smokers in preva- lence surveys. Most of the studies were considered in the section on cough and in Table 1. It is interesting that in most of these studies non-smokers report sputum production more frequently than cough. TABLE 2.--Summary of reports on the prevalence of sputum in relation to smoking London Transport .._._.........._.._. ~... ._ 1961 Post Offic% . . . . . .._......_.... -.~ _... ~.._ 1961 Flick..... .__..._._. ..__...._........_...... _ 1959 Olsen: ( Numhw of suhjrctn United Kingdom . . . . . . . . . . .._. . . .._..... ~- Denmark.-.........--.....~.-..-...-.--...- 1 Percentages standardized for age. T'wcfnt with sputum 30.4 34. 2 21.9 11.1 204 13 R 1 4". 3 ' lY.8 1 13. R 19.4 16. 9 7 0 1% i 10 II 64. 7 24. 5 27. 7 11.4 - 0 R. :3 Ferris and Anderson (61) studied a sample of the population of a town; their results are presented as percentages: standardized for age. The sample sizes were 542 males and 695 females. Among males 40.3 percent of smokers and 13.8 percent of non-smokers admitted to sputum production with the corresponding figures for females being 19.8 percent for smokers and 9.4 percent for non-smokers. Thus, sputum production in each of the diverse populations was found associated with smoking and a consistent difference between smokers and non-smokers was present in regard to sputum production. (c.1 Cough and Sputum.-The closely associated symptoms of cough and sputum have been combined in the results of a number of epidemiologic sur- veys. Table 3 shows the prevalence of cough and sputum in smokers and in non-smokers among samples studied. Of particular interest is the series of comparisons made by Higgins and his colleagues (88, 90, 92. 93, 95)) on samples drawn from contrasting pop- ulations, selected for their different backgrounds. Lapse rates were low, and a high degree of uniformity was achieved in the collection of informa- tion. In the disparate groups studied-including male and female subjects, older and younger, and varyin g in degree of dust exposure and exposure to rural or urban environment-the consistent direction and extent of the dif- ference between prevalence rates in smokers and non-smokers demonstrates a strong relationship hetween smokin g and productive cough in a variety of different situations. and the predominance of smoking as a determinant of these symptoms. 281 TABLE 3.-Summary of reports on the prevalence of cough and sputum i,, rehion to smoking Author i year (153) 1.400 (l.3) (156) .iz WC 91 ;:3 43 I 83 --I---- Non- 1 Smokers / x,,,, smokws 1 i SInok;.,, -__- __ --. 1: flf 33 ifi 364 1,468 451 46 81 52 - 23. 9 17.2 : I 4 !, 24.0 30.0 (, :i , 29.8 Ii 1 29.1 L. 44.7 ',4 :i , 11.0 6. 0 1 .* I (8 51.0 2.11 23.1 4. i 1% 6 4 !4 7. 2 u The percentages of symptoms noted by Oswald and Medvei (1501 are unusually high because occasional cough or sputum is included, in addi- tion to more frequent or persistent symptoms. The results are not shown in Table 3, which considers only smoking and cough with sputum; among males, 63.7 percent of 2,617 smokers and 47.7 percent of 985 non-smokers in Oswald and Medvei's study had cough or sputum. Among females, 63.2 percent of 970 smokers and 47.7 percent of 1.272 non-smokers admitted to either or both of these symptoms. Payne and Kjelsberg (153) presented data on respiratory symptoms, lung function, and smoking habits in the adult population of Tecumseh, Michigan, where a comprehensive epidemiological study is being made of the entire community. Cough and sputum were graded in severity as Grade I or Grade II, the latter being defined 3s both cough and phlegm, of which at least one was present throughout the day for three months in the year or longer. The prevalence of Grade II sy-mptoms is noted in Table 3. Dur- ing an interview period continued for 18 months, authors were able to show that the prevalence of symptoms did not vary significantly with the season of the year. Cough and sputum at the Grade II level were admitted to by 11 percent of 1.400 cigarette-smokin, m males, and 2 percent of 364 non- smoking males. The corresponding figures for females were 6 percent of 888 smokers and 2 percent of 1,X% non-smokers. These Grade II symptoms increased in prevalence with advancing age in men, and in women up to 49 j ears. It is interesting to note that lesser degrees of cough and sputum, classed 3s Grade I symptoms. showed little change in frequency after 19 years of age in either sex. In both sexes, Grade I symptoms of cough and sputum uere considerably more prevalent among smokers than among non- smokers-45 percent of 1,400 smokers and 19 percent of 364 non-smokers among the males, and 29 perucnt of 888 smokers and 17 percent of 1,468 non- smokers among the females. Phillips and his associates (156) studied two groups: one of male em- ployees in a steel-making plant, examined as part of an industrial hygiene program, and containing sub-groups with different types of industrial ex- posure, and a second group consisting of 300 patients in a Veterans Ad- ministration Hospital who were chosen at random, except for exclusion of cases of specific pulmonary diseases such as tuberculosis or tumor and cases of congestive heart failure. Chronic cough was defined as daily cough with sputum for a period of one year or more. Various possible environ- mental factors-geographic area, air pollution, specific work environment. and smoking-were considered. Fifty-one percent of 823 cigarette smokers were recorded as having cough, and 2 percent of 451 non-smokers. In a tabulation of chronic cough by age in decades, for cigarette smokers and non-smokers, it was shown that the increasing prevalence of chronic cough with age was much greater in the cigarette-smoking group. Read and Selby (159) in a mixed group of 302 subjects, some of them clinic patients, some patients' friends, and some hospital staff, found that male smokers admitted to cough or sputum ten times as often as did male non-smokers, and to cough and sputum five times as often. In their female subjects the ratios for these categories were eight to one and four to one. Liebeschuetz (120) in his study of parachute brigade members found. as might be expected, a much lower proportion of subjects with cough and sputum; these do not include subjects previously noted in Table 1 as having cough alone. Considering these surveys as a group, it appears that the presence of cough, sputum, or the two symptoms combined, is consistently more frequent among smokers than non-smokers, in a variety of samples drawn from populations differing so widely in other respects that this association ma) be taken to be a general one. TABLE 4.-Summary of reports on the prevalence of breathlessness in relation to smoking Refer- Number of subjects Smokers 1.19R 2. 530 272 166 222 93 is 20 315 z 1.400 Rx4 1. 292 Non- jmokers 14. 5 25.3 R. 5 9. 0 19. R 9. 7 9% 42 i 285 Some of these surveys are limited in one respect. and some in another. The degree to which bias has been avoided varies; several of the survevs quoted are open to criticism in this regard. but in others considerable pains have been taken to avoid any possihility of suggesting a relationship which mav not trulv exist. It would be Mrong to extrapolate from. say. a hospital population to the general public. but the groups surveyed vary enough that the evidence demonstrates clearly that cigarette smokers more often report symptoms of cough. sputum. or both. than do non-smokers. t d. I Breathlessness.-Table 4 summarizes the prevalence of breathlessn?ss as reported in surveys of various populations. Balchum and others (16) in their survey of mill workers. reported a greater prevalence of breathlessness among the smokers in their sample, Tabulation of the frequency of this complaint by pack-years of smoking experience showed a less smooth gradient than for prevalence of cough and sputum. Densen and others 144), who studied respiratory symptoms in transit workers and postmen in New York City. found that 25.3 percent of 2,530 smokers and 16.9 percent of 514 non-smokers admitted to breathlessness of Grade II or worse iindicated by positive answers to specific questions on the questionnaire). Fletcher and Tinker (67)) in a study of Transport Executive employees and Post Office employees, had only one non-smoker out of 40 complain of breathlessness. and 38 smokers out of 438. These figures are for workers complaining of dyspnea (a positive answer to the question, "DO you have to walk slower than most people on the level?" or "Do you have to stop after a mile or so on the level at your own pace?"). In the four studies by Higgins listed in the table. the difference in prevalence of breathlessness between smokers and non-smokers is more variable. In his study 188) in the agricultural district of the Vale of Glamorgan, the author bresents prevalence figures for the various symptoms among females in two age groups. those under age 45, and those over age 45. His reason for doing so is the considerable difference in frequency of the smoking habit between women in these two age-groups. In both the age groups of females, the prevalence of breathlessness is greater among the non-smokers. but the difference is not statistically significant. Female smokers in the over 45 age groups have rather more cough and sputum and wheeze than the non-smokers. but apparently have less breathlessness. In his study in Annandale (93 1 the prevalence of breathlessness among all men and all women studied MBS greater in the non-smokers than in the smokers. although the numbers of non-smoking men and of smoking women were small. When males aged 55 to 64 are considered. from the three surveys 1901, breathlessness is more prevalent among the smokers. and the same thing applies to the t\\ o different age groups of males studied in Staveley (92 I. Payne and Kjelsberg i 153 I : in their survey of a total community, ha\-e stated that among the men, cigarette smokers were affected more often with breathlessness at all ages. Among the women, cigarette-smokers had a higher prevalence of breathlessness than non-smokers below the age of 40, and above this age the non-smokers had a higher prevalence. Considering all ages together. twice the proportion of male smokers admitted shortness of breath 286 compared to non-smoking males; the prevalence of shortness of breath among females was the same for smokers and non-smokers. Short et al. (176)) in a study of answers to a questionnaire on routine medi- cal examination for insurance purposes, obtained a larger percentage of com- plaints of breathlessness amon g smokers than among non-smokers. Hammond 182) also presents figures for the frequency with which breath- lessness was noted in answer to a questionnaire by 18.697 men and 24.371 women. The relationship between breathlessness and smoking is less clear than the relationship between cough and smoking. A significantly greater proportion of complaints of breathlessness was encountered among male and female cigarette smokers, both for total complaint of breathlessness and complaint of breathlessness "more severe than slight." The ratio of ob- served-to-expected complaints of breathlessness among male smokers was 1.97 for the total number with this complaint, and 2.62 for those complain- ing of breathlessness more severe than slight. The ratios for females were 1.36 and 1.49. A consideration of the frequency of complaints of shortness of breath in smokers and in non-smokers, by age group and by sex, shows that the excess of breathlessness among cigarette smokers is greater and more consistent for men than for women. The older age groups of women show only a slight excess. Thus, the relationship between smoking and the symptom of breathless- rrcss is less general than the relationship between smoking and cough or sputum, which is found in all age-sex groups in a variety of different pop- ulations. For males the association is clear: male cigarette smokers com- plain of breathlessness more often than do non-smokers, particularly in the older age groups. Females present a less uniform pattern. In several sur- veys, females show a higher prevalence of breathlessness in non-smokers than in smokers, particularly in the older age-groups. The reasons for this sex difference have not been explained. (e.) Smoking and Chest Illness.-The percentage of smokers and non- smokers who reported chest illness in the three vears prior to the interview TABLE 5.-Summary of reports on history of chest illness in the past 3 years in relation to smoking I .-__ _-- .~~ 114-422 o-64-20 date is presented in Table 5. For men, the prevalence was consistently higher among smokers, and in one study (93), the association of smoking and chest illness was apparent for the younger (25-34) as well as the older males (5% 6.11. For female smokers and non-smokers, the prevalence of chest illness was about the same. cf.) Combinations of Symptoms.-A number of prevalence studies (7,54, 61, 62. 77, 150 ) hav-e reported results, either totally or in part, under diag nostic headings which cannot be translated into single symptoms. The symptom combinations and the names applied to them varied; some of the studies gave the percentages of smokers and non-smokers with "any" signs or symptoms rather than specified combinations. The results are presented in Table 6. TABLE 6.-Su.mmary of reports on the prevalence of combinations of certain symptoms in relation to smoking Smokers .___~ (7) 3.214 (54) 779 I::{ 340 209 NOD Smokers NOW smokers smokws -- 677 524 21.7 10.3 29.4 19. 5 ' 24.9 ' 7.3 ' 17.5 ' 9.4 42. 6 15. 0 20.0 10.0 43.0 31. 4 Per@ant with symptoms 16. 1 9. 7 15.4 9.1 Ashford and his colleagues I 71 found twice the proportion of "respira- tory symptoms" among Scottish coal mine workers who smoked than among those who did not smoke. "Respiratory symptoms" were regarded as pres- ent in those who have caugh or sputum all day for more than three months per year and walk slower than others on the level, or wheeze, or if the weather affects their chest. or if they have had a chest illness in the last three years. Those who had wheeze and who claimed the weather affected their chest were also classed under "respiratory symptoms." Edwards and others (541 I-resented the percentage of smokers and non- smokers with bronchitis. according to clinical assessment by one of 11 general practitioners coooerating in the survey. No attempt to standardize the diagnosis was reported. Of ii!, smokers. 29. I percent had "bronchitis" compared with 19.5 percent of 524 non-smokers. Ferris and Anderson (61: presented the prevalence of "irreversible ob- structive lung disease." which was defined as the report that wheezing or whistling in the chest occurred most days and nights, that the subject had to stop for breath when walking at his own pace on the level, or had a forced expiratory volume in the first second of expiration ( F.E.V. 1.0) of less than 00 percent of the total forced expiratory volume. According to this defi- nition. male smokers showed a 24.9 percent prevalence of irreversible 288 obstructive lung disease, compared with 7.3 percent of male non-smokers. The corresponding percentages for females were 17.5 percent and 9.4 per- cent. These percentages were age-standardized. ln a study conducted in a flax mill, Ferris, et al (621 presented the prev- alence of "chronic respiratory disease," defined as productive couEh on four days of the week, for three months of the year: for three successive years; or wheezing in the chest most days and nights; or breathlessness. of Grade III or more, in the winter; or asthma diagnosed by the physician at the time of the survey; or F.E.V. 1.0 less than 60 percent of forced vital capacity. rnder this definition, 42.6 percent of 54 male smokers and 15.0 percent of 20 male non-smokers had "chronic respiratorv disease." For females. the figures were 10.0 percent of 10 smokers and lo.0 percent of 60 non-smokers. Goldsmith and others c 77'). in their study of longshoremen. classified the subject as having a "respiratory condition" if he had ever had asthma or bronchitis, or currently was "troubled by constant coughing." With this definition, 43.0 percent of 1:238 moderate or heavy smokers had a respira- tory condition, compared with 31.4 percent of 744 non-smokers. Oswald and Medvei (1501, defining "bronchitis" as disability from acute exacerbations of chest symptoms, or breathlessness, or both, found a prel-- alence of 16.1 percent among 2,617 male smokers. and of 9.7 percent among 985 non-smokers. In their female subjects, 15.4 percent of 970 smokers compared with 9.1 percent of 1,272 non-smokers had "bronchitis." Although these various combinations of symptoms are not comparable. the consistency and extent of the differences between prevalence of symp- tom combinations in smokers and non-smokers are striking. (g.j Relationship between Symptoms or Signs and Amount Smoked.-In several surveys, smoking categories were based on the daily consumption or total lifetime consumption (16, 61, 67, 82. 90, 153, _ In the majority. the Prevalence of cough and sputum increased with amount smoked. A recent study (82) showed that those who smoked cigarettes of low nicotine content tended to cough less than those who smoked cigarettes of high nicotine con- tent. Other symptoms and measurements of pulmonary function show a less clear relationship between prevalence and amount smoked. fh.) Rebztionship bettceen Symptoms and Signs and Method of Smokinp.- The numbers of pipe and cigar smokers in many prevalen,ce studies are so small that conclusions about the effects of these methods of smoking are not reliable, but they all tend to show that pipe and cigar smokers are likely to be intermediate between non-smokers and cigarette smokers in prevalence of Symptoms and signs. (i.) Vent&tory Function-Pulmonary tests and the method of presenting results, though varyin g widely, are important features of the prevalence surveys. ln the study by Ashford and others 171 of 4,014 coal miners, the forced exPiratory volume in the first second of expiration (F.E.V. 1.0'1 of non- smokers was slightly higher than that of the smokers. and a small but sta- tistically siunilicant difference was found even after correction for differ- ences attributable to physique. No consistent relationship was reported between the amount smoked and the average F.E.V. 1.0. 289 Balchum and others (16) reported that 19.3 percent of 1,194 srnoken and 7.8 percent of 243 non-smokers had an "abnormal" test, an F.E.Vr. l.O of less than 70 percent. When the "abnormal" test was compared \,ith the number of pack-years of cigarettes smoked, a steady increase in tl,,. proportion of men with decreased F.E.V. 1.0 was found with inereasirlz pack-years. Ferris and Anderson (61) showed a progressive decrease in the ,,,,,a,1 F.E.V. 1.0 in successive age groups for male smokers, male non-smoker, and female non-smokers. In males. there was also a regular decrease i,, F.E.V. 1.0 within each age group with increase in the number of cigarrtt,., currently smoked. In females, there was little difference in the F.E.V. l.(, between smokers and non-smokers except in one age group. The peak expiratory flow rate showed a decrease with age and a decrease within th, age groups w.ith cigarette smoking. Chivers (36) showed that smoking. age. and height were correlated "ia. nificantly with the expiratory flow rate. The older and shorter men ha,1 greater impairment associated with smoking. Flick and Paton (68) demonstrated a distinct decline, beginning at about 40 years of age. in expiratory flow rate among smokers, but no appare,,t change among non-smokers until 70 years of age. Fletcher and Tinker (67), measuring expiratory flow rates by the Peak Flow Meter, found one group of smokers, but not another, had lower value. than the non-smokers. In a later paper (58). Fairbairn, Fletcher and Tinker reported that the Peak Flow Meter appeared to be a less satisfactory screen. ing test than the forced expiratory volume. Franklin and Lowell (73), in a study of 1,000 apparently healthy factor, workers, found the mean expiratory flow rate during the third quarter 01 maximal forced expiration to be approximately 20 percent less in "heal\ smokers" than in "light smokers." "Heavy smokers" were defined as thos, who had smoked 30 pack-years or more, and "light smokers" less than 111 pack-years. Higgins (88) showed a decrease in F.E.V. 0.75 among smokers of 15 grams or more of tobacco per day. compared with non-smokers and with those who smoked less than 15 grams a day. For this test, there was ncl significant difference between non-smokers and the lighter smoking group. Peak how measurements indicated a difference between heavy and light smokers. and also between nonsmokers and light smokers. In each lo-year age group over 45, the peak flow was lower in smokers than in non-smokers. but the numbers were small. Th ese differences are not explained by differ. ences in age, social class, or occupation. The difference between smoker5 and non-smokers in peak flow measurement was not seen in tests of women. Higgins ( 90) summarized the difference in F.E.V. 0.75 in a variety of different samples of the population. Tabulations for 16 different groups included miners and ex-miners in varying pneumoconiosis categories and non-miners in the same district, and agricultural workers in two different areas in Britain. In the 13 group.. s in which comparisons were feasible. non-smokers recorded a higher F.E.V. 0.75 than the smokers. The small over-all difference in means was recorded (as indirect Maximum Breathing Capacity) as 50 liters per minute, which was significant at the one percent level. By pooling subjects with different occupations in the older age groups, differences between light and heavy smokers were apparent, though not statistically significant. Higgins commented on a strong trend in the prevalence of persistent cough and sputum, with amount of tobacco smoked. without a significant trend in ventilatory capacity. His possible explanation of the difference is that smokers are more likely to give up smoking or re- duce the amount smoked, once their lung efficiency becomes impaired. than they are when their only symptoms are cough and sputum. In their study of miners and foundry workers in Staveley I 92 j. Higgins and his colleagues showed a decrease in the F.E.V. 0.75 in smokers. Non- smokers, light smokers. and heavy smokers ( 15 grams per da!- and over I ranked in that order for decreasing F.E.V. 0.75, both in men aged 25 to 3-l and in those aged 55 to 61. The d ff i erence between the non-smokers and the light smokers was smaller than the difference between the light and the heavy smokers in the younger age group; in the older age group the dif- ference was larger between non-smokers and light smokers. Olsen and Gilson ( 148) measured the F.E.V. 0.75 in a sample of a pop- ulation in Denmark for comparison with British population samples. Cig- arette smokers had a lower mean F.E.V. 0.75 than cigar smokers or pipe smokers who in turn had a higher mean than non-smokers. but these differ- ences were not statistically significant. If non-smokers. cigar smokers, and pipe smokers are grouped-together, non-cigarette smokers had a significantly higher mean F.E.V. 0.75 than the cigarette smokers. Payne and Kjelsberg (153)) who presented mean values of F.E.V. 1.0 for men and women by age group and by smoking category, found a lower mean value for cigarette smokers than for non-smokers in each age group of men Over 19. In the 16-to-19 ape group. cigarette smokers had a slightly higher mean value than non-smokers. A comparison of the mean values by age group for non-smokers and for cigarette smokers shows a decline with advancing Years in both, but more rapid in the cigarette smokers. Women also show a decline of F.E.V. 1.0 with advancing vears. but this is no more marked and no more rapid in the cigarette smokers than in the non-smokers. The reduction in F.E.V. 1.0 in cigarette smokers amounted to 7 percent and :< percent of the mean values in non-smoking men and women respectively when values adjusted to the over-all mean age of 40 years were compared. Read and Selby (159) measured peak flow rates in smokers with cough. and in smokers with cough and sputum. To a statistically significant extent. male smokers without cough or sputum showed a more rapid fall in peak ilow rate with age than expected. Male smokers with cough showed a still more rapid fall with age. and those with cough and sputum. the most rapid fall. Amount smoked had no obvious effect. Results were similar for women. Revotskie and his colleagues i 165), who grouped smokers in Framingham as never smoked, light smoker, medium smoker, and heavy smoker. found that the F.E.V. 1.0 measurements show a gradient from never smoked to heavy smoker in the "normal" subjects, both for males and females: in the other groups this gradient is not clear. The "Puffmeter" ratios tended in the same direction. but in less clear-cut fashion than the F.E.V. 1.0 measurements. 20 I Goldsmith and others (77) showed that smokers, regardless of amount smoked. have a slight diminution in the pulmonary function test results, Eden in the absence of respiratory symptoms. The total vital capacity was murh less sensitive in this regard than the F.E.V. 1.0 or the "Puffmeter" Longshoremen with "respiratory conditions," and particularly th reading, 0%~ with shortness of breath, had a more marked decrease in pulmonary function Cough was associated with the greatest diminution of pulmonary function measurement. The relationship between cigarette smoking and abnormal results of pul. monary function tests is more difficult to evaluate from the published SUf,.p,., than is the relationship between symptoms and cigarette smoking. pL,I. monary function test results are influenced by several factors, among which are age, physique: and perhaps occupation. When allowance is made for these factors. there appears to be a clear difference in the ventilatory funr. tion between smokers and non-smokers. In the majority of prevalence surveys, the subjects were not forbidden to smoke pcor to pulmonary function testing. Since acute alterations due to smoking might be mix. interpreted as due to a permanent abnormality, it is important to examine the magnitude and significance of the acute effects of smoking on pulmonary function. Rickerman and Raracb (2Oj found no consistent alterations in vital capacity or in maximum breathing capacity before and after their patients and normal subjects smoked three cigarettes. Simonsson (177) found a small decrease in the F.E.V. 1.0 in 13 ,,f 16 young subjects after smoking, and the difference for the group was statistically sic. nificant. No significant change was found in the total capacity. Several authors have studied more sensitive tests of airway resistance and lung co,,,. pliance. Eich. Gilbert and .4uchincloss (56) made compliance and airway resistaac? measurements, using an esophageal balloon technique, on a group of nine healthy ad& five of whom had respiratory symptoms. No difference was detected after one cigarette. In a group of emphysematous patients, a statistically significant increase in airflow rp. sistance was found, but without significant change in compliance. Attinger and others (8) reported no statistically significant difference in expiratop airflow resistance or compliance, but in a later study of subjects with pulmonary diseasr. significant physiological changes-increased mechanical resistance and increased work of breathing--were noted after smoking one or two cigarettes. Motley and Kuzman (142) studied the lung volumes, spirometry, blood gas exchaner. and pulmonary compliance in 141 subjects, before and after smoking two cigarettes. Not all of these measurements were made on all subjects. There was no significant change in the mean values of vital capacity performed after smoking, some subjects showing a d errease, and others an increase. Six of the normal subjects showed a decreased com- pliance after smoking. In 33 subjects with cardiac or respiratory disease, 17 had a sip. nificant decrease in romplianrr after smoking. The authors felt that a decrease in pul. monary romplianre was the only notable abnormality which followed smoking acut+ Forced rxpiratory volume and airflow rcsiktance studies were not included. Miller i ]34a), who constructed pressure-volume work loops, demonstrated increased airflow rP of the same age, and the ventilatory function of non-smokers in all agr groups was significantly higher than that of the smokers. Among smokcn of 50 years of age and above, the prevalence of pneumoconiosis tended to bP lowest among the men who smoked the most and highest among men whr, smoked the least. However, the prevalence of pneumoconiosis was higher in ex-smokers than among smokers and non-smokers, except in the oldest age group, suggesting that men with pneumoconiosis tend to reduce their tobacco consumption. The possibility that factors of selection eliminatp some persons with symptomatic pneumoconiosis from study groups should also be considered in the evaluation of these studies. In a sample of 11317 men aged 40 to 65 who worked in a variety of non. dusty and dusty environments, a greater prevalence of bronchitis (dail! cough for at least the preceding six months, productive of one teaspoon of sputum per day) was found in moderate and heavy smokers 127). Betweerl the non-smokers and the heavy smokers, a significant difference was found at all age levels, and also between non-smokers and moderate smokers except in the oldest age group. Although effects from dust exposures could be noted. it appeared that cigarette smokin, 01 was the dominant etiologic factor in "chronic bronchitis" in this selected group. Among alkaline dust workers it was found that the dusts in the working environment did cause some increase in respiratory illness but the sig. nificance of the dusts in the production of respiratory disability, either functional or pathological, was not as important as the number of cigarettes smoked daily (36). 298 In a study of 1.274 steel workers. non-smokers had a comparatively low incidence of chronic cough, regardless of their job classification or condi- tions of work or residence. Th ere was a direct relationship between chronic cough and the number of cigarettes smoked daily in each occupational category (156) . Cigarette smoking was of greater importance in deter- mining the prevalence of chronic cough than was the occupational exposure. In a study of New England flax mill workers, 161 subjects were subjected to a questionnaire and measurements of pulmonary function to determine the presence of "chronic non-specific respiratory disease." The prevalence of such a syndrome. based on a certain combination of symptoms or signs. was related to age. sex. smoking habits. years of exposure to dust. and estimated inhaled quantity of dust. The effect of smoking "far out-shadows any effect due to age or occupational exposure to dust" (62). The studies by Higgins and his colleagues (87. 88. 89. 91. 92 I show that smoking and occupational exposure are both related to the prevalence of chronic respiratory disease but do not allow quantitative assessment of their relative importance in the populations defined. As this series of studies was undertaken to demonstrate any effect from industrial exposure. and the popu- lations surveyed were such that exposure to occupational dusts was more varied than in the general population. the importance of the effect of smoking in this group of studies on the production of respiratorv symptoms is rather convincing (1231. The authors comment in one of the papers in this series: "So important is the influence of tobacco smoking that it is essential to allow for differences in smoking in comparable groups before drawing `conclusions about the importance of other factors." In a recent study of bituminous coal miners (103,) ex-smokers had pul- monary function results and prevalence of respiratory symptoms comparable to those of non-smokers; no impairment was attributed to pure pipe or cigar smoking. Cigarette smokers had the most symptoms of respiratory disease and. except for vital capacity, they had the lowest pulmonary function. The authors comment: ". . . although smoking definitely impairs pulmonary function, the impairment of pulmonary function by years worked under- ground is clear and separate from the effect of smoking." In a study of 7,404 metal mine workers, aged 35 years and older. a com- parison was made of the effects of 20 years' aging and smoking on pulmonary- ventilation, as measured by the F.E.V. 1.0 in individuals without X-ray evi- dence of silicosis. A decrease of 23 percent occurred with the process of aging 20 years. For heavy smokers (those who smoked for 25 years or more and now smoke more than 20 cigarettes a day 1, there was an additional de- cline of 10 percent over that of aging alone. "The decline in pulmonary function associated with heavy smoking was equivalent to the decline that comes about by the process of aging 10 years. For the entire group of metal mine workers, the reduction in pulmonary function assmiated with smoking was equivalent to half the effect of heavy smoking, or about five years of aging" (128). The population at risk from occupational exposure is relatively small com- pared to the population of cigarette smokers. Among occupational groups, cigarette smoking is an important variable that must be considered in all 299 studies of rhronic hronchopulmonary disease. the relative importance of cigarette smokin, In most studies, but not all, u is greater than occupational ex. posures in the production of symptoms and signs of chronic bronchitis ur emphysema. SUMMARY Tobacco smoke is a heterogenous mixture of a vast number of compounds. several of which have the ability to produce damage to the tracheobronchial tissues and lung parenchyma. Retention of inhaled cigarette smoke particles in the respiratory system of man is about 80-90 percent complete with breatl, holding of two-to-five seconds. Particles penetrate deeply into the respira. tory tract and are deposited on the surface of the terminal bronchi&. respiratory bronchioles, and pulmonary parenchyma. Little information j, available concerning the specific toxic properties of the particulate phaW components. Gas phase components probably have a diffuse though not uniform pattern of distribution. It seems likely on the basis of the physical characteristics of gas absorption and distribution, that a substantial portioa is retained along the upper bronchial tract. Certain of the gases known to be present in cigarette smoke are capable of producing pulmonary damaPe in experimental animals and man. Cigarette smoke produces significant functional alterations in the upper airways. Like several other agents, cigarette smoke can reduce or abolish ciliaty motility in experimental animals. Post-mortem examination of bronchi from smokers s.hows a decrease in the number of ciliated cells, shortening of the remaining cilia, and changes in goblet cells and mucouY glands. The implication of these morphological observations is that func. tional impairment would result. Cigarette smoke is also capable of interference with functions in the lower airways. In animal experiments, cigarette smoke appears to affect the phy. sical characteristics of the lung lining layer and to impair alveolar stability. Alveolar phagocytes ingest tobacco smoke components and assist in their re- moval from the lung. This phagocytic clearance mechanism decompensates under the stress of protracted high-level exposure to cigarette smoke and tn- bacco smoke components accumulate in the pulmonary parenchyma of experimental animals. The acute effects of cigarette smoking result in an increase in airway rr. sistance but clinical expression of this change in pulmonary function is ncft common. The chronic effects of cigarette smoking upon pulmonary func- tion are manifested mainly by a reduction in ventilatory function as measurer! by the forced expiratory volume. Histopathological alterations occur as a result of tobacco smoke exposure in the tracheohronchial tree and in the lung parenchyma of man. Changes regularly found in chronic bronchitis-increase in the number of goblet cells. and hypertrophy and hyperplasia of bronchial mucous glands-are more often present in the bronchi of smokers than non-smokers. In experimental animals, cigarette smoke consistently produces significant functional altera. 300 tions in the upper and lower airways. Such alterations could be expected to interfere with the cleansing mechanisms of the lung. Pathological changes in pulmonary parenchyma, such as rupture of al- veolar septa and fibrosis, have a remarkably close association with past his- tory of cigarette smoking. Th I ese changes cannot be related with rertaint? IO emphysema or other recognized diseases at the present time. Chronic bronchitis and pulmonarv emphysema are the chronic hronrho- Ibulmonary disease* of greatest health significance. Epidamiologiral evidence provides the most important information relating cigarette Pmokinc to chronic bronchitis and emphysema. All seven of the major prospective qtudies show a higher mortality rate for chronic bronchitis and emphysema among cigarette smokers than among non-smokers. In the few studier; that have examined mortalitv rates separatelv for the tjro conditions. chronic bronchitis or emphysema, both rates ar, higher among cigarette smokers than among non-smokers. In one of the studies. the risk of mortalit!- from rhronic bronchitis was four times greater among cigarette smokers than among non-smokers. Emphysema was listed as a cause of death 13 times more frequentlv among smokers in one studv. and 71& times more frequpntlv among smokers in another study. Extensive prevalence studies. based largely on prevalence of specific Fymptoms and signs rather than imprecise diagnostic labels. show a consis- tently more frequent occurrence of cough, sputum, or the two symptoms combined. in cigarette smokers than in non-smokers. These manifestations are the clinical expressions found in chronic bronchitis. The results of the prevalence surveys. however. offer less direct evidence relating cigarette Smoking to pulmonary emphysema. as clinical diagnosis of this disease is less exact. Breathlessness, which may result from emphysema or airway obstruc- tion in chronic bronchitis, is associated with cigarette smoking -in males. Particularly in the older age groups. but not females. Similarly. a consistent association of cigarette smokin, w and chest illness is more evident for males. In the prevalence surveys in which various combinations of respiratory manifestations have been studied, a greater prevalence of these conditions is found consistently among cigarette smokers. The majoritv of clinical studies have noted a relationship between ciga- rette smoking and chronic bronchitis and emphysema. Cigarette smoking is a more Scommon habit in the United States among patients with chronic bronchitis or emphysema than in the control groups studied. The clinical studies also show a decrease in clinical manifestations of chronic broncho- Pulmonary disease after cessation of smoking. Examination of experimental evidence shows that the lung may be dam- aged by noxious agents found in either tobacco smoke or atmospheric pol- lution. In the United States, Ihe noxious agents from cigarette smoking are much more important in the causation of chronic broncho[mlmonar~ disease than are those present as community air pollutants. In the United Kingdom, persons who smoke cigarettes and are exposed frequentl! to at- mospheric pollutants are at greater risk of developing disabling respirator! di%se and death than those exposed to either alone. 301 The relative importance of cigarette smoking also appears to be mu,+, greater than occupational exposure as an etiologic factor for the chronic bronchopulmonary diseases. Cigarette smoking does not appear to cause asthma; in rare instances allergy to tobacc,o products has been ascribed a causative role in asthma: like syndromes. Evidence does not support a direct association between smoking and in. fectious diseases of the respiratory system. The category, influenza and pneumonia, contributes moderately to the excess mortality of cigarett? smokers but other data are r?ot available to extend this observation. Th,. sssociation of cigarette smoking and tuberculosis does not appear to be ;, direct one, but both are associated with the use of alcohol. Only for "stomatitis nicolina" and the epithelial changes in the laryn, i? there sufficient documentation to substantiate the clinical opinion that non. malignant alterations in the mouth. nose. or throat are induced by smoking. The changes in the mouth are more often associated with pipe smoking hut disappear after cessation of smoking. CONCLUSIONS 1. Cigarette smoking is the most important of the causes of chronic, bronchitis in the [-nited States. and increases the risk of dying from chronic bronchitis. 2. A relationship exists between pulmonary emphysema and cigarettp smoking but it has not been established that the relationship is causal. The smoking of cigarettes is associated with an increased risk of dying fronl pulmonary emphysema. 3. For the bulk of the population of the United States, the importance oi cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than that of atmospheric pollution or occupational exposures. -L Cough, sputum production. or the two combined are consistently morr frequent amon? cigarette smokers than among non-smokers. 5. Cigarette smoking is associated with a reduction in ventilatory fun,.- tion. Among males, cigarette smokers have a greater prevalence of breath lessness than non-smokers. 6. Cigarette smoking does not appear to cause asthma. 7. 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Brit Med J 2: 1104-8, 1961. 160. Reid, D., Fairbairn, A. S. ,1ir pollution and other local factors in res- piratory disease. Brit J Prev Sot Med 12: 94-103: 1958. 161. Reid, D. D. General epidemiology of chronic bronchitis. Proc Roy Sot Med 49: 767-71, 1956. 162. Reid, L. Chronic bronchitis and hypersecretion of mucus. Lect Sci Basis Med 8: 235-8, 1958-59. 163. Reid, L. Measurement of the bronchial mucous gland layer: A diag- nostic yardstick in chronic bronchitis. Thorax 15: 132-41, 1960. 164. Reid, L. M. Pathology of chronic bronchitis. Lancet 1: 275-8. 195-1. 165. Revotskie, N., Kannell, W., Goldsmith, J. R., Dawber, T. R. I'ulmo- nary function in a community sample. Amer Rev Resp Dis fi6: 907-11, 1962. 311 166. Rigdon, R. H. Effect of tobacco condensate on the respiratory tract of the white Pekin duck. AMA Arch Path (Chicago) 69: 55-63,1960. 167. Rivera, J. A. Cilia, ciliated epithelium and ciliary activity. Int Ser Monogr Pure Appl Biol 15: 1-167, 1962. 168. Rosen, F. L. Bronchial asthma in the young male adult. Ann Allerg 4: 247-60, 1946. 169. Rosen, F. L., Levy, A. Bronchial asthma due to allergy to tobacco smoke in an infant. A case report. JAMA 144: 620-1, 1950. 170. Ryan, R. F., McDonald, J. R., Devine, K. D. The pathologic effects of smoking on the larynx. AMA Arch Path (Chicago) 60: 472-80, 1955. 171. Sanderud, K. Squamous metaplasia of the respiratory tract epithelium. 2. Relation to tobacco smoking, occupation and residence. Acta Path Microbial Stand 4.3: 47-61, 1958. 172. Saunders, W. H. Nicotina stomatitis of the palate. Ann Otol 67: 618-27, 1958. 173. Schoettlin, C. E. The health effect of air pollution on elderly males. Amer Rev Resp Dis 86: 878-97,1962. 175. Shah, J. R., Warawadekar, M. S., Deshumkh, P. A., Phutane, P. N. In- stitutional survey of pulmonary tuberculosis with special reference to smoking habits. Indian J Riled Sci 13: 381-92, 1959. 176. Short, J. J., Johnson, H. J., Ley, H. A., Jr. The effects of tobacco smok- ing on health. A study of 2.031 medical records. J Lab Clin Med 24: 586-9, 1939. 177. Simonsson, B. Effect of cigarette smoking on the forced expiratory flow rate. Amer Rev Resp Dis 85: 534-9, 1962. 178. Sollmann, T., Gilbert. A. J. Microscopic observations of bronchiolar reactions. J Pharmacol Exp Ther 61: 272-85, 1962. 179. Stokinger, H. E.. Wagner. W. D., Dobrogorski, 0. J. Ozone toxicity studies. 3. Chror?ic injury to lungs of animals following exposure at low levels. AMA Arch Industr Health 16: 51L-22, 1957. 180. Sweet, H. C., Wyatt, J. P., Fritsch, A. J.. Kinsella, P. W. Panlobular and centrilobular emphysema: Correlation of clinical findings with pathologic patterns. Ann Intern Med 55: 565-81, 1961. 181. Thoma. K. H. Stomatitis nictrtina and its effects on the palate. Amer J Orthodont 27: XLli. 1911. 182. Thurlbeck. W. RI. 4 cliniro-pathological study of emphysema in an .\merican hor;pital. Thorax 18: 59-67, 1963. 183. Thurlbeck. W. M.. Angus. G. E. The relationship between emphysema and chronic bronrhitis as assessed morphologically. Amer Rev Resp Dis 87: 815-3, 1965. 181. Thurlbeck. W. M.. i\ngus, G. E., Pare. J. A. P. Mucous gland hyper- trophy in chronic bronchitis, and its occurrence in smokers. Brit J Dis Chest 5i: 73-7X. 1963. 185. Truhart. H. Ein heitra;: zur nicotinwirkung. Dorpat, 1869. Thesis, 70 p. 186. U.S. Departnlrnt of Health. Education, and Welfare. Disability ap- plicants under the old-age survivors and disability program. 1960 selected data. Januar\- 1962. 312 187. Von Oettingen, W. F. Toxicity and potential dangers of nitrous fumes. Public Health Bull 272: l-34, 1941. 188. Vassar, P. S., Culling, C., S aunders, A. M. Flourescent histiocytes in sputum related to smoking. AMA Arch Path iChicago\ 70: 649-52, 1960. 189. Walker, I. C. The treatment of patients with bronchial asthma with subcutaneous injections of proteins to which they are sensitive. J Med Res 36: 423-80, 1917. 190. Westermark, T. Gaseous ions and their possible role in the etiology of lung cancer and some observations on free charges in cigarette smoke. Acta Med Stand 170: tSupp1 369) 119-20, 1961. 191. Wolff, W. -I., Tuttle. J. G., Godfrey, J. M. Radioautographic method for studying deposition of cigarette smoke in the dog lung. Abstract Fed Proc 13: 32-4, 1954. 192. Wolff, W. A.. Purdom. E. G.. Isenhower, J. A. The use of radio- isotopes as tracers in cigarette smoke. N Carolina Med J 15: 159- 63, 1954. 193. Wright, G. W.. Lloyd. T. Th e pulmonary reaction of normal and emphysematous persons to inhalation of SO,, fly ash. and moisture. 3d Air Pollution Research Seminar. U.S. Public Health Service. 194. Zamel, N., Youssef, H. H., Prime, F. J. Airway resistance and peak expiratorv flow-rate in smokers and non-smokers. 1960. Lancet 1: 1237-8, 1963. New Orleans, 313 Chapter 11 Cardiovascular Diseases Contents INTRODUCTION . . . . . . . . . . . . . . . . . . . . PERTINENT PHARMACOLOGY . . . . . . . . . . . . . GENERAL OBSERVATIONS ON CORONARY HEART DIS- EASE . . . . . . . . . . . . . . . . . . . . . . . . . SMOKING AND CORONARY HEART DISEASE . . . . . SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF CIGARETTE SMOKERS . . . . PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO CARDIOVASCULAR DISEASE . . . . . . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . CONCLUSION . . . . . . . . . . . . . . . . . . . . . . REFERENCES. . . . . . . . . . . . . . . . . . . . . . List of Tables TABLE 1. Death rates per 100,000 from arteriosclerotic and degenerative heart disease by sex and age, United States, 1958-60 . . . . . . . . . . . . . . . . TABLE 2. Ratios of mortality rates for coronary heart disease, male smokers to non-smokers, by age and amount smoked, in selected studies . . . . . . . . . . . Page 317 317 320 322 325 326 327 327 327 328 321 324 316 Chapter 11 __ .- INTRODUCTION It has been suggested repeatedly that smoking may ha\-e adverse effects on the cardiovascular system. Recently. studies of large groups of people have shown that cigarette smokers in particular are more prone to die early of certain cardiovascular disorders than non-smokers. Chief among theFe dis- orders is coronary artery disease. and the present chapter deals mostly with this subject. The chapter begins with a summary of information ahout the acute effects of smoking on the cardiova.scular system. This is followed b\- a brief account of coronary disease, its frequency in different kinds of people. and the many factors known or thought to affect the likelihood of its develop- ment. The aim here is not to reviebj critically our knowledgr of coronary disease hut only to give background for what follows. Next is summarized the information currently availahle from study of large population groups on the association of cigarette smoking with an increased tendency to hal-e coronary disease. There follows a brief discussion of smoking and non- coronary cardiovascular disease. Finally, there is a short review of evidence relating to the question of whether cigarette smokers may, as a group, differ from non-smokers in ways not caused by smoking itself. Mortality ratios showing the association between cigarette smoking and deaths from cardio- vascular disease, especially coronary disease, do not indicate the magnitude of the burden. This can be better appreciated from consideration of the following facts: cardiovascular disease deaths now total more than 700,000 annually in the United States. Of these more than 660,000 were due to heart disease, with more than 500,000 due to arteriosclerotic heart disease includ- ing coronary disease. The remaining approximately 40,000 were ascribed to disease of other parts of the cardiovascular system. Deaths from lung cancer total approximately 39,000. A mortality ratio of 1.7 for coronary heart disease among cigarette smokers in the seven prospective studies repre- sents from 32.9 percent to 51.7 percent of all excess deaths: whereas the much higher lung cancer mortality ratio of 10.8 from the same studies repre- sents only 13.5 percent to 24.0 percent of total excess deaths (Chapter 8. Tables 19, 25). PERTINENT PHARMACOLOGY The acute cardiovascular effects of smoking in man and experimental ani- mals are like those caused by nicotine alone. A smoker who inhales gets usually l-2 mg of nicotine from a cigarette (56,57). Low concentrations of nicotine stimulate sympathetic ganglia, and high concentrations paralyze them. Parasympathetic ganglia respond in the same way but are less sensitive. iY ice ine t can also have a sympathomimetic effect 317 by causing the discharge of norepinephrine and epinephrine from chromaffin cells in various tissues, including heart: vessels, and skin (10, 11, 9). In addi- tion, nicotine produces effects reflexly by stimulating the chemoreceptors of the carotid and aortic bodies. Wh en nicotine is given intravenously in in- creasing doses to dogs or cats the first effects, at about 1 microgram,/kg body weight, are increased breathing and sympathetic stimulation, with predomi- nant vasoconstriction, cardiac acceleration, and rise in blood pressure, re- sulting from stimulation of the aortic and carotid bodies (17). Doses of 4 to 8 micrograms/kg can stimulate pulmonary and coronary chemoreflexes which produce opposite effects. If all these receptors are inactivated, much higher doses are needed to evoke the cardiovascular effects of sympathetic stimulation, presumably through action on sympathetic ganglia or chromaffin tissue. Intravenous administration of nicotine in the experimental animal causes a discharge of epinephrine from the adrenal medulla, and in man heavy cigarette smoking prnduces an increased urinary excretion of catecholamines (B&99). Smoking l-2 cigarettes causes in most persons, both smokers and non- smokers, an increase in resting heart rate of 1.5-25 beats per minute, a rise in blood pressure of 10-20 mmHg systolic and 5-15 mmHg diastolic (76, 78, 85, 86). and an increase in cardiac output of about 0.5 l/min/sq.m (75). There is a decrease in digital blood flow and a consequent drop in finger and toe temperature (31, 78,103). Th e d ecrease in peripheral blood flow which normally follows smoking does not occur in a sympathectomized limb, in- dicating that the effect is mediated primarily by the sympathetic nervous system rather than through the release of catecholamines from other sites or the direct effect of nicotine upon the smooth muscle of the blood vessels themselves (103) . Intravenous nicotine, and probably cigarette smoking as well, can produce a slight transitory increase in the blood flow to resting calf muscle (79). In the dog, nicotine and cigarette smoke cause an increase in coronary flow as the blood pressure, cardiac output, and heart work increase (30, 53). These effects. resemble those of epinephrine. Nicotine has been found to cause a transient decrease in cardiac oxygen utilization followed by a slight increase ( 53) . Relatively little information is available about the effect of smoking on coronary blood flow in man. In normal subjects it is re- ported that cigarette smoking produces an early increase in coronary flow as heart work increases. but there is little change in oxygen utilization by the myocardium i2). With continued "steady state" smoking the coronary flow and cardiac oxygen utilization are maintained at the resting level in both normal subjects and persons with coronary heart disease, despite in- creased blood pressure, heart rate, and heart work ( 74). A larger experi- ence must be gathered in this field before statements about the acute effects of smoking on the human coronary circulation can be made with assurance. The atherosclerotic rabbit heart, like the normal rabbit heart: shows an initial drop in coronary flow on administration of nicotine, but demonstrates less of a subsequent increase above the resting level than does the normal heart (97). These effects are said to be equivalent to those produced by norepinephrine in doses one-tenth as large as the nicotine dose. 318 Little or no change in the electrocardiogram of most normal persons or cardiac patients, except for an increase in rate, is produced by smoking or by the intravenous injection of an equivalent dose of nicotine (82, 98). In some persons there is a slight depression of the S-T segment and a flattening of l-2 mm in the T wave of the limb leads. These changes are not like those associated with my-ocardial ischemia. Rarely in persons with true angina. an attack of pain is precipitated by smoking. An ill-defined syn- drome consisting of chest pain. palpitation. and shortness of breath, known as "tobacco angina". has been described as occurring in smokers who do not have organic heart disease. but it is rarely diagnosed today (73, 82). Extrasvstoles and other cardiac arrhythmias have been reported to be caused bv smoking. but such cases appear to be unusual. I The b a IS ocardiogram obtained from a high-frequency table is some- II' t times changed by smoking a cigarette from a normal pattern to one said to be typical of coronary disease (78, 91 I Th is phenomenon is rare in healthy persons below 50, becomes increasingly common with advancing years in apparently healthy persons. but is particularly prone to occur at any age in persons with actual coronary disease. The effect has been used as a "stress test" to help uncover coronary disease. but false positive and negative results are common. The ballistocardiopaphic changes on smoking have been variously interpreted as resulting from impaired myocardial contractility I 78`)) from changes in the peripheral circulation (82), or from uncertain causes related to the physical properties of the high-frequency table as well as changes in the circulation. Cigarette smoking causes an increase in the concentration of serum-free fattv acids in man ( 50), apparently mediated by stimulation of the sympa- thetic nervous system (51). Although continued administration of epine- phrine to dogs over many hours can produce substantial increases in serum cholesterol, phospholipids, and triglycerides, such an effect has not yet been reported from nicotine or tobacco smoke (48, 92). The clotting time of the blood can be decreased 50 percent or more in ex- perimental animals by stimulation of the sympathetic nervous system or hy administration of epinephrine (12, 13, 14)) but attempts to demonstrate that cigarette smoking alters the clotting properties of the blood in man have been unsuccessful i5, 68). A decrease in platelet survival in viva has been found after smoking (68) . Cigarette smokers have been reported to show substan- tial decreases in hematocrit, hemoglobin, and platelet counts after abstinence of l-2 weeks (25)) but hemoglobin concentrations are alike in smokers and non-smokers of the same population group (4). Attempts have been made to induce atherosclerosis in rats by the chronic administration of nicotine for periods up to a year without sucwss (93). Tobacco has antigenic properties (29, 43). Rats can be sensitized to to- bacco extracts by intraperitoneal injection. Over a third of smokers demon- strate a positive-"immediate" skin reaction to such extracts while only about 10yc of non-smokers are said to give positive tests. The presence of serum reagins in persons with positive skin tests has been demonstrated by passive transfer techniques. Persons with thromboangiitis obliterans and smokers with occlusive vascular disease of other types are said to show a much higher incidence of positive skin tests than healthy smokers. The cardiovascular 7 14-422 O-64-22 diseases which have been related to smoking, however, do not in general resemble those usually ascribed to an immune mechanism. In man and experimental animals smoking or the injection of nicotine causes increased secretion of antidiuretic hormone. The renal effects of this are easily demonstrable but the quantity of hormone secreted in response to smoking is probably too small to have significant vascular effects (17 ) . In summary, the acute cardiovascular effects of smoking and of nicotine closely resemble those of sympathetic stimulation. and to a considerable extent are mediated by excitation of the sympathetic nervous system. No additional or unique cardiovascular effects have been demonstrated which. in the light of our present understandin,. 0 seem likely to account for the observed association of cigarette smokin, c with an increased incidence of coronar\- disease. CENERAL OBSERVXTIONS ON CORONARY HEART DISEASE Heart disease is the most common cause of death in our population. and coronary disease is the commonest variety of fatal heart disease (59'1. Iri 1961 there were 1:701..522 deaths from all causes in the United States. Heart disease deaths numbered 663.391 of which 502.351 were due to arterio- sclerotic heart disease. The disorder consists of obstruction or narrowing of the coronary arteries. reducing the blood supply to the heart muscle. The underlying cause of the obstruction is coronary atherosclerosis. but an acute coronarv artery occlu- sion is often caused by the formation of a blood clot in a d&eased arterv. The common manifestations of coronary disease are an$na pectoris. recur- rent brief attacks of chest pain caused by inadequate blood supply to the heart muscle: myocardial infarction, or necrosis of a portion of the heart muscle due to acute loss of blood supply; congestive heart failure, a chronic state caused bv inability of the heart to pump enough blood to satisfy the demands of thk body; and sudden death resulting from cardiac standstill or ventricular fibrillation. There are considerable differences in the prevalence of coronary heart disease in different countries, and often in different ethnic and socio-economic, groups within a particular country (ML 02 1. The reported death rate of arteriosclerotic heart disease. which is Ibrimarily coronary disease. is higher in the United States than in other countries. it is also quite high in Yew Zealand. Australia.`South Africa, Canada. and Finland. and moderately hi?h in Great Britain. The death rate in Norway, Sweden, and Denmark is roughI> half that in the high death rate countries I 1.5 I. The death rate in Japan appears to be about one-sixth that in the United States, although persons of Japanese origin living in the United States are said to have a death rate similar to that of the Fenera i)opulation of this country i.52). Because of changing diagnostic skills and revisions in nomenclature of disease, it is d&cult to be certain of the change in incidence of coronar! disease in the United States oter the pas! few decades, but there is a general opinion that the incidence is increasin, m in this country and in England. 320 particularly in the younger male group (59, 62, 65, 83). In 1955 the mortality rate from arteriosclerotic heart disease was reported to be about 240 per 100,000. Although this is an increase of more than 50% over the rate in 1940, it has been estimated that less than 157; of the increase represented a real chance in incidence of the disease, the remainder depending upon changes in diagnosis, in nomenclature and in the age of the population (59 1. Since 1955 the death rate from coronary disease (ISC 420) and from arteriosclerotic and degenerative heart disease (I%420 and 422) has con. tinued to increase gradually. In 1960 the age-adjusted death rate from 420 and 422 was 330 per 100,000 for white males and 150 for white females ( 55 ) . Although the basic cause or causes of coronary heart disease are obscure, certain factors other than smoking are known or thought to predispose to the condition or to be associated with an increased incidence. The incidence of coronary heart disease in men under 45 is about 5 times as great as that in women (Table 1) ( 15, 20,59, 62). In both sexes the inci- dence increases with advancing years. After the menopause the incidence increases rapidly in women, and at age 80 the death rates from coronary disease are about the same for the two sexes. Coronary thrombosis plays a relatively more important role in precipitating myocardial infarction in young men than it does in old men i 105 1. In studies of large population groups coronary disease has been associated with elevation of the serum cholesterol, hypertension, and marked overweight (19, 20, 24, 36,46, 59,62). Some individual characteristics have been said to be associated with coro- nary disease. There is a significant familial tendency to develop it (36, 69, 81, 96). Persons with a mesomorphic constitution are said to be more vul- nerable than endomorphs and ectomorphs (36, 62, 88). A coronary-prone 1)ersonality has been described as the aggressive, competitive person who takes on too many jobs, fights deadlines, and is obsessed by the lack of adequate time for the performance of his work (33,34,35). TABLE I.-Death rates per 100,000 f rom arteriosclerotic and degenerative heart disease* hy sex and age, United States, 195840 A c"' G roll p TMall= Frmah rloth SITC- Under 35------------------------------ 3.3 1.2 2.2 3544--------------------------------- 90.2 18.3 53.3 45-54 ------__-_-_____----------------- 353.7 79.3 213.5 55-64 -------___-----_----------------- 928.5 314.5 610.2 65-74 _________________________________ 2129.2 1082.0 1569.5 75orover------------------------------ 4765.1 3738.4 4179.7 *Includes IX numbers 420 and 422. Source: WHO Epidemiological and Vital Statistics Report, Vol. 16, No. 2, 1963. Certain occupations have been said particularly to favor the development of coronary disease, notably those which feature responsibility and stress (34, 81, 87), and which are sedentary in nature (71. Others (58, 72, 901 have not found that executives are more prone to coronary disease than non- executive 1)ersonnel. Ph; . ~slcians have been said to habe 3 or 4 times as much coronary disease as farmers or laborers 187): and general prac~titioners to 321 have 3 times as much as dermatologists (80). Occupations involving much physical activity are said to be protective (66, 67, 77). City life has been said to be more closely associated with coronary disease than suburban life, and men who drove more than 12,000 miles a year seemed, in one study, more 1Jrone to the disease than those who drove less (64). It has been widely held, and occasionally denied, that a diet high in saturated fat predisposes to the development of coronary disease (46, 52, 69, 81). A correlation between the national incidence of coronary disease and the percentage of food calories available as saturated fat has been re- ported among those countries for which adequate data exist (46). The serum cholesterol tends to rise when saturated fat is added to the diet, and it falls significantly when unsaturated fat is substituted (46). It has also been sug- gested that general over-nutrition? rather than excess saturated fat predis- poses to coronary disease, on the grounds that the correlation of coronary disease with total available calories or sugar consumption per capita is as good as that for percentage of calories in fat (106). In general, it is apparent that multiple personal and environmental factors can markedly affect the incidence of coronary disease. SMOKING AND CORONARY HEART DISEASE Over the last two decades a considerable number of epidemiologic studies on different populations, employing different techniques, have shown with remarkable consistency a significant relationship between cigarette smoking and an increased death rate from coronary heart disease in males, par- ticularly during middle life. There has been little dissenting evidence. The association of coronary disease with the use of tobacco in other forms has not been striking. The documentation for these statements is given in the following paragraphs. Particularly important is the information in Chapter 8, Mortality. English et al. 126) found the incidence of coronary disease in male patients at the Mayo Clinic about 3 times greater in cigarette smokers than in non-smokers in the 40-59 year age range, but found little relation to smoking above 60. Russek 181) reported a similar relationship, but less striking, in young men with coronary disease. Mills (64) in a study of reported mortality in a Cincinnati population found that heavy smokers in the 30-59 )-ear age range had twice as high a death rate from coronary disease as non-smokers. Male Seventh Day Adventists: who are non- smokers. were found by Wyrlder and Lemon (104) in a study based on hospital admissions to hale significantly less coronary disease and to de- velop it later in life than the general male hospital population. Haag and Hanmer I ST I reported that employees in the tobacco industry. \\ ho tend to smoke heavily. had a lower death rate for cardiovascular disease than the general population ill their geographic region. but no report was made of mortality rates within the tobacco-worker group, divided by smok- ing habits. The study has been criticized on this and other grounds ( 16 I. Large-scale prospective studies of mortality in British phyairians ( Doll and Hill, 21 I _ United States males 50-69 recruited by volunteer workers 322 ( Hammond and Horn, 38, 39.40.42) and \`.A. Life Insurance policyholders i Darn: 22) have confirmed the association of death from coronary disease with cigarette smoking. In the British study, a step-wise association was found between the amount of tobacco consumed (not entirel! cigarettes) and the mortality from coronary disease. The association occurred in the X-54 !-ear age range. but not in older men. Hammond and Horn found a similar graded relationship between coronary deaths and cigarette smok- ing. the death rate being more than twice ai great in men who smoked over a pack a da\- as in non-smokers. Men who had stopped smoking for more than a !ear at thr start of the study had a coronary death rate lower than those who continued. Studies on special groups of men. such as longshoremen (Buerhley et al. :: I membrrs of a fraternal order i Spain and Nathan. 89) and industrial employees (Paul et al. 71) which. in the latter two instances. incorporated clinical coronary disease. as well as coronary deaths. also have shown a relationship bet\\een coronary disease and smoking. The relationship It-as closer for men under 51 than for older men, and closer for myocardial infarcts and death than for angina pectoris (70,891. The long-term prospective studies of cardiovascular disease in Framing- ham (19, and in Albany 124) which have featured a painstaking sparch at regular interrals for clinical manifes;tations of disease. have. on pooling the data (Doyle et al. 23) shown a threefold increase in the incidence of myocardial infarction and coronary deaths in men who are hea\!- ciga- rette smokers as compared to non-smokers. pipe and cigar smokers. and former cigarette smokers. In the pooled data the incidence of angina per- toris did not shoM a significant association with cigarette smoking. The lack of this particular relationship had been suggested on the hasis of clinical experience (White and Sharber. 102 I. An apparent interplay of fa,ctors relating to smoking and occupation turned up in a short-term studv of the development of roronar) heart dis- ease in a general North Dakoia population (Zukel et al., 107). Farmers had about half the incidence of myorardial infarction experienced b!- others. In farmers. smoking had no appreciable effect on the incidence of infarc- tion. but in others the incidence of infarction was twice as high among smokers as among the non-smokers. The farmers who smoked cigarettes smoked less heavily than males in other occupational groups. In Chapter 8. Mortality, there is summarized the most recent infor- mation availahle from 7 large completed or current prospective smoking and death rate studies (Doll and Hill; Hammond and Horn ; Darn; Dunn, Linden and Breslow; Dunn. Buell and Breslow ; Best, Josie. and Walker; and Hammond ). The median mortality ratio for coronary disease of current cigarette smokers to non-smokers is 1.7 irange 1.5-2.01. Table 2 presents data from some of the large prospective s.tudies on the ratio of mortality rates due to coronarv heart disease of male qniokers to non-smokers, by age and amount smoked. The ratios tend in ;pnrral to increase uith amount smoked and to decrease with adl-anciq a;:r. The data from the first 22 months. of Hammond`s (41 I current study help to show the size of the coronary problem. For this purl)ose. actual uumbers of deaths ma\ be more informative than mortalit\- ratios. Of nearlv 10.000 deaths of men aged 45-i'). 40 percent were ascribed to coronaq disease. 51.i pervent of the 2.030 "excess deaths" associated with cigarette smoking were caused by coronary disease. In approximate terms, nearly half of middle-aged and elderly males in the United States die of coronarl disease. About half of the+,r males smoke cigarettes. Cigarette smokers ha\-e heen found it) several studies to have 1.7 times as high a coronar! death rate as non+mokers. If cigarettes actually caused the additional coronar\ deaths of smokers. they tvould account for many- deaths of middle-aged and elderly males in this countr). Like other studies (19. 21, 22. 23. $2'21 this one shows that the ratio of !smokers' coronary death rates to those of non- smokers inc,rcuses prog:`e+i\el, \\ ith tile [tail\ cigarette consumption. In addition. at each le\cl of consumption the ratio inrreases with the amount of inhalation reported I)\- the smokers. Others (21, 23. 26, 891 have indicated 324 that the risk of death from coronary disease in male cigarette smokers relative to that in non-smokers is greater in middle age than old age, and Hammond's current study supports this. Th e mortality ratio was 3.09 in the age range 4S49. and in successive decades t+as 2.20. 1.58. and 1.38. Men who stop smoking ha\-e a lower death rate from coronary disease than those who continue (23, 42. Si) . In the study of Hammond and Horn (42) the decrease in death appeared onI!- after a year. Angina pectoris is less closely related to cigarette smoking than myocardial infarction and sudden death. In the combined Albany-Framingham expe- rience (23)) angina pectoris showed no o\er-all relationship with smoking, and the association has not been strong in other studies (71, 89). In summary. a significant association has been established between cigarette smoking and the incidence of myocardial infarction and sudden death in males, especially in middle life. in population groups whose members appear so far to be liniilar except for sniokin,n habits. The question of whether they are, in fact, similar except for smoking is. of course, basic to the problem of whether cigarette smoking actually promotes the development of coronary disease or k-hether it is closeI\- associated with some other factor or factors which promote the development of coronary disease. It has been pointed out that angina pectoris, which indicates advanced coronary atherosclerosis. is less closely associated with cigarette smokin, 11 than is m!-ocardial infarction. and that this suggests that any etiologic role of smoking in myocardial infarc- tion should relate more to acute occlusive mechanisms, such as intravascular thrombosis or coronary spasm, than to the development of chronic arterial disease. SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE In surveys of large groups cigarette smoking has not been found to be associated with an incrra*ed pre\ alence of h\ pertension ( 3, 4. 19, 47, 49 1. The study of Hammond and Horn I 4.0, 42 I d;d not sho\v an increased death rate from hppertension in smokers. However. Darn 122 1 found that the death rate of cigarette smokers from h\ I)crtension with heart disease was 1.53 times that of non-smokers. and frhm h!-pertension without heart dis- ease. 1.41 time3 that of non-smokers. Hammond's current stud\ she\+ s similar figures I41 1 . Smoking has not been found to be associated with an increased mortalit!- rate from chronic rheumatic heart disea>e 122. 41. 42 1. Hammond and Horn ( !2) found a Inoderate increase in the mortalit) rate from cerebral vascular disease in cigarette smokers as compared to non-smokers I ratio 1.30 I. Darn (22 I reported a ratio of 1.33. and Ham- nlolld 141 1 a ratio of 1.43. Although non-HI philitir aortic aneurysm is a relatilell infrequent cause of death. the mortalit\ ratio for snlokrr; to non- smokers in thi:. diagnostic, c,ategor\ is larse in relation to the ratios in other cardiol ascular disorder>. In the stud\ of llalmnc~ncl atld Horn (,t2 1 it was 2.72. and in Hanl~t~ond's current .-tudv I I1 I it is 3.10. It has been reported (100) that diabetic males who smoke have a 50% greater incidence of clinically detectable arteriosclerosis obliterans in the legs than those who do not smoke. In general, however, there is little information about the relation of smoking to peripheral arteriosclerosis. Most experienced clinicians advise patients with obliterative peripheral arte- rial disease to stop smoking (45). Buerger's disease, or thromhoangiitis obliterans, has been traditionally associated with smoking. and the literature contains numerous clinical re- ports describing the arrest of Buerger's disease when smoking is stopped and its reactivation on resumption of smoking. The existence of Buerger's disease as an entity separate from arteriosclerosis obliterans has been re- centlv challenged ( 1011, but well defended (61). It -is apparent that much mere work will have to be done to determine what relationship may exist bet\\-een non-coronary occlusive vascular dis- ease, aneurysmal disease, and smoking. CHARA4CTERISTICS OF CIGARETTE SMOKERS If it could be shown that cig;arette smokers and non-smokers had signifi- cant constitutional differences apart from any differences that might be caused by smoking itself, then a possibility w-ould exist that some predisposition of smokers to a particular disease might also be of constitutional origin and not caused by smoking. Cigarette smokers have, in fact, been found to differ as a group from non-smokers, but the differences, such as serum cholesterol concentration and resting heart rate, could have resulted from the smoking habit itself, so far as present knowledge indicates. The concentration of serum cholesterol has been found to be slightly higher in smokers than in non-smokers by a number of investigators (6, 18, 49, 63, 95)) but others have found no relationship (1, 54). Dawber (19) found not only that serum cholesterol was higher in smokers than in non-smokers but also that it remained higher in those who stopped smoking. Smokers tend to be leaner than non-smokers, but to gain when they stop smoking (3, 18,491. A few personality differences have been reported between cigarette smokers and non-smokers. F rle man's type A men i the coronary type) tended to be ' d heavy smokers (33 j. Smokers are said to be more easily angered and to eat more when under stress (94). They have been reported to marry oftener. to change jobs more frequently. to be more often hospitalized, and to par- ticipate more actively in sports; than non-smokers (60). Thomas I 94. 95 I hai rel)or ted that the parents of medical students \vho smoke have a significantl!- higher incidence of arteriosclerotic and hyper- tensive cardiovascular disease than parents of non-smokers. Clearl!-. this finding is open to more than c,ne interpretation. Smokers tend to have a higher heart rate than non-smokers (3. 94 1. The matter of constitutional predisposition to smoking has been inves- tipated in twins. It has been found I 27. 2X. 32 I that the smoking hahits of monozygotic twins are siynifirantly morr alike than those of diz\-gotic tGne. even when memhers of a tw-in pair are brought up separately. 326 In spite of some bits of suggestive evidence the existence of basic consti- tutional differences between smokers and non-smokers is not presently established. The constitutional hypothesis, which links smoking and predis- position to disease, is discussed in detail in Chapter 9, Cancer. PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO CARDIOVASCULAR DISEASE Even less conclusve information is available on the role of psycho-social factors of smoking in relation to cardiovascular disease. Studies which have focussed on this are limited in number according to Heinzelmann (44 1. Even fewer. he found, are those which have specifically examined the relative weight of these variables or their interaction. Reviewing those available, he observes that the evidence is highly fragmentary and uncertain. The findings suggest that the relationship between smoking behavior and coronary heart disease may reflect the influence of stress factors and/or personality mechanisms. However, they permit no definitive statements with respect to the relative role of pyscho-social factors and smoking in relation to etiology of the disease. SUMMARY 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 ciga- rette 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 other 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 ciga- rette smoking and coronary disease has causative meaning than to suspend judgment until no uncertainty remains. CONCLUSION Male cigarette smokers have a higher death date from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance. 327 REFERENCES 1. Acheson, R. M., Jessop, W. J. E. T b o acco smoking and serum lipids in old men. Brit Med J 2: 1108-1111, 1961. 2. Bargeron, L. M.. Jr., Ehmke, D., Gonlubol, F.: Castellanos, A., Siegal, A., Bing. R. J. Effect of cigarette smoking on coronary blood flow and mpocardial metabo.`ism. Circulation 15 : 251-257, 1957. 3. Blackburn, H., Brozek, J., Taylor, H. L. Common circulatory meas- urements in smokers and nonsmokers. Circulation 22: 1112-1124. 1960. 4. Blackburn. H. W., Brozek, J., Taylor, H. L., Keys, A. Cardiovascular and related `characteristics in habitual smokers and nonsmokers. In: James, G., Rosenthal, T. ed. Tobacco and Health. Springfield. Thomas. 1962. p. 323-351. 5. Blackburn, H., Jr., Orma. E., Hartel, G., Punsar, S. Tobacco smok- ing and blood coagulation: Acute effect on plasma stypven time. Am J Med Sci 238: M-451, 1959. 6. Bronte-Stewart, B. Cigarette smoking and ischaemic heart disease. Brit Med J 1: 379-385, l%l. 7. Brunner, D., Manelis, G. M yocardial infarction among members of communal settlements in Israel. Lancet 2: 1049-1050, 1960. 8. Buechley, R. W., Drake, 1~. M., Breslow, L. Relationship of amount of cigarette smoking to coronary heart disease mortality rates in men. Circulation 18: 1085-1090: 1958. 9. Burn, J. H. Action of nil:otine on the heart. Ann N Y Acad Sci 90: 70-73, l%O. 10. Burn, J. H.. Leach. E. H., Rand, M. J., Thompson, J. W. Peripheral effects of nicotine and acetycholine resembling those of sympathetic stimulation. J Physiol 148: 332-352, 1959. 11. Burn, J. H., Rand. M. J. Action of nicotine on the heart. Brit Med J 1: 137-139, 1958. 12. Cannon, W. B., Gray, H Factors affecting the coagulation time of blood. 11. The hastening or retardin g of coagulation by adrenalin injections. Am J Physiol 34: 232-242, 1914. 13. Cannon. W. B.. Mendenhall. W. L. Factors affecting the coagulation time of blood. III. The hastenin g of coagulation by stimulating the splanchnic nerv-es. Am J Physiol 31: 243-250, 1914. 14. Cannon. W. B.. Mendenhall, W. L. Factors affecting the coagulation time of blood. IV. The hastening of coagulation in pain and rmo- tional excitement. Am J Physiol 34: 251-261, 1914. 15. Cardiovascular diseases mortality. 19541956, 1958-1960. WIlO. Epidemiological Vital Stat Rep 16: 115-205, 1963. 16. Case, R. A. AI. Smoking habits and mortality among workers in ciga- rette factories. Nature (London 1 181 : 84-86, 1958. 17. Comroe. J. H., Jr. The pharmacological actions of nicotine. Ann N Y Acad Sci 90: 48iii, 1960. 18. Damon, A. Constitution and smoking. Science 134: 339-341, 1961. 328 19. Dawber, T. R., Kannel, W. B., Revotskie, N., Stokes, J.. Kagan, A., Gor- don, T. Some factors associated with the development of coronary heart disease. Six years' follow-up experience in the Framingham study. Amer J Public Health 49: 1349-1356, 1959, 20. Dawber, T. R., Moore, F. E., Mann, G. V. II. Coronary heart disease in the Framingham study. Amer J Public Health 47 (Suppl. I : 4-24. April 1957. 21. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. Brit Med J 2: 1071-1081, 1956. 22. Dorn, H. F. Tobacco consumption and mortality from cancer and other diseases. Public Health Rep 74: 581-593, 1959. 23. Doyle, J. T., Dawher, T. R., Kannel, W. B., Heslin, A. S., Kahn, H. A. Cigarette smoking and coronary heart disease. Combined experience of the Albany and Framingham studies. New Eng J Med 266: 796 801, 1%2. 24. Doyle, J. T., Heslin, A. S., Hilleboe, H. E., Formel, P. F. Early diag- nosis of ischemic heart disease. New Eng J Med 261: 10961101, 1959. 25. Eisen, M. E., Hammond, E. C. The effect of smoking on packed cell volume, red blood cell counts, hemoglobin and platelet counts. Canad Med Ass J 75: 520-523, 1956. 26. English, J. P., Willius, F. A., Berkson, J. Tobacco and coronary disease. JAMA 115: 1327-1329, 1940. 27. Fisher, R. A. Cancer and smoking. Nature (London) 182: 596,1958. 28. Fisher, R. A. Lung cancer and cigarettes? Nature (Londonj 182: 108, 1958. 29. Fontana, V. J. Tobacco hypersensitivity. Ann N Y Acad Sci 90: 138-141, 1960. 30. Forte, I. E., Williams, A. J., Potgieter, L., Schmitthenner, J. E., Hafken- schiel, J. H., Riegel, C. Coronary blood flow and cardiac oxygen metabolism during nicotine-induced increases in left ventricular u-ork. Ann N Y Acad Sci 90: 174-185, 1960. 31. Freund, J., Ward, C. The acute effect of cigarette smoking on the digi- tal circulation in health and disease. Ann N Y Acad Sci 90: 85-101, 1960. 32. Friberg, L., Kaij, L., Dencker, S. J., Jonsson, E. Smoking habits of monozygotic and dizygotic twins. Brit Med J 1: 1090-1092: 1959. 33. Friedmann, M., Rosenman, R. H, Association of specific overt behavior pattern with blood and cardiovascular findings. JAMA 169: 1286 1296, 1959. 34. Friedman, M.. Rosenman, R. H.? Carroll, V. Changes in the serum cholesterol and blood clotting time in men subjected to cyclic varia- tion of occupational stress. Circulation 17: 852-861, 1958. 3.5. Friedman, M., St. George, S., Byers, S. O., Rosenman, R. H. Excretion of catecholamines, li-ketosteroids, 17-hydroxycorticoids and 5-hydroxyindole in men exhibiting a particular behavior pattern (A) associated with high incidence of clinical coronary artery dis- ease. J Clin Invest 39: 758-763, 1960. 32!2 36. Gertler, M. M., Woodbury, M. A., Gottsch, L. G., White, P. D., Rusk, H. A. The candidate for coronary heart disease. Discriminating power of biochemical hereditary and anthropometric measurements. JAMA 170: 149-152, 1959. 37. Haag, H. B., Hanmer, H. R. S mo mg habits and mortality among k' workers in cigarette factories. Industr Med Surg 26: 559-567,1957. 38. Hammond, E. C. The effects of smoking. Sci Amer 207(l) : 3-15. July 1962. 39. Hammond, E. C. Smoking and death rates-a riddle in cause and effect. Amer Sci 46: 331-354, 1958. 40. Hammond. E. C. S mo il in relation to heart disease. k ; g Amer J Public Health 50: 20-26, 1960. 41. Hammond, E. C. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 42. Hammond, E. C., Horn, D. Smoking and death rates-report on forty- four months of follow-up of 187,783 men. I. Total mortality; II. Death rates by cause. JAMA 166: 1159-1172,1294-1308,1958. 43. Harkavy, J. Tobacco allergy in vascular diseases. Rev Allerg 11: 189-212, 1957. 44. Heinzelmann, F. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 45. Hines, E. A. The effects of tobacco on blood pressure and in peripheral vascular diseases. Proc Mayo Clin 35: 337-343, 1960. 46. Jolliffe, N. Fats, cholesterol, and coronary heart disease. A review of recent progress. Circulation 20: 109-127, 1959. 47. Kannel, W. B. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 48. Kaplan, A., Jacques, S.: Gant, M. Effect of long-lasting epinephrine on serum lipid levels. Am J Physiol 191: 8-12, 1957. 49. Karvonen, M., Keys, A., Orma, E., Fidanza, F., Brozek, J. Cigarette smoking, serum-cholesterol, blood-pressure, and body fatness. Ob- servations in Finland. Lancet 1: 492494, 1959. 50. Kershbaum, A., Bellet, S., Dickstein, E. R., Feinberg, L. J. Effect of cigarette smoking and nicotine on serum free fatty acids. Cir Res 9: 631-638, l%l. 51. Kershbaum, A.: Khorsandian, R., Caplan, R. F., Bellet, S., Feinberg. L. J. The role of catecholamines in the free fatty acid response to cigarette smoking. Circulation 28: 52-57, 1963. 52. Keys, A. Diet and epidemiology of coronary heart disease. JAMA 164: 1912-1919, 1957. 53. Kien, G. E., Sherrod. T. R. Action of nicotine and smoking on coro- nary circulation and myocardial oxygen utilization. Ann N Y Acad Sci 90: 161-1'73. 1960. 54. Konttinen, A. Cigarette, smoking and serum lipids in young men. Brit Med J 1: 1115-1117, 1962. 55. Krueger, D. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 56. Larson. P. S. Absorption of nicotine under various conditions of tobacco use. Ann N Y Acad Sci 90: 31-35.1960. 330 57. Larson, P. S., Haag, H. B., Silvette, H. Tobacco: Experimental and clinical studies. Baltimore. Williams and Wilkins Company, 1961. 932 p. 58. Lee, R. E., Schneider, R. F. Hypertension and arteriosclerosis in ex- ecutive and non-executive personnel. JAMA 167: 1447-1450.195s. 59. Lew. E. A. Some implications of mortality statistics relating to coro- nary artery disease. J Ch ronic Dis 6: 192-209, 1957. 60. Lilienfeld. A. M. Emotional and other selected characteristics of ciga- rette smokers and non-smokers as related to epidemiological studies of lung cancer and other disease. J Nat Cancer Inst 22: 259-282. 1959. 61. McKusick. V. A.; Harris. W. S.. Otteson. 0. E., Goodman, R. M.. Shelley. W. M.. Bloodwell, R. D. Buerger's Disease: A distinct clinical and pathological entity. JAMA 181: 5-12, 1962. 62. Miller. D. C.; Stare. F. J., White. P. D., Gordon, J. E. The community problem in coronary heart disease: A challenge for epidemiological research. Amer J Med Sci 232: 329-359, 1956. 63. Miller, D. C., Trulson. M. F.: McCann, M. B., White, P. D., Stare, F. J. Diet, blood 1' `d IPI s and health of Italian men in Boston. Ann Intern Med 49: 1178-1200. 1958. 64. Mills. C. A.. Porter, M. M. Tobacco smoking and automobile driving stress in relation to deaths from cardiac and vascular causes. Amer J Med Sci 234: 35-43, 1957. 65. Morris, J. N. Recent history of coronary disease. Lancet 1: 1-7, 1951. 66. Morris, J. N.. Heady-. J. A., Raffle, P. A. B. Physique of London bus- men. Epidemiology of uniforms. Lancet 2: 569-570, 1956. 67. Morris, J. N., Heady, J. A., Raffle, P. A. B., Roberts, C. G., Park, J. W. Coronary heart-disease and physical activity of work. Lancet 2: 1503-1057, 1111-1120, 1953. 68. Mustard, J. F., Murphy, E. A. Effect of smoking on blood coagulation and platelet survival in man. Brit Med J 1: 846, 1963. 69. Page, I. H., Stare, F. J., Corcoran, A. C., Pollack, H., Wilkinson, C. F. Atherosclerosis and the fat content of the diet. Circulation 16: 163, 1957. 70. Paul, 0. Personal communication to the Surgeon General's Advisory Committee on Smoking and Health. 71. Paul, O.? Lepper, M. H., Phelan, W. H., Dupertius, G. W., MacMillan, A., McKean, H., Heebok, P. A longitudinal study of coronary heart disease. Circulation 28: 20-31, 1963. 72. Pell, S., D'Alonzo, C. A. Myocardial infarction in a one-year in- dustrial study. JAMA 166: 332-337, 1958. 73. Pickering, G. W., Sanderson, P. H. Angina pectoris and tobacco. Clin Sci 5: 275-288, 1945. 74. Regan, T. J., Frank, M. J., McGinty, J. F., Zobl, E., Hellems, H. K., Bing, R. J. Myocardial response to cigarette smoking in normal subjects and patients with coronary disease. Circulation 23 : 365- 369, 1961. 331 Chapter 12 Other Conditions 714-422 O-64-23 Contents RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE . Conclusion ...................... References ...................... TOBACCO AMBLYOPIA ................. Conclusion ...................... References ...................... SMOKIIXG A!XD CIRRHOSIS OF THE LIVER ...... Conclusion ...................... References ...................... MATERXR;AI, SMOKING AND INFAXT BIRTH WEIGHT . Conclusions .... ................ References ..... ................ SMOKING AWD ACCIDEKTS .............. Conclusion ..... ................ References ..... ................ List of Tables TABLE 1. Summary of methods used in retrospective and cross- bectional studies of peptic ulcer and smoking . . . TABLE 2. Summary of results of retrospective and cross-sectional studies of peptrc ulcer and smoking . . . . . . . TABLE 3. l- have concomitantI>- been introdurrd in the approach to the smokers. and the complex nature of the ht>alinp prn(`- ess, it is difficult to interpret this ohservation. 337 T\HI.K L.-Summary of methods used in retrospeclive and cross-sectional studies of peptic ulcer and smoking Controls Collection of data No. 5(lo I'ntirnts admitted b~twrn l!l13 nlrll l!l26. Only casrs with complctr smoking his- tory sclrctrd. 1. Retrospective review of rcmrds at Peter Bent Brigham Hospital. 2. Ulcer diagnosis probably wll established. `L'ro\$cll, (IX, I!134 .I1 M M&F I- ._ .- 1 .- io 3" .) Not stated 400 275 1. Interviewed by investigator. 2. Ulcer diagnosis confirmed by X-ray and/or surgery. l- Samplr of population in Columbus, Ohio. No details eivrn. Mills, (14) 18.V) Not stated I- Allihonc and Flint, (1) 19.58 l?n~lmd 107 Consecutive admissions to hos- pital of patients with gastric and duodenal hemorrha@z or verforation. 107 Matrhrd hy aw, sex, and time of admission from aeute general surgical cmcrprncy admissions. Patients and rontrols inter- virwcd hy same observer. Patients with non-olwr dis- wscs. Each case nlatched with 2 control patients of same sex. 5-yew agr group. and same type of place of residence. Male patients matchrd by social class. ists were examined and intrr- of all such men on thcsc lists, I- -l. Doll, Jones, and Pywtt 0, It)68 327 Oastric; 338 Duodenal. Ulcer patients in Doll and Hill Lung Cancer Study plus ,additional patients in Central Middlesex IIosvi- tal. , 143 ners' t 84L 1. Same interrieners and ques- tionnaire in ewes and r011tr0ls. 2. ~Jlccr diapnosis probably well established. -. 1,737 men aglxl rxl and over on 11 General Pratt viewed by these practitioners. Hepresents ah (Y% non-response due to death and/or untraced Edwards, McKcown. and Whitfield (ll), 193 Of 14.1 considered to have a peptic ulcer, 53 were con- Ar~ncd by X-ray. TABLE 2.-Summary of results of retrospective and cross-sectional studies of peptic ulcer and smoking Percent Non-smokers Percent Hcary Smokers or hvcragc hmo"nts USEd 1nrcstigator ________ CaSCS Controls -__- -___- Barnett (21 Total Gastric :: Duodenal 20 ; Trowel1 (18) Mills (14) Allihone and Flint (I) Doll et al. (71 3R .54 -1 carrtric Glstric F 5::; 66.8 4. 7 M F 10.6 1. 1 11. 1. 3 1 Duodenal Duodennl M 3. I 5.8 M 10.2 12. 7 F 53.7. 62.0 1 F 1 9 1. 9 Edwards ct al. (11) Perrcnt of Peptic Ulcer hy Smokine Catceory Never smokcd~......--.......-.-~..~...-....--....~~....~... 6.0 Formerly smoked. __ .._.. . . . . ..__......._._..-.......-.... ~.. 6.7 Cigarcttrs: Pipc and cigarettes . ..~. ..~ . . . . .._......._..-_..--...- .._._ 6. 5 TABLE 3.-Expected and observed deaths and mortality ratios for ulcer of stomach and duodenum ++ among current cigarette smokers, from seven prospective studies Investigator Type of Ulrcr Hammond and Horn (13)" . .._..._ ~... Duodenal . . .._. . . . . . Both types ~~..~..-_..~..~ Dorn (S)**.............~......-....-..- Gastric ~~._...-......-._.~ Duodenal _ ~. ._- _ Both types .._ -..~_.. Hammond (lZ)~~~.................-...- Gastric Both typcs.~ .._........_.. Doll and Hill (fi) .._. -_- . . . . . . ..__...... Both types . . .._... . . .~... Dunn et al., Occupational (9)....-.-... Roth types Dunn et al., Legion (lO).~~...- ._..._. ~. Both t)pcs ~.~...~~_.~...~ Best et al. (5) __._._._....._ ..__..__. ~. Iloth types _... ~~._~ _.... Yncludcs ISC numbers 5dn, 541. **The Hammond and IIorn data arc frcnn their original puhlishcd report; the other rcsult~ lisfcrl include more recent data as tahulatrd ior the Conunittcc (SW Ch:qacr 8). 339 Numerous investigators have studied the clinical and physiological effects of snloking on gastric motility and acid secretion in humans with and with- out peptic, ulcer. Great vaiiation of gastric motility and secretion was observed in response to cigarette smoking. Some workers found inhibition of gastric motilit>- (15, 17). Batterman (3 1 showed three types of response in normal subjects and ulcer patients after smoking one cigarette. In one-third no effect was observed. another third complete inhihition of motor activity for a time, and in the rest a period of hypermotility \vas followed by normal or subnormal activity. Smoking appears to produce y;ariable effects also on gastric secretion. In a few studies. gastric secretion increased, while in others no change was obserl-ed or there was depression of secretory activity (4, 15, 16, 17). Ad- ditional studies of the effect of smoking on gastric secretory activity and motility are needed to explain the biological meaning of the statistical asso- ciation between cigarette smoking and peptic ulcer. CONCLUSION Epidemiological studies indicate an association between cigarette smoking and peptic ulcer which is greater for gastric than for duodenal ulcer. REFERENCES 1. Allibone, A.. Flint. F. J. Bronchitis, aspirin, smoking and other factors in the etiology of peptic: ulcer. Lancet 2: 179-82, 1958. 2. Barnett, C. W. Tobacco smoking as a factor in the production of peptic ulcer and gastric neurosis. Boston Med Surg J 197: 457-9. 1927. 3. Batterman. R. C. The gestro-intestinal tract. In: Wynder, E. L. ed. The Biologic Effects of Tobacco. Boston, 1955. Chapter 5, p. 133-S). 4. Batterman. R. C.. Ehrenfeld. I. The influence of smoking upon the managrmcnt of the peptic ulcer l'atient. Gastroenterology 12: 575-85. 19 19. 5. Best. E. W. R.. Josie. G. H.: Walker. C. B. A Canadian study of mor- talit! in relation to smoking habits, a preliminary report. Canad J I'uh Health 52: Y-106: 1961. 0. Ihll. 1-L. llill. A. 1~. Lun g cancer and other causes of death in relation to ~mc~kin~: A r;rcond report on the mortality of British doctors. Rrit \It~l J 2: IOYl-21, 1956. 7. Doll. R.. Jones. F. A.. P!:;ott, F. Effect of smoking on the production and maintenance of gastric, and duodenal ulcers. Lancet 1: 657-62. 1'XX. 8. Darn. 14. F. Tobarco consumption and mortality from cancer and other disrases. Public Health Rep `i-1: 581-93, 1959. 9. Dunn, J. E., Linden, G., Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub Health 50: 1475-87, 1960. 10. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department of Public Health, Special Report to the Surgeon General's Advisory Committee on Smoking and Health. 11. Edwards, F., McKeown, T., Whitfield, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, 1959. 12. Hammond, E. C. Special report to the Surgeon General's advisory Committee on Smoking and Health. 13. Hammond, E. C., Horn, D. Smoking and death rates-Report on forty-four months of follow-up of 187,783 men. II. Death rates by cause JAMA 166: 1294-1308, 1958. 14. Mills, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio Med J 46: 1165-70, 1950. 15. Packard, R. S. Smoking and the alimentary tract: A review. Gut 1: 171-4, 1960. 16. Schnedorf, J. G., Ivy, A. C. The effect of tobacco smoking on the alimentary tract. JA1lIA 112: 898-903, 1939. IT. Steigmann. F., Dolehide, R. U., Keminski, L. Effects of smoking tobacco on gastric acidity and motility of hospital controls and pa- tients with peptic ulcer. Amer J Gastroent 22: 3991109, 1954. 18. Trowell, 0. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 80%9. 1934. TOBACCO AMBLYOPIA For more than a century clinicians have attributed certain cases of amblyopia-dimness of vision unexplained by an organic lesion-to the use of tobacco. The distinguishing characteristic of tobacco amblyopia is a specific type of centrocecal scotoma. Since this disease was defined as a distinct clinical entity for the first time in 1930 (4)) the medical literature prior to this date is of relatively little value in the' critical evaluation of the problem (3 ). No epidemiological studies with adequate controls are available to establish for this disease a relative risk among smokers and nonsmokers. Clinical impressions associate tobacco amblyopia with pil)e and cigar smoking and very rarely with cigarette smoking. It has been suggested that this disease, which is now rare in the United States, occurs mainly in individuals with a nutritional deficiency which presumably renders the retina or optic nerve unduly sensitive to tobacco (1,5). Objective attempts at experimentation have been extremely rare and most of the literature is related to uncontrolled clinical impressions ( 2 I. CONCLUSION Tobacco amblyopia had been related to pipe and cigar smoking by clinical impressions. The association has not been substantiated by epidemiological or experimental studies. REFERENCES 1. Heaton, J. M.: McCormick. A. J. A., Freeman, A. G. Tobacco Amblyopia: A clinical manifestation of vitamin B-12 deficiency. Lancet 2: 286- 90, 1958. 2. Potts, A. M. Special report to the Surgeon General's Advisory Commit- tee on Smoking and Health. 3. Schwartz, J. T. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 4. Traquair, H. M. Toxic Amblyopia, including retro-bulbar neuritis. Trans Ophthal Sot U K 50: 351-85, 1930. 5. von Sallmann, L. Special report to the Surgeon General's Advisory Committee on Smoking and Health. SMOKING AND CIRRHOSIS OF THE LIVER Epidemiological studies have noted an association between cigarette smok- ing and mortality from cirrhosis of the liver. The mean mortality ratio for cirrhosis of the liver calculated from all prospective studies was 2.2 (Table 19, Chapter 8). The individual ratios in six of these studies ranged from 1.3 in the Canadian veterans study ( 1) to 4.0 in the California occupational study (3). The earliest prospective study, by Doll and Hill (2) reported no deaths from cirrhosis of the liker among non-smokers. The small amount of information on the biological effects of nicotine and tobacco smoke on the liver of experimental animals is contradictory (5). In several studies (4, 6, 7) it has been reported that heavy smokers also tend to drink alcoholic liquors excessively. It is well established that heav) consumption of alcohol and nutritional deficiencies are associated with in- creased mortality from cirrhosis of the liver. The increased death rate from cirrhosis among smokers may reflect the consumption of alcohol and asso- ciated nutritional deficiencies rather than the effect of cigarette smoking. CONCLUSION Increased mortality of smokers from cirrhosis of the liver has been shown in the prospective studies. The data are not sufficient to support a direct or causal association. 342 REFERENCES 1. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mortality in relation to smoking habits. a preliminary report. Canad J Pub Health 52: 99-106, 1961. 2. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation to smoking: A second report on the mortality of British doctors. Brit Med J 2: 1071-81, 1956. 3. Dunn, J. E., Linden, G.: Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub Health 50: 1475-87, l%O. 4. Heath, C. W. Differences between smokers and non-smokers. AMh Arch Int Med 101: 377,1958. 5. Larson, P. S., Haag. H. B.. Silvette, H. Tobacco-experimental and clinical studies. A comprehensive account of the \\-orld literature. Balliere, Tindall S Cox. London. 1961. p. 319-321. 6. Matarazzo, J. D.. Saslow, G. Psychological and related charartcristi,cs of smokers and non-smokers. Psycho1 Bull 57: 493, 1960. 7. McArthur, C., Waldron, E., Dickinson, J. The psychology of smoking. J Abnorm Sot Psycho1 56: 267-275, 1958. MATERNAL SMOKING AND INF:lNT BIRTH WEIGHT Five retrospective and two prospective studies have shown an association between maternal smoking during pregnant)- and birth I+.eight of the infant (2, 4, 5, 6, 8, 9, 10). Women smoking during pregnancy have babies of lower birth weight than non-smokers of the same social class. They have also a significantly greater number of premature deliveries (defined as birth weight of 2,500 grams or less) than the non-smoking controls. While several studies reported a slightly c oreater neonatal death rate of the children of smokers 12. 5), others did not demonstrate any significant difference in the fetal and neonatal death rates of the two groups (6, 7). Studies on alterations of placental morphology and function as a response to smoking are insufficient for judgment. The difference in infant weight may be due to vasoconstriction of the placental blood vessels (1) or to toxic substances such as CO in the circulation of the smoker and fetus (3'1. It is not known whether the lower hirth weight of the infants of smokers has any clinical significance. In one of the groups studied ( 5 I there \+as less need for surgical induction of labor among mothers who smoked. CONCLUSIONS 1. Women who smoke cigarettes during pregnancy tend to have babies of lower birth weight. 2. Information is lacking on the mechanism by which this decrease in birth weight is produced. 3. It is not known whether this decrease in birth weight has any influ- ence on the biological fitness of the newborn. 343 REFERENCES 1. Essenherp, J. M., Schwind, J., Patras, A. The effects of nicotine and cigarette smoke on pregnant female albino rats and their offsprings. J Lab Clin Med 25: 708-17, 1940. 2. Frazier, T. M., Davis, G. H., Goldstein, H., Goldberg, I. D. Cigarette smoking and prematurity: a prospective study. Amer J Obstet Gynec 81: 98%96, 1961. 3. Haddon, W. Jr., Nesbitt, R. E. Smoking and pregnancy: carbon mon- oxide in hlood during gestation and at term. Obstet Gynec 18: 262-7, 1961. 4. Herriot, .4., Billewicz, W. F., Hytten, F. E. Cigarette smoking in preg- nanq. Lancet I : 771-3, 1962. 5. Lowe. C. R. Effect of mother's smoking habits on birth weights of their children. Brit Med J 2: 673-6, 1959. 6. O'Lane, J. M. Some fetal effects of maternal cigarette smoking. Obstet Gvnec 22: 181-4, 1963. 7. Save], L. E., Roth, E. Effects of smoking on fetal growth. Obstet Gynec 20: 313-6, 1962. 8. Simpson, W. J. A preliminary report on cigarette smoking and the in- cidence of prematurity. Amer J. Obstet Gyn'ec 73: 808-15. 1957. 9. Villumsen. A. L. Cigarette smoking and low birth weights: A prelimi- nary report. Ugeskr Lang 124: 630-1, 1962. 10. Yerushalmy. J, Statistical considerations and evaluation of epidemio- logical evidence. In: James. George and Rosenthal. Theodore eds. Tobacco and Health. Springfield. Ill. Charles C. Thomas. 1962. p. 208-30. SMOKIYG AND ACCIDENTS Smoking has heen aF.Gociated with a variety of accidents. Among these. fires hale the most obvious and important consequences. In a special stlld\ of home accident fatalities in 1952 through 1953. the Public Health Ser\-ic,e and the Sational Safet! Council reported that 231 I 18c; ) of 1.21-1. deaths from fires 6f known origin were due to cigarettes. cigars or ])ipel; I1 1. The Rletropolitan Life Insuranre Compan!- reported that of 352 deaths in 1956 and 19X anlo p their polir! holder5 from fires and burns with know11 causes in and about the home. ii7 I lC,(; ) were due to smoking 12 1. Of I)h!-sioloFic,al responsr%s rrlated to dri\ inp. snlokin= degrades detectah]!- only thr differralltial hrightne~,s threshold and thi, effect increases \\ith amount of c,tll,kirlg I 1 I. ThcL el)iclemiologic~al data a\ ailaljle on the effect- of srnokillg on traflir ac,r.itlerlts are inconcluiir-e. It has been she\\ n that a level of carhos!-hemogltrl,in of .5 percent- -a le\rl rvhich is not uncon1mon among heat v cigarette smokers i 3. 6) ~~deprca~es visual perception to as great an extent as anosia at KOOO to 10,090 feet altitude (4, 5). 344 CONCLUSION Smoking is associated with accidental deaths from fires in the home. No conclusive information is available on the effects of smoking on traffic accidents. REFERENCES 1. Home Accident Fatalities: 1952-1953. National Office of Vital Statistics,, U.S. Public Health Service, 1956. Mimeographed report. Table 12. 2. How fatal accidents occur in the home. Metrop Life Insur Statist Bull 4Q: 6-8, November-December, 1959. 3. Larson, P. S., Haag, H. B.. Silvette, H. Tobacco: Experimental and Clinical studies. Baltimore, Williams and Wilkins. 1961. Carhoxy- hemoglobin, p. 107-110. 4. McFarland, R. A., Moseley, A. L. Carbon monoxide in trucks and buses and information from other areas of research on carbon monoxide. altitude and cigarette smoking. In : Conference proceedings: Health, medical and drug factors in highway safety. National Academy of Sciences-National Research Council Publication 328, 1954. Sect. 4.17-4.33. 5. McFarland, R. A., Roughton, F. J. W., Halperin, M. H., Niven, J. I. The effects of carbon monoxide and altitude on visual thresholds. J Aviat Med 15: 6, 381-94, 1944. 6. Schrenk, H. H. Results of laboratory tests. Determination of concen- tration of carbon monoxide in blood. Pub Health Hull 278: 36-49, 1942. 345 Chapter 13 Characterization of the Tobacco Habit and Beneficial Effects of Tobacco Contents CHARACTERIZATION OF THE TOBACCO HABIT . . . . Nicotine . . . . . . . . . . . . . . . . . . . . . . . Distinction Between Drug Addiction and Drug Habituation . Tobacco Habit Characterized as Habituation . . . . . . . Relationship of Smoking to Use of Addicting Drugs . . . . Measures for Cure of Tobacco Habit . . . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . BENEFICIAL EFFECTS 01' TOBACCO . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . Page 349 349 350 351 352 354 354 355 356 356 348 Chapter 13 CHARACTERIZATION OF THE TOBACCO HABIT NICOTINE Of the known chemical substances present in tobacco and tobacco smoke. only nicotine has been given serious pharmacological consideration in rela- tionship to the tobacco habit. Lewin (17) stated. "The decisive factor in the effects of tobacco, desired or undesired, is nicotine . . . and it matters little whether it passes directly into the organism or is smoked." Support for this statement is based mostly on rationalizations from smoking behavior. analoPT to other habits involving pharmacological agents and. to a much lesser extent, on established scientific fact. The latter may be summarized brielly as follows: 1. Only plants with active pharmacological principles have been employed habitually by large populations over long periods; e.g., tobacco (nicotine) ; coffee, tea, and cocoa (caffeine) ; betel nut morsel (arecoline) ; marihuana (cannibinols) ; khat (pseudoephedrine) ; opium ( morphine) ; coca leaves (cocaine) ; and others (see Lewin, 17). 2. Denicotinized tobacco has not found general public acceptance as a substitute (16, pp. 531-532). 3. Chewing tobacco and using snuff, although providing oral gratification, also furnish nicotine for absorption to produce systemic effects (34). 4. Many but not all smokers can detect a reduction in nicotine content of cigarettes (9) . 5. The administration of nicotine mimics the subjective effects of smoking (13). In uncontrolled experiments Johnston administered nicotine hypodermically, intravenously, or orally to smokers and non-smokers. Non- smokers found the effects "queer," whereas many smokers, including John- ston himself, claimed the subjective effects to be identical to those obtained by inhaling cigarette smoke and found that the urge to smoke was greatly reduced during nicotine administration. In spite of the anecdotal nature of most of this information, the facts are that nicotine is present in tobacco in significant amounts, is absorbed readily from all routes of administration, and exerts detectable pharmacological effects on many organs and structures including the nervous system. The classical pharmacological characterization of nicotine-cellular stimulation followed by depression which is noted in isolated tissue and organ systems- has been invoked to explain the widely differing subjective responses of smokers, many of whom describe the effects as stimulating ("smoking relieves the depression of the spirits"), while others obtain a soothing and tranquiliz- ing effect (16, p. 533). Wilder (33) summarized the literature by noting ". . . observations that cigarette smoking obviously serves a dual purpose: it will mostly pick US UP 349 when we are tired or depressed and will relax and sedate us when we are tense and excited." In order to ascribe such biphasic effects solely to the direct action of nicotine it would be necessary to discount psychological re- sponses and alterations in mood from all other types of stimuli associated with smoking or the use of tobacco, an obvious impossibility. Although Knapp and Domino (15) have shown nicotine in small amounts to exert potent arousal effects in the electroencephalogram in animals, this evidence is difficult to interpret as it relates to smoking in man. A consensus among modern authors (27) appears to be that smoking, and presumably nicotine, exert a predominantly tranquilizing and relaxing effect. The act of smoking is of such complexity that the difficulties associated with objective analysis of whether smoking induces pleasure by creating euphoria or by relieving dysphoria renders objective analysis virtually impossible. The anecdotal literature suggests that sedation plays a more important subjective role in pipe and cigar smoking than with cigarette smoking. Since most pipe and cigar smokers do not inhale, this suggests that bronchial and pulmonary irritation from cigarette smoke after inhaling may contribute an important sensory input to the central nervous system which could modify the sedative effects of nicotine. so that some individuals would describe the experience as stimulating rather than sedative. Heavy cigarette smokers who inhale often describe the act as a pleasant sensory experience which constitutes for them one of the prime drives to continue to smoke. Freedman (10) used the term "pulmonary erotism." Mulhall ( 19 ) and Robicsek i 22) have commented on this concept. An interesting psychoanalytical approach by Jonas (14)) which postulates central nervous system counterirritation to constant pul- monary irritation from smoking, is based upon this concept. If pulmonary irritation is a pleasure factor it probably is not related to nicotine alone but to other irritants in smoke and could represent a non-specific increase in afferent sensory discharge from the whole respiratory tract. A gap in knowl- edge exists in this area. F ur th ermore, until carefully controlled experiments with nicotine are conducted in man, the literature will be burdened further with anecdote and hypothesis rather than fact. DISTINCTION BETWEEN DRUG ADDICTION AND DRUG HABITUATION Smokers and users of tobacco in other forms usually develop some degree of dependence upon the practice. some to the point where significant emo- tional disturbances occur if they are deprived of its use. The evidence indi- cates this dependence to be psychogenic in origin. In medical and scientific terminology the practice should be labeled habituation to distinguish it clearly from addichm, since the biological effects of tobacco, like coffee and other caffeine-containing beverages: betel morsel chewing and the like, are not comparable to those produced by morphine, alcohol, barbiturates, and many other potent addicting drugs. In fact. to make this distinction, the World Health Organization Expert Committee on Drugs Liable to Produce Addiction (35) created the following definitions which are accepted throughout the wcrld as the basis for control of potentially dangerous drugs. 350 Drug Addiction Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its charac- teristics include: 1) An overpowering desire or need (compulsion) to continue tak- ing the drug and to obtain it by any means; 2) A tendency to increase the dose; 3) A psychic (psychological) and generally a physical depend- ence on the effects of the drug; 4) Detrimental effect on the indi- vidual and on society. Drug Habituation Drug habituation (habit) is a con- dition resulting from the repeated consumption of a drug. Its charac- teristics include: 1) A desire (but not a compulsion) to continue taking the drug for the sense of improved well- being which it engenders: 2) Little or no tendency to increase the dose; :H Some degree of psychic depend- ence on the effect of the drug, but absence of physical de- pendence and hence of an abstinence syndrome; 4) Detrimental effects, if any, pri- marily on the individual. TOBACCO HABIT CHARACTERIZED AS HABITUATION Psychogenic dependence is the common denominator of all drug habits and the primary drive which leads to initiation and relapse to chronic drug use or abuse (25). Although a pharmacologic drive is necessary it does not need to be a strong one or to produce profound subjective effects in order that habituation to the use of the crude material becomes a pattern of life. Besides tobacco, the use of caffeine in coffee, tea, and cocoa is the best ex- ample in the American culture. Another example, the chewing of the betel morsel, exists on a world scale comparable to tobacco and involves several hundred million individuals of both sexes and of all races, classes, and religions (17). The morsel contains arecoline from the areca nut, an ingre- dient of the mixture. It is a very mild stimulant of the nervous system which is ordinarily no more detectable than nicotine subjectively. The morsel is chewed from morning to night, from infancy to death, and creates a craving more powerful than that for tobacco. As with tobacco, oral gratification plays an important role in this habit. Thus, correctly designating the chronic use of tobacco as habituation rather than addiction carries with it no implication that the habit may be broken easily. It does, however, carry an implication concerning the basic nature of the user and this distinction should be a clear one. It is generally accepted among psychiatrists that addiction to potent drugs is based upon serious personality defects from underlying psychologic or psychiatric dis- orders which may become manifest in other ways if the drugs are removed (32). Even the most energetic and emotional campaigner against smoking and nicotine could find little support for the view that all those who use tobacco, 7 14-422 Q-64-24 351 coffee, tea, and cocoa are in need of mental care even though it may at some time in the future be shown that smokers and non-smokers have different psychologic characteristics. RELATIONSHIP OF SMOKING TO USE OF 14~~~~~~~~ DRUGS TJndoubtedly, the smoking habit becomes compulsive in some heavy smokers but the drive to compulsion appears to be solely psychogenic sinrc, physical dependence does not develop to nicotine or to other constituents of tobacco nor does tobacco, either during its use or following withdrawal. create psychotoxic effects which lead to antisocial behavior. Compulsion exists in many prades. from the habit pattern of the cigarette smoker who subconsciously reaches into his pocket for a cigarette and may even light his lighter before he realizes that he is already holding a lighted cigarette in his lips, to the heroin addict who becomes involved in crime, sometime5 ill murder, in his search for drugs to satisfy his addiction. Clearly there ip a significant difference. not only in the personality involved but also in thr effects upon the user and his relationship to society. Proof of physical dependence requires demonstration of a characteristic and reproducible abstinence syndrome upon withdrawal of a drug or chemical which occurs spontaneously, inevitably, and is not under control of the sub. ject. Neither nicotine nor tobacco comply with any of these requirements (26). In fact, many heavy smokers may cease abruptly and, while retaining the desire to smoke, experience no significant symptoms or signs on with- drawal. On the other hand. it is well established that many symptoms and a few signs which may be observed objectively by others may occur follow- ing cessation of smoking, but no characteristic abstinence syndrome occurs (16, p. 539). Rather. a gamut of mild symptoms and signs is experienced and observed as in any emotional disturbance secondary to deprivation of a desired object or habitual experience. These may be manifest in some per. sons as an increased nervous excitability, such as restlessness, insomnia. anxiety, tremor, palpitation. and in others by diminished excitability, such as drowsiness, amnesia, impaired concentration and judgment, and dimin- ished pulse. The onset and duration of these withdrawal symptoms arr reported by different authors in terms of days (20)) weeks (30)) or months (12, 28)) obviously an inconsistency if one attempts to relate these to nicotine d eprivation. In contrast to drugs of addiction, withdrawal from tobacco never constitutes a threat to life. These facts indicate clearly the absence of physical dependence. This view is supported further by consideration of the diversity of methods which are reported (16, pp. 540-546) to be successful in treatment of smok- ing withdrawal. Most methods have been based strictly on symptomatic treatment; for those who are depressed: stimulants such as caffeine, thee- bromine, and metrazol; and for those who are excited, sedatives, barbiturates. and the like. Hansel ( 11) treated his patients by stimulating them in the daytime with 10 to 15 mg of dextroamphetamine and putting them to sleep at night with a sedative. At least this treatment has the advantage that it does not interfere \\ith the usual patterns of diurnal and nocturnal behavior. 352 In contrast to addicting drugs, the tendency to continue to increase the dose of tobacco is definitelv self-limiting because of the appearance of nicotine toxicity. Undoubtedly there is a considerable variation among individuals in inherited capabilities to tolerate nicotine. In some individuals this may completely deprive them of the pleasure of using tobacco 130). Although some tolerance is also acquired with repeated use. this is not sufficient to permit the nervous system to be exposed to ever-increasing nicotine concen- trations as is the case with addicting drugs. This in itself mav militate against the development of the adaptive changes in nerve cells which create physical dependence. It is a well-known fact among smokers and other users of tobacco that certain toxic effects such as nausea and vomiting. which accompanv the initial use of tobacco, disappear with repeated use. This tolerance is only relative and excessive use may at any- time initiate these signs and symptoms even in the heavy smoker or other user (6). Acquired tolerance may take two forms: (a) A low grade tissue tolerance in mucous and pulmonary membranes to the irritants in tobacco or tobacco smoke (8). This probably involves adaptive changes in cell membranes. similar to those which occur with other local irritants, and a reduction in sensory nervous input permitting more prolonged exposure to those irritants without unpleasant subjective manifestations. (b) Sp eci c or an o erance to nicotine which is also relatively low grade fi g t 1 and comparatively short-lived. This tolerance, which may permit the ad- ministraton of nicotine in quantities several times larger than those which would induce toxic signs and symptoms initially (13)) varies with age (17), sex (30), and duration of exposure. Differences in metabolic disposition are not enough to account for tolerance (7. 29, 31). Animal studies indicate considerable tolerance to small but little if any to convulsant or lethal doses (2, 4). Another form of adaptation to tobacco wfhich is psychologic in origin is also common to many other drug habits. It might better be termed tolera- tion than tolerance; the user "puts up with" symptoms of irritation and nicotine toxicity which are unacceptable to the novice. Many smokers accept persistent cough, bouts of nausea, and other unpleasant manifestations of irritation and toxicity. Much controversy concerns the relationship of smoking to other drug habits especially to those agents which are addicting like alcohol, the opiates, and others. Since the motivating factor in the habitual use of drugs of any type is the desire to change the status quo in order to achieve pleasure, to relieve monotony, to abolish tension or grief, etc., it is not unusual that many in- dividuals in search of such gratification will habitually rely on several sub- stances. Attempts to establish cause and effect relationships among the several habits have not been meaningful. A more plausible explanation is that the personality characteristics which lead to the search for change may find mild expression in smoking, coffee and moderate alcohol drinking, and in an exaggerated form by abusing the narcotic and stimulant drugs of addiction. 353 MEASURES FOR CURE OF TOBACCO H.ABIT Measures directed at the cure of the tobacco habit have heen designed l~rincipall\ to modifv or abolish the psj-chogenic. sensory. or pharmacologic drives ( 18. pp. .i-10-%1 I. In the psvchotheral)rutic area these include psychoanalytic technics, hvpnotiam. antismokin, ~7 campaigns hased upon fear of health consequences, religion. group ps!-chotherapy (similar to Alcoholics Anonymous), and tranquilizing or stimulant drues. Modification of tobacco taste by astringent mouthwashes (silver nitrate and copper sulfate I. hitters I quinine, quassia I. local anesthetics (benzocaine lozenges I. substitution of o&r tastes (essential oils and flavors), and pro- duction of a dq mouth iatropine or stramonium) are all measures which ha\,e heen aimed at diminishing the sensory drives. Administration of oral lobeline. a substance from Indian tobacco, with Meak nicotine-like actions as a nicotine substitute has had rather extensive trial I 5. 21: 36 )$ and commercial preparations are available. Carefully controlled studies have failed to establish the \-alue of lobeline (1, 18, 24). Of the methods cited above, those which deal with the psychogenic drives have been the more successful since ultimate realization of the goal involves the firm mental resolve of the individual to stop smoking. There is no acceptable evidence that this goal can be achieved solely by modifying sensory drives or using tobacco substitutes. The habitual use of tobacco is related primaril! to psychological and social drives, reinforced and perl)etuated hy the pharmacological actions of nico- tine on the central nerl-ou': system, the latter being interpreted subjectively either as stimulant or tranquilizin g dependent upon the individual response. `iicotine-free tobacco or other plant materials do not satisfy the needs of those who acqtlire the tobacco habit. The tohacro hahit should he characterized as an hnbitrtn~ior7 rather than an nrlt/ic/ion. itI c~onf~lrnlit\~ with acceljted World Health Organization defini- tion5. since onc'e estahlishrd there is little tendency to increase the dose; l)sychic hut not ljh! sical dependence is de\elol)ed: and the detrimental effects are primaril!- on thy indi\ itlual rather than society. Ko characteristic absti- l:en(.e's:\tldrclmc is dr\eloped uljon withdrawal. Acquired tolerance. r\-et\ though comparati\-elv low grade. is important in Ir\errolning nausea and other mild signs of nicotine toxicity and is a factor in continued 11s~ of tobacco. Discontinuation of snloking. although ljosressing the difficulties attendant upon extinctiotl of an\ conditioned rellex. is accoml)lished best by reinforc- irl= factors which interruljt the l~s.\chogeuic drives. Nicotine substitutes or supplementary medications have not been pro\-en to be of major benefit iI1 breaking the habit. 354 BENEFICIAL EFFECTS OF TOBACCO Evaluation of the effects of smoking on health would lack persl)ecti\-e if no consideration was given to the possible benefits to be derived from the occasional or habitual use of tobacco. A large list of possible phvsical benefits can be compiled from a fairly large literature. much of which is based upon anecdote or clinical impression. Even in those circumstances where a substantial body of fact and experi- ence supports the attribute, the purported benefits are comparatively inconse- quential in a medical sense. Examples are: (a) maintenance of good intestinal tone and bowel habits (23) _ and (b) an anti-obesity effect upon reduced hunger and a possible elevation in blood sugar (3). Insofar as these are supported by fact they represent tangible assets and cannot be totally dismissed. On the other hand. it would be difficult to support the position that these attributes would carry much weight in counter-balancing a significant health hazard. But it is not an easy matter to reach a simple and reasonable conclusion concerning the mental health aspects of smoking. The purported benefits on mental health are so intan$ble and elusive. so intricately woven into the whole fabric of human behavior, so subject to moral interpretation and censure, so difficult of medical evaluation and so controversial in nature that few scientific groups have attempted to study the subject. The drive to use tobacco being fundamentally psychogenic in origin has the same basis as other drug habits and in a large fraction of the American popu- lation appears to satisfy the total need of the individual for a psychological crutch. An attempted evaluation of smoking on mental health becomes more realistic if one is willing to confront the question. ridiculous as it may seem. What would satisfy the psychological needs of the 70,000,OOO Americans who smoked in 1963 if they were suddenly deprived of tobacco? Clearly there is no definitive answer to this question but it may be illuminated by analogy with the past. Historically, man has always found and used substances with actual or presumed psychopharmacologic effects ranging in activity from the innocuous ginseng root to the most violent poisons. In China, traditions and custom endowed the ginseng root with remarkable health-giving properties. The strength of this belief was so strong and the supply so short that the root often became a medium of exchange. The value of the root increased in direct proportion to its similarity in appearance to the human figure. The remarkable aspect of this situation is that the ginseng root is his- torically the world's most renowned placebo, since science has failed to es- tablish that it contains any active pharmacologic principle. It would be redundant to recount here all of the potent substances at the other end of the scale. It will suffice to note that this human drive is so uni- versal and may be so powerful that man has always been willing to risk and accept the most unpleasant symptoms and signs-hallucinations and delusions, ataxia and paralysis, violent vomiting and convulsions, poverty and malnutrition, destructive organic lesions; and even death. 355 If the thesis is accepted that the fundamental nature of man will not change significantly in the foreseeable future. it is then safe to predict that man will continue to utilize pharmacologic aids in his search for contentment. In the best interests of the public health this should be accomplished with sub- stances which carry minimal hazard to the individual and for society as a whole. In relating this principle to tobacco it may be reemphasized that the hazard. serious as it may be, relates mainly to the individual, whereas the in- discriminate use of more potent pharmacologic agents without medical super- vision creates a gamut of social problems which currently constitutes a major concern of government as indicated by the recent (1962) White House Con- ference on Narcotic and Drug Abuse (32). SUMMARY Medical perspective requires recognition of significant beneficial effects of smoking primarily in the area of mental health. These benefits originate in a psychogenic search for contentment and are measureable only in terms of individual behavior. Since no means of quanti- tating these benefits is apparent the Committee finds no basis for a judgment which would v eigh benefits versus hazards of smoking as it may apply to the general population. REFERENCES 1. Bartlett, W. A.. Whitehead, R. W. The effectiveness of meprobamate and lobeline as smoking deterrents. J Lab Clin Med 50: 278-81, 1957. 2. Behrend. A.. Thienes, C. H. The development of tolerance to nicotine by rats. J Pharmacol Exp Ther 48: 317-25, 1933. [Abstract] J Pharmacol Exp Ther Proc 42: 260, 1931. 3. Brozek, J., Keys, A. Changes in body weight in normal men who stop smoking cigarettes. Science 125: 1203, 1957. 4. Dixon. W. E., Lee, W. E. Tolerance to nicotine. Quart J Exp Physiol 5: 373-83, 1912. 5. Dorsey, J. L. Control of the tobacco habit. i\nn Intern Med 10: 62% 31: 1936. 6. Edmunds, C. W. Studies in tolerance, l-nicotine and lobeline. J Phar- macol Exp Ther 1: 27-38, 1909. 7. Edmunds, C. W.. Smith. M. I. Further studies in nicotine tolerance. J Pharmacol Exp Ther 8: 131-2, 1916. Also: J Lab Clin Med 1: 315-21, 1915-16. 8. Farrell. H. The billion dollar smoke. A working truth in reference to cigarettes and cigarette smoking. Nebraska Med J 18: 226-8, 1933. 9. Finnegan, J. K.. Larson, P. S., Haag, H. B. The role of nicotine in the cigarette habit. Science 102: 94-6, 1945. 10. Freedman, B. Conditioned reflex and psychodynamic equivalents in alcohol addiction. An illustration of psychoanalytic neurolom, with rudimentary equations. Quart J Stud Alcohol 9: 53-71, 1948. 11. Hansel, F. K. The effects of tobacco smoking upon the respiratory tract. South M J 47: 745-9, 1954. 12. Head, J. R. The effects of smoking. Illinois Med J 76: 83-287, 1939. 13. Johnston, L. Tobacco smoking and nicotine, Lancet London 2: 742, 1942. 14. Jonas, A. D. Irritation and counterirritation. i\ hypothesis about the autoamputative property of the nervous system. New York Vantage Press, 1962. 368 p. 15. Knapp, D. E., Domino, E. F. Action of nicotine on the ascending retic- ular activating system. Int J Neuropharmacol 1: 333-51, 1962. 16. Larson, P. S., Haag. H. B., Silvette, H. Tobacco: Experimental and Clinical Studies. Baltimore, The Williams & Wilkins Company, 1961. 932 p. 17. Lewin, L. Phantastica: Narcotic and stimulating drugs: Their use and abuse. London, Kegan Paul, Trench, Truhner, 1931. 335 p. 18. Miley, R. A., White, 1'. G. Giving up smoking. Brit Med J 1: 101, 1958. 19. Mulhall, J. C. The cigarette habit. Trans Amer Laryng Assn 17: 192- 200, 1895. Also: Ann Otol 52: 714-21, 1943; and N Y Med J 62: 686-8, 1895. 20. Ochsner, A. Smoking and cancer: A doctor's report. N Y J Messner, 1954. 86 p. 21. Rapp. G. W., Olen, A. A. Lobeline and nicotine. Amer J Med Sci 230: 9, 1955. 22. Robicsek, M. U. H. Eine neue Therapie der Nikotinsucht oder dieKunst, das Rauchen zu lassen. Fortschr Med 50: 1014-5, 1932. 23. Schnedorf, J. G., Ivy, A. C. The effects of tobacco smoking on the alimentary tract. An experimental study of man and animals. JAMA 112: 898-904, 1939, 24. Scott, G. W., Cox, A. G. C., Maclean, K. S., Price, T. M. L., Southwell, N. Buffered lobeline as a smoking deterrent. Lancet 1: 54-5, 1962. 25. Seevers, M. H. Medical perspectives on habituation and addiction. JAMA 181: 92-8, 1%2. 26. Seevers, M. H., Deneau, G. A. Tolerance and dependence to CNS drugs. In: Root, W. S., Hoffman, F. G. eds. Physiological Pharmacology, N Y Acad Press, 1963. p. 565640. Vol. 1: Nervous system. 27. Silvette, H., Larson, P. S., Haag, H. B. Medical uses of tobacco past and present. Virginia Med Monthly 85: 472-84, 1958. 28. Swinford, O., Jr., Ochota, L. Smoking and chronic respiratory dis- orders. Results of abstinence. Ann Allerg 16: 4X-8, 1958. 29, Takeuchi, M., Kurogochi, Y., Yamaoka, M. Experiments on the re- peated injection of nicotine into albino rats. Folia Pharmacol Jap 50: 669, 1954. 30. Von Hofstatter, R. Uber Abstinenzerscheinungen beim Einstellen des Tabakrauchens. Wien med Wschr 86: 42-3, 73-6, 1936. 31. Werle, E., Muller, R. Uber den Abbau von Nicotin durch tierisches Gewebe. II. Biochem 308: 355-8, 1941. 32. White House Conference on Narcotic and Drug Abuse. Sept. 27-28, 1962. Proc Govt Print Off, 1963. 330 p. 357 33. Wilder. J. Paradox reactions to treatment. New York J Med 57: 3348-52. 1957. 34. Wolff. W'. 4.. Giles. W. E. St u ies on tobacco chemistry. d - Fed Proc 9: 24G, 1950. 35. World Health Organization. Expert Committee on Addiction-Produci,,,, Drugs. Se\,enth Report. 15 p. r I Its Techn Rep Ser NO. 116, I9.j:. , 36. Wright. 1. S.. Littauer, D. Lobeline sulfate, its pharmacology and uw in the treatment of the tobacco habit. JAMA 109: W-54, 193;. 358 Chapter 14 Psycho-Social Aspects of Smoking Contents Pap. INTRODUCTION .................... 36 I DEMOGRAPHlC FACTORS ............... .?(,I Age ......................... :I6 I Smoking by Socioeconomic Level ............ 36_ Occupation ...................... 36" Education ...................... 363 Sex.. ....................... 363 Race. ........................ 363 Marital Status .................... 361 Religion ....................... 364 Rural versus Urban .................. 361 Summary. ...................... 361 PERSONALITY AND SMOKING. ............ 30; Extroversion and Introversion. .............. 30-l Neuroticism ...................... 306 Psychosomatic Manifestations. ............. 36; Psychoanalytic Theory ................. 36: Summary. ...................... 3hH TAKING UP SMOKING ................. 36H Parents' Smoking Patterns ............... 36'3 Intelligence and Achievement .............. 331 Some IIypotheses on the Heginning of Smoking ...... 3: I Status Striving .................... 3;' Rebellion Against Authority .............. 373 Smoking as a Response To Stress and as a Tension Release . . :3,:\ DISCONTINUATION .................. 374 SUMMARY ....................... 376 CONCLUSION ...................... 3;; REFERENCES. ..................... 3:; 360 Chapter 14 INTRODUCTION The smoking habit has been found to be linked with several demographic variables (such as age: sex: socioeconomic level, etc.), with a number of general behavioral patterns (such as degree and kind of participation in a variety of social activities). with psychological characteristics (such as in- telligence, school achievement. etc.). and with certain personality variables isuch as intro- and extroversion. gregariousness. feelings of inferiority. need for status, etc.). A brief general discussion will be followed by a review of empirical evi- dence linking demographic characteristics with smoking. Certain psycholog- ical-personality variables will then be considered, followed by a review of what is known about the beginning of the smoking habit and about its dis- continuation. Finally, general conclusions will be drawn about the present state of knowledge. The term "smoking," unless otherwise specified, refers throughout to cig- arette smoking only, because almost all research in the area has dealt only with cigarette smoking. DEMOGRAPHIC FACTORS A clear and authoritative demographic description of smokers is not readily available from any one study on the subject. The considerable differences in the characteristics of the smoking population as reported by various studies can probably be explained by one or more of the following factors: 1. Samples were drawn from populations differing in geographical loca- tion and in a number of other population characteristics. 2. Data in the several studies were collected during different years be- tween the 1930's and 1962. Therefore, some differences in re- ported data could be due to time trends. 3. Methods of gathering information differed among the studies. 4. Data were analyzed and/or grouped in different ways. Nonetheless certain trends seem to be well established. AGE As far as is known from actual data, few children smoke before the age of 12. probablv less than five percent of the hors and less thar: one t'ercent of the girls. b rom age 12 on. however, there is a fairlv regular increase in the prevalence of smoking. At the 12th grade level, `between 40 to S5 361 percent of children have been found to be smokers. By age 25, estimate, of smoking prevalence run as high as 60 percent of men and 36 !lerce,,; of women. There is a further increase up to 35 and 40 years after Ichich a drop is observed. In the 65 and over age group, prevalence of smoking in only approximately 20 percent among men and four percent among ~~-olllt',, These distributions are based on cross-sectional rather than longitudi,,,,; data and may be subject to considerable change over the years as each F,.r,. eration of smokers carries its own smoking pattern into higher age bracktqc, It is also conceivable that increased public attention to possible hazarll. of smoking within the last few years has led to some decrease m the numl,,., of smokers, a decrease not evenly distributed among the several age erou,,., Since these statistics were collected several years ago. they may not r+,.t current age distributions. More recent but limited data suggest that th,s,.(. has been an increment in smoking prevalence at all age levels since the earl\ fifties (7, 13, 23, 26, 31 j. Horn (11) estimates that 10 percent of later smokers "develop the halsit with some degree of regularity" b f their high school years. e ore their teens and 65 percent duril,; It seems. then. that the )-ears from the early tefLtl, to the ages of 18-20 are significant years in exposing people to their first smoking experiences. SMOKING BY SOCIOECONOMIC LEVEL Empirically, socioeconomic level is usually determined by means of one or several separate and measurable variables such as income, educatic,,,. occupation and type of residence. Despite the use of different determinants of class status. there is rathrr consistent evidence that smoking patterns are related to socioeconomic lr\~l in that the lower or working classes contain both more smokers and earlier starters. This has been found in America as well as in England (3,4.10.2?. 27). As to separate class-linked variables. income does not seem to be relatrfl in a consistent manner to prevalence of smoking either in England I 391 or in the U.S.A. (261. There does appear to be some tendency to\tar(l fewer male smokers among those with a yearly income below $2.000 iax of 19561 and. in the older groups only. \vith an annual income over $.S.n00. On the other hand, income does relate positively to the quantity of cigarettr- consumed. OCCUPATION Almost as many different ways of classifving and grouping occupations have been used as there ar? studies dealing with this variable. making conl- parisons extremely difficult. Moreover. most groupings are not \er! meaningful since the\- used broad and rotnprehensive job clasaification- which obscure some of the most important orcul)ational characteristics. For example. the category "professional" encotnpasses (as do other rate- gories) a tremendous range of occupations. These vary widely amon? 362 themselves with respect to many characteristics that may be significantly associated with smoking habits. For these and other reasons it is not sur- prising that data reported on the relationship between occupation and cigarette smoking are anything but easy to interpret. Nonetheless. if occu- pation is used merely as a class-index, these data are in accord with those obtained in reference to other socioeconomic indices: whitecollar, profes- sional, managerial and technical occupations contain fewer smokers than craftsmen, salespersons, and laborers. Unemployed have been found to be somewhat more likely to smoke than employed (23) . According to Lilienfeld (19). smokers change jobs significantly more often than non-smokers. Specific data as to reasons for such changes are not given, however, making this variable difficult to interpret. Repeated job changes may be indicative of neurotic traits as the author proposes, but they may also be due to other reasons which create psychological pressures to which smoking is one possible response. EDUCATION The relationship between smoking and education is unclear. Lilienfeld (19) failed to find educational differences between smokers and non-smokers in his 1956 probability sample of adults in Buffalo, New York. Matarazzo and Saslow (23) also concluded that educational attainment, in terms of highest grade completed, does not differentiate smokers from non-smokers. Hammond (8): on the other hand. reported a curvilinear relation among men between 45 and 79 years of age. S ma ers k were under-represented among those who never attended high school and among college graduates. and over-represented in all the categories between. Because of the strong relationship between education and occupation, the trends found in regard to occupation may reflect those found in regard to education: those occupations normally associated with high education show, by and large, a smaller prevalence of smokers. SEX Fewer women smoke than men and their smoking is almost entirely restricted to cigarettes. However, the proportion of women smokers has increased faster than that of men smokers in recent years. Horn (11) reports that a recent American Cancer Societv survev showed an increase since their 1955 survey of five percent (from 3?i to 36 percent). Salber and Worcester (28) suggest on the basis of a sample of senior students at Newton, Mass., high schools that "women. particularly Jewish women. may soon overtake men in the number who smoke." RACE The proportion of smokers is roughly the same among whites and non- whites (7) and relations of smoking to sex and age also were comparable 363 in the t\vo groups. But many more heavy smokers (more than one pack per day) were found among whites: as compared with non-whites, in the case of both men and women. Since. as was reported earlier, income H'as found to relate to amount, though not to prevalence, of smoking. this racial difference could reflect economic differences between whites and non-whites, MARITAL STATUS Smoking (of any kind') is most prevalent among the divorced and widowed and least among those who have never been married, except that amol,g persons over 45. nerer-marrieds are as likely to be smokers as the marrictl, (7). RELIGION There is evidence of lower smoking rates within some religious sects which condemn smoking (161 and among persons who hold devout religious beI& For example, less smoking was found among Harvard students who werp religious and whose parents were devout; and non-smokers seem morp inclined to attend church than smokers 13, 22, 37). Both Horn (111 and Straits and Sechrest (37 ) report over-representation of smokers amr)t~F Catholics, a church in which more tolerance is shown towards smoking than among some Protestant churches. As in all such correlational studies it is impossible to say whether there is a direct causal link between religion and abstention, or whether POIW . . . . other factors account both for the rellglous convlctlons and the abstenti~l~l from smoking. RURAL VERSUS URBAN There are proportionally fewer smokers in rural than in urban areas. 1)~ the smallest percentage of smokers is within the rural farm population. The rural non-farm population is more like the urban population with only slightly fewer smokers than in the latter. No relationship of smoking to size of community has been established. No convincing interpretation can 1~8 offered in view of the lack of additional data. SUMMARY OF DEMOGRAPHIC FACTORS iKo single comprehensive theory to explain smoking is suggested by thpy* demographic data taken by themselves. In fact. the only known attempt at formulating a theory I+ hich is. at least partly. related to or based on suc~h data revolves around a hypothesis relating smoking, or not-smoking. to introjected culture standards linked to social class norms in our societ! (21,22). Nonetheless, there are many. though not always clear, relationships ht.- tween smoking and a variety of social and economic variables. Taken al- together, there emerges the picture of smokin, w as a behavior that has over many years become tied closely to man\- of the complexities of our present society. There can he no doubt that smoking as a habit is determined in some measure by a variety of such social forces as are reflected in demo- graphic data of the kind reviewed ahove. But it will he some time before the specific interrelations can be disentangled. Since man is not a passive target of such forces but an active participant, no possible explanation can omit consideration of the way in which he reacts to and, in turn, creates such forces. in short. a consideration of personality factors. PERSONAI,ITY AND SVOKING All research studies on the relation hetls.reen smokin? and personality select one or several. more or less distinct personalitv traits or characteristics for scrutiny. For example. they mav try to test h!-l)othrFes on the interre- lation between smoking and introversion. smoking and nruroticism. smoking and anxiety. etc. A few students have tripd to describe personality e)-n- dromes by a synthesis of several such traits. .4t the present state of knowl- edge. however. it is more fruitful and more valid to speak not in terms of a "smoker personality." but rather in terms of discrete personality charac- teristics which may he found to he associated with smokers. Certain difficulties are encountered in reconciling findings from the sev- eral studies. Sometimes authors use identical terms even though there is some doubt that they refer to the same concept. For example. the term "neuroticism" in one study ma\- refer to a personality trait as measured by certain psychological tests. in another to a classification of observed so-called nervous behavior. When data from studies using the one are at variance with data from studies using the other. it is dimcult to say whether these studies really are yielding contradictor-v findings. or whether differences in such data are due to the fact that they reflect different variables. In addi- tion. psychological techniques for the assessment of personality are still of uncertain validity. some possibly of little or no value. For example. in a number of studies the investigators have made up a priori scales. tests or questionnaires without any reported attempts at estahlishinp their reliahility or validity. EXTROVERSION AND INTROVERSION One of the best-designed studies (1. 61 was rarrird out in England using representative samples and objective techniques using question$ previousl? developed by Epsenck and claimed by him to "have been found to be . . . reasonably valid measures of three personality traits, extroversion. neuroti- cism, and rigidity." (6). If one accepts the author's claim that the question- naire really did measure these traits. a very significant rrlationqhip was found between extroversion and smoking. Heavy- smokers were more extroverted than medium smokers; these were more extroverted than light smokers and 365 ex-smokers; and both non-smokers and pipe smokers were least extroverted Two consecutive studies with different representative samples yielded th; same results, and the association of smoking with extroversion lvas als,, supported by several other investigators, such as McArthur et al (221 a,,,] Schubert (341. Another study by Straits and Sechrest (371 using the S,,,.i,l Introversion Scale from the Minnesota Multiphasic Personality Inventory (,,, a rather small and probably biased sample did not support this finding, The general picture which emerges from Eysenck's study and from others is one of smokers tendmg to hve faster and more intensely, and to be ,,,,~r,. socially outgoing. Several studies, using behavioral rather than psychological test data. `",,- port this picture. Davis (41 describes young smokers as "more gregari,,,,< and socially advanced" than non-smokers. similar findings. McArthur et al (22) re,,,,n However, a compilation of actual participation of smokers and non. smokers, respectively, in a number of specific social activities as reported 11, several investigators (4, 13, 19, 30) yields conflicting data. Smoker< a&. reported to participate more in such social activities as dancing, courtship and fraternities-in line with what would be expected of extroverted irldi. viduals. As to participation in sports, findings in some studies favor the smoker, in others the non-smoker. Non-smokers were found by one investi. gator to show greater social participation in organizations and to hold more . . offices-activities more associated with extro- than with mtroversion. Smokers show greater interest in TV and movies, non-smokers in reading books. Studies and cultural activities are over-represented among non- smokers. These conflicts in the data as collected do not necessarily reflect real con- flicts, however. Some sports may be of a less gregarious or extroverted nature than others (for example, swimming or tennis as compared to foot- ball). Offices in college organizations also may range from president of a cultural club to class president. It is altogether possible that this rarrar can accommodate introverted as well as extroverted students. Lumping together heterogeneous activities under one broad descriptive term, as done in so many studies on smokers' behavior, may obscure real relationships. In any case. M-hile the association between extroversion and smoking is fairly well supported by available evidence, less certainty exists as to the exact nature of this association. It is possible that extroversion is directl! related to smoking as a habit pattern, that is, that smoking is an expression of this kind of personality, as most authors seem to imply. It is equall! plausible that the extrovert. by virtue of his greater participation in various social activities. exposes himself more to social stimuli to pick up old re-enforce the smoking habit. He may also be more susceptible to social influence. NEUROTICISM Several studies. using a variety of methods. have investigated variables related more or less vagueI\ with u hat mav be subsumed under the term neuroticism. Such variables include neuroticism as a personality trait in- 366 ferred from such varied indices as psychological tests, existence of anxiety states, "nervousness," somatic symptoms, unusual restlessness in terms of job and residence, and others. Most studies support the contention that neuroticism, in this wide sense, is indeed associated with the smoking habit f 16. 18, 19,24,25). A few studies fail to demonstrate any relationship of smoking behavior with one or another of these neurotic characteristics. Straits and Sechrest (37) found no significant difference in anxiety as measured by Taylor's Manifest Anxiety Scale (in contrast to Matarazzo who did). Eysenck et al. (l), using a neuroticism-scale. did not find any significant relationship of neuroticism either to tvpe or degree of smoking. He does suggest, however, that "inhaling may be more prevalent among the more neurotic and notionally disturbed." `The state of our knowledge in respect to the smoking-neuroticism svn- drome can be best summarized this way: Despite the individual deficiencies of many of the studies, despite the great diversity in conceptualization and research methods used. and despite certain discrepancies in reported findings. the presence of some compara- bility between them and the relative consistency of findings lend support to the existence of a relationship between the smoking habit and a person- ality configuration that is vaguely described as "neurotic." However, there are no acceptable studies that help decide how this relationship arises, to what degree (if at all) neuroticism leads to the beginning and/or to the continuation of smoking, or to what degree if at all: it accounts for habitu- ation and resistance to discontinuation. PSYCHOSOMATIC MANIFESTATIONS In a study by Matarazzo and Saslow (23)) smokers report more psycho- somatic symptoms than non-smokers in responses to the "Saslow Psycho- somatic Screening Inventory." However, differences were significant in only one of three groups tested. In the English study by Eysenck (1) heavy, medium and ex-smokers of cigarettes were found to have the largest number of psychosomatic disorders, non-smokers the least, light cigarette and pipe smokers being intermediate. None of these differences, however, were statistically significant. There is no persuasive evidence that smoking and psychosomatic ailments are associated to any important degree. PSYCHOANALYTIC THEORY Psychoanalysts have advanced the hypothesis that smoking, like thumb- sucking, is a regressive oral activity related to the infant's pleasure at his mother's breast (36). It is claimed that male thumbsuckers are very likely to smoke and drink in later years. The frequently observed fact that those who stop smoking show increased food consumption, weight gains and use of chewing gum also supports the oral hypothesis. However: Kissen (15) argues that this could be explained in terms of purely physiological responses. 7 14-422 O-64-25 367 McArthur et al. (22) found a positive statistical relationship between the ability to stop smoking and the number of months of breast feeding. He also reports that thumb-sucking in childhood was more common among men who continued to smoke. The data provided are insufficient to assess these claims, but they do at least suggest that the oral hypothesis warrants further investigation. SUMMARY OF PERSONALITY AND SMOKING Some investigators have attempted to synthesize many of the differences in personality characteristics, as they have been found or suggested by a variety of studies, into a comprehensive "smoker personality." What emerges in each case is an artifact. "While smokers do differ from non-smokers in a variety of characteristics, none of the studies has shown a single variable which is found exclusively in one group and is completely absent in the other" (23). Nor has any single variable been verified in a sufficiently large proportion of smokers and in sufficiently few non-smokers to consider it an "essential" aspect of smoking. "While this is true for aZZ of the variables . . . it is especially true for the variables measuring personality characteristics . . . a clear-cut smoker's personality has not emerged from the results SO far published in the literature" (23). Nonetheless, there appear enough differences between smokers and non- smokers to warrant the assertion that there are indeed different psychological dynamics at work. However, in what ways these differ, and to what extent these differences are cause, or effect, or both, is not yet known. TAKING UP SMOKING All available knowledge points towards the years from the early teens to the age of 20 as a significant period during which a majority of later smokers began to develop the active habit. For this reason, many studies have focused on smoking among youths, almost exclusively selecting high school and college students as their subjects. The trend to an inverse relationship between smoking and socioeconomic level is more pronounced when smoking among children is examined in the light of parents' socioeconomic status. For example, Salber and MacMahon (27) report significantly fewer smokers among Newton, Mass., public school students (grades 7 through 12) in the upper than in the lower socioeconomic levels. Horn et al. (13) found a significant inverse positive relationship between parents' education and children's smoking behavior in students in the Portland, Oregon, high school system, although this relationship dimin- ishes with grade, becoming negligible by the senior year. Several other studies, with more narrowly selected samples, yielded similar results. Smoking patterns among children could be influenced by their parents' smoking patterns which, in turn, are affected by the latter's social class-linked characteristics. On the other hand, the social class level of children them- 368 selves is associated with a number of factors that could influence their behavior. For example, children from better homes may go to different schools, may show higher learning ability and motivation, may associate with different kinds of peers, may engage in different kinds of social activities, and so forth. All these factors could have a bearing on their smoking, inde- pendent of, or in addition to influences exerted by their parents. There can be little doubt that all of these observations must be considered in any attempt to answer the question of initiation of smoking. PARENTS' SMOKING PATTERNS Horn et al. (13) found a strong association between parents' and children's smoking habits. There is a consistent increase in the number of high school smokers from their freshman to their senior years, regardless of sex or parental habits. But within each year there are significantly more smokers in families where both parents smoke than in families where neither parent smokes. Various combinations of smoking practices of father and mother respectively, also affect children's habits differentially. Horn's findings are supported by those of Salber and MacMahon (27) obtained from Newton, Mass., high school students. This congruity between parents' and children's smoking habits has led some investigators to ascribe, explicitly or implicitly, simple and direct causal properties to parents' smoking behavior. It has even been asserted that the most effective way to diminish smoking radically among children would be to decrease smoking among their parents. However, such con- gruity could be due to several factors. Parents could exert direct and force ful influence on their children ; the attitudes and practices of smoking parents could create a general atmosphere of permissiveness in the home; conflict between parents' exhortations and their actual behavior could influ- ence children's perception of the pros and cons of smoking. Selection of social associates on the basis of similar attitudes and behavior norms may lead to a social life on the part of the parents involving other families (and their children) who smoke, thus providing additional social smoking stimuli for their own children. Then, there is the availability of cigarettes in a home where parents smoke which could facilitate the child's first steps to- wards smoking. Finally, the possibilities of similarity in personalities of parents and children cannot be ruled out. Even in families where neither parent smokes there is a striking increase with age in smoking among children. Moreover, congruity between the two generations diminishes with each year from freshman to senior year. That this trend of diminishing congruity continues into college is suggested by the findings of Straits and Sechrest (37) w h o report from a sample of 125 male college students that smokers are not more frequently from families in which both parents smoke. The most plausible (though not necessarily the only) interpretation is that, as children grow older, they themselves, as well as their relationship to the home, change. With approaching adulthood and its associated new social patterns, other influences supplant those of the parents. The children 369 spend increasing amounts of time away from their immediate families and their direct supervision and are increasingly exposed to other social influ- ences. They begin to exert their independence more and more. In fact, as will be seen later, hypotheses to the effect that taking up smoking may be a symptom or an expression of strivin, 0 for self-assertion have been advanced and have received some support from various investigations. It is quite possible that parents' influence affects the age at which children start smoking much more than it affects the ultimate taking or not taking up of the habit. With very few exceptions, the association between parents' and children's smoking behavior has been investigated only via inferences drawn from statistical relationships. Th e exceptions offer data that are mostly of doubt- ful validity (mainly because of unsophisticated techniques for eliciting self- reports by children or because of non-representative sampling) or are insuf- ficient for the derivation of any even moderately firm conclusions. No study employing appropriate and intensive methods on adequate samples has heen found which examined the nature of the psycho.social dynamics. Therefore, all interpretations of the association between parents' and children's smoking habits must remain on the level of hypotheses, no matter how suggestive the data may appear to be. INTELLIGENCE AND ACHIEVEMENT Children's intelligence does not seem to be related to whether they take up smoking or not. Earp (5)) Matarazzo et al (24)) Kissen (15), and Mat- arazzo and Saslow (23) all failed to find significant correlations between in- telligence measures and prevalence of smoking. Salber et al (32) report that among boys from the Newton, Mass. public schools, non-smokers in every grade have "a higher mean IQ than discon- tinued smokers who, again, have higher mean IQ's than smokers . . . the trend in girls, though similar in direction, is less marked." However, no statistical tests are reported and an approximate check on the reported data by means of several t-tests does not support the authors' contention. In the same study a high relationship was found between achievement scores obtained from school grades and non-smoking, and the authors con- clude that `?he difference in smoking habits results from differences in aca- demic achievement rather than intelligence." Earp (5) found that more smokers than non-smokers among Antioch College students failed to graduate. Lynn (20) claimed that non-smoking adolescents make higher grades (but scholastic averages according to age were found sometimes to favor the smokers). Horn et al. (13) present evidence that there is a higher proportion of smokers among high school students who are older than the modal age of their classmates. The authors describe such students who are older than their classmates as students who "tend to be scholastically unsuccessful" implying that under-achievement may relate to their smoking. However, since smoking is age-linked among high school students, statistical differences between older and younger students within any by their age differences. given school grade can be accounted for 370 Thomas (38) and Lilienfeld (19) f ound no differences between smokers and non-smokers in academic standing and in number of years of schooling completed, respectively. In general, the evidence seems somewhat to favor a moderate tendency towards less satisfactory achievements by smokers than by non-smokers. Again, the question of "why" is difficult to answer. It is most unlikely that smoking itself could be responsible. It is possible that whatever accounts for poorer classroom performance may also account for the higher smoking prevalence. It is also possible that smoking is an effect of frustration, or of other psychological reactions to such failure to maintain high scholastic standards. SOME HYPOTHESES ON THE BEGINKING OF SMOKING Davis (4) deduces from responses to the question "how did you come to start?" two factors that explain the beginning of smoking: a sociability- imitative and a wish-for-adult-status factor. Support for this hypothesis is seen in the similarity between parents' and children's smoking habits. Other studies (2, 3, 5, 13) also support it. Despite this agreement amon g several studies, at least along general lines, and despite the plausible, common-sense nature of the hypothesis, it is not an altogether satisfying one. First, evidence is derived largely from self- reports. These may or may not reflect valid insight on the part of the respondents. Second, the similarity between parents' and their children's smoking behavior lends itself to such other, and perhaps more plausible, interpretations as have been presented earlier. Third, the explanations for first smoking, such as "curiosity," "saw others smoke" or "someone offered me a cigarette" (reported by investigators) come to mind easily and this may account for the frequency with which children offer them rather than other possible explanations requiring both deeper insight and more introspective efforts. Considering that during adolescent years the problem of becoming an adult is universal and that smoking has probably become a very pervasive symbol of adulthood in our society, the hypothesis fails to explain why so many children, under the very same circumstances fail to become smokers. A collection of self-inspective reports from smokers, even though probably representing valid reasons for those respondents who give them, is not sufficient to explain why these respondents, but not others, become smokers. In order to have greater confidence in this hypothesis, it is necessary to know whether non-smokers do not also have the "wish for adult status"; whether, if they do, they do not see smoking as appropriate symbolic behavior; if they do not see it as such a symbol, why some do and others do not; and if non-smokers do see it as such a symbol, why do they not take up smoking. As to "imitation," it is less an explanation than a description of what occurs. In somewhat more dynamic terms, one might think of it as conform- ing behavior in the sense that conformity with the behavioral norms of one's social reference groups may be a means for gaining social acceptance. Although the hypothesis has a persuasive ring and has some suggestive 371 evidence, all that can be said is that these two factors, imitation and desire for adult status, may play a role in inducing some, and perhaps many. c,hil] to take up smoking. ( WI1 STATUS STRIVING Some students of smoking behavior have looked at the dvnamir> ,,f "striving for status" in a broader sense, as a manifestation of InterrPlnted basic psycho-social needs. T o b e accepted by one's reference persons. I'artir. ularly one's peer groups, to develop self-esteem and an acceptable self.imapr. and to cope with painful feelings of inadequacy, are such basic psycho-social needs. Of these, striving for adult status is only one aspect. It is entire]\ possible that, if smoking is related to the latter, it may be more in terms ,;f keeping abreast of one's peers than in terms of deliberately wanting to be an adult. Horn (11) points out that there emerges from a variety of studies a "syndrome of intercorrelated measures that seem to have in common thP failure to achieve peer group status or satisfaction." The reference is to such reported findings as that smoking is more frequent among students who are older than their classmates, fall behind their peers in scholastic standing, become drop-outs, and choose easier over more demanding curricula. This relation between under-achievement and smoking has generally been inter. preted in terms of compensation. Salber et al. (32) suggest, "it may be that children who do not achieve this desirable state (good standing with family and peers) because of poor academic grades, find in taking up smoking a way of demonstrating their maturity and achieving acceptance in a peer group whose values are some- what different from those of the academically more successful student." In a wider sense, Horn (11) regards smoking as a "compensatory behavior, a symptom of other problems of emotional health." Other authors have found evidence of greater participation of smokers in sports (although this evidence is not entirely consistent), of smokers' more daring war records, of their poorer disciplinary records, and of impulsive. rebellious behavior, especially on the part of heavy smokers 120, 22, 33i. The findings from anthropometric studies of students' physiques which de- tected an association between physical masculinity and non-smoking (351 has also been cited as support for this interpretation. Once again there is considerable evidence to render the hypotheses advanced very plausible but not altogether satisfactory. A number of ques- tions can be raised. First of all, the evidence that scholastic underachieve- ment may be to some measure responsible for smoking ias is more or less strongly implied by some authors) is not very impressive. For example, in all studies reviewed, the fact that a student does not perform as well as his peers in the classroom is accepted as prima-facie evidence that he feels psy chologically frustrated or socially deprived. The underlying assumption is that children generally see scholastic achievement as an important goal to strive for, and that even partial failure to achieve this goal is sufficiently dis- turbing to them to lead to compensatory behavior. This assumption is open to question especially among population groups in whose hierarchy of values 372 the pursuit of intellectual goals does not rank very high. Many children from lower socio-economic levels (who contribute considerably to the ranks of "underachievers" and among whom smoking is more prevalent), may be among those who ascribe relatively little importance to competing success- fully with their peers in classroom performance. NG studies have demon- strated that there is a relation between smoking and underachievement as a psychological variable. The evidence concerning greater participation of smokers in sports is, as stated earlier, not consistent. Nor is the evidence on each of the other vari- ables that are presumed to be indicative of status deprivation or status striving. Other questions can be raised. Even if smokers do participate in more sports, do engage in more dating and courtship behavior I 1) and generally do manifest more "masculine behavior." why need this be interpreted as "compensatory" behavior rather than a reflection of actual masculinity? If these behaviors are mere demonstrations of masculinity, why should smoking be taken up as an additional, certainly less self-evident, demonstration of masculinity? Why is it that smoking, a habit acquired increasingly by women, should persist in carryin g with it such a pervasive symbolic meaning of masculinity? And again there is the troublesome question as to why some, but not so many others, choose this particular means of giving evidence of their masculinity? At present, there is persuasive, but not convincing evidence that smoking among adolescents may in many cases be related to needs for status among peers, self-assurance, and striving for adult status. REBELLION AGAINST AUTHORITY Since a need for independence, a striving for adult status and more stature among one's peers in an adolescent are associated with rebellion against authority, the hypothesis relating smoking with such rebellion is a logical extension of the foregoing hypothesis. While rebellion may play a role, perhaps an important one, there is not much evidence for it. Claims in the literature are at best based on circum- stantial, suggestive evidence, linked to conclusions by a chain of questionable assumptions. SMOKING AS A RESPONSE TO STRESS AND AS A TENSION RELEASE Stress seems to be related to smoking, as it does to a score of other habits. There is some evidence that the experience of stressful situations contributes to the beginning of the habit, to its continuation, and to the number of cigarettes consumed (4, 14, 22). Kissen (15) concludes that "cigarette consumption increases in relation to the occurrence of some emotionally stressful situations. Such situations therefore appear to play a part in per- petuating smoking. The interpretation of what is emotionally stressful may depend on its particular significance to the individual, that is: it may depend on the personality traits of the individual." 373 A plausible case can be made that the experience of stress together with social situations favorable to smoking can provide the trigger to initial experiments with smoking as well as a mechanism to reinforce the habit once estabhshed. Considerable evidence lends credence to this hypothesis. "Nervous" traits, anxiety, and over-reaction to environmental stimuli have been found to be very prevalent among smokers as compared to non-smokers. Under. achievement, that is failure to live up to one's expected norms, may produce stress if the experience is relevant to a person's needs and values. Cart- wright et al. (3) found that men often tended to start smoking when the, took their first wage-earning job. This could be due to the tensions and anxieties associated with the event, together with new social influences and. perhaps, the new-found freedom from home restraints. The same explana. tion could be advanced for the observed increase in initial smoking amona young men in military service (7). More direct, but possibly less reliable, is evidence from self-reports of smokers. With great consistency, investigators have reported that smokers state they tend to smoke, or to smoke more, under temporary stress-pro. ducing experiences. As McArthur et al. (22) point out, such short-lived fluctuations in response to brief stress episodes would not be detected by survey methods that elicit information on smoking behavior at only one point in the smokers' lives or even, as in McArthur's case, at yearly inter. vals. Here again different and more intensive research methods are called for. Existence of an association between stress and tensions on the one hand. and smoking behavior on the other can probably be accepted with a reason- able degree of confidence. It should be noted, however, that stress, as here used, is defined in terms of an inner psychological-physiological response to certain external events. The fact that a number of people may be exposed even simultaneously to the same stressful life situation does not necessarily mean that all of them experience stress or experience it to the same extent and in the same way. Whether they do, in what way: and to what extent depends. among other things, on the psychological meaning that the situation has for them. This, again, points to the need to supplement broad correlational studies with research that more specifically examines constellations of the several interdependent variables within and without the individual. Furthermore, the role of smoking relative to the tension which presumably evokes it is not at all clear. Is smoking merely an expression of tension or does it serve as a reducer of psychic tension? If the fatter, is it effective, that is, would tension actually be less while smoking a cigarette than while not doing so? No research has apparently dealt with this problem. DISCONTINUATION Consideration of factors involved in discontinuation of smoking may help understand the nature of the habit itself.* *Because the present chapter is concerned only with psycho-social aspects, discussion of methods of discontinuance or their relative effectiveness has been dealt with elsewhere (see Chapter 13). 374 Even less is known about discontinuance than about beginning of smoking. However. there is good evidence that it is related to the beginning of the habit, its nature, and its duration. The rate of smokers who discontinue has consistently been found to be highest among those who start late in life, have smoked the least number of years: and whose average cigarette consumption has been smallest (7, 11: 16, 22). Most frequent reasons for discontinuing given by children who had been fairly regular smokers but had quit, were lack of enjoyment and dislike for smoking. Interestingly, these reasons differ from reasons given by children who have never smoked for not taking up smoking. These latter are more along health, aesthetic and moral lines (29). Among adult smokers who quit (the 1955 census data list about 11 per- cent, a rate that has probably increased in the intervening years), the most frequent reasons given were "various health considerations, the expense, moral reasons, and a test of one's will power" (9, 16). Relatively few people refer to publicity about lung cancer (17). but this may he changing with increased public attention to this issue. Also, the surprising lack of reference to fear of disease among respondents may be a function of certain inhibitions to admitting such a negative motive for what is generally re- garded as an intelligent and desirable thing to do. A study carried out in 1957 by Lawton and Goldman (17) yielded some interesting results that throw some light on the effects of intellectual elements in relation to discontinuation of smoking and at the same time raise some puzzling questions. Two groups of scientists, matched for age and sex: and for the scientific nature of their interests formed the subjects. One consisted of 72 well- known lung cancer scientists, the other of experimental psychologists. Significantly fewer of the cancer specialists than of the psychologists were smokers, and the same difference existed in respect to the number of persons in each group who believed cigarette smoking to be a cause of lung cancer. But there was no difference in respect to the number of persons in the two groups who had discontinued smoking within the past five years, nor in respect to the number of smokers who expressed dissatisfaction with their smoking habits, Most interesting, however, was the finding that when those in the two groups who believed smoking to be a cause of cancer were com- pared, it was the psychologists who expressed more dissatisfaction with their own smoking, and who exhibited a significantly lower prevalence of smoking, a higher rate of attempted discontinuations, and a higher rate of deliberately diminished amount of cigarettes consumed. There is no readily available convincing explanation for this finding, but it does demonstrate that the smoking habit is linked with so many aspects of a person's psychological make-up that mere intellectual awareness of risks involved, even among those with rather intimate and intensive con- tact with the subject, is insufficient to overcome other dynamic factors involved. On the other hand, Horn (12) related that among several approaches used to modify high school children's smoking habits, the "remote" approach involving a logical appeal to the intelligence of the boys and girls proved 375 to be the relatively most effective one. There was evidence, according to Horn, that "this approach was most effective among those who smoked in emulation of their parents, and less SO among those who smoked for the more emotionally tinged reasons of compensation or rebellion." Unfortu. nately, it is not entirely clear from the description of the study how trust. worthy was the identification of the motives underlying these children's smoking. Yet, these results agree logically with the position that there is no single cause or explanation of smoking, but that smokers may start. continue, and discontinue smokin g in response to different inner needs and external influences, social and other. SUMMARY Scientific investigations into the psycho-social aspects of smoking are relatively recent and, except for a few large-scale and systematic studies, leave much to be desired from the standpoint of methods and conceptions. However, evidence from a few sound studies, and converging evidence from many studies, none of which could stand up by itself under exacting scrutiny, permit the following statements concerning the relationship between psycho- social characteristics and smoking behavior: 1. As far as is known from actual data, few children smoke before the age of 12, probably less than five percent of the boys and less than one percent of the girls. From age 12 on, however, there is a fairly regular increase in the prevalence of smoking. At the 12th grade level between 40 to 55 percent of children have been found to be smokers. By age 25, estimates of smoking prevalence run as high as 60 percent of men and 36 percent of women. There is a further increase up to 35 and 40 years after which a drop is observed. In the 65 and over age group. prevalence of smoking is only approximately 20 percent among men and 4 percent among women. 2. Smokers and non-smokers differ in a number of demographic character- istics but no single comprehensive theory to explain smoking is suggested by the demographic data taken by themselves. 3. Although smokers are different from non-smokers psychologically and socially, there are many differences among smokers and among non-smokers, so that some smokers may be like some non-smokers. 4. Smoking appears to be not one behavior but a range of psychologically diverse behaviors each of which may be induced by a different combination of factors and may serve different needs. Therefore no single explanation can suffice. 5. Social stimulation appears to play a major role in a young person's early and first experiments with smoking. 6. There is suggestive evidence that early smoking may be linked with self-esteem and status needs although the nature of this linkage is open to different interpretations. 7. No scientific evidence supports the popular hvpothesis that smoking among adolescents is an expression of rebellion against authority. 376 8. No differences in intelligence between smoking and non-smoking chil- dren have been found, but smokers are more frequent among those who fall behind in scholastic achievements. 9. No smoker personality has been established but certain personality fac- tors have been reported to be associated with smoking, among them extro- version, neuroticism, and a disproportionate prevalence of psychosomatic manifestations. 10. Stress appears to be less associated with prevalence of smoking than with fluctuations in amount of smoking. 11. The cultural milieu seems to have a strong influence, a permissive cul- tural climate tending to promote and a rejecting or outright prohibitive one to inhibit smoking. 12. Less is known about discontinuation than about beginning of smoking. although there is good evidence that it is related to the beginning of the habit, its nature, and duration. CONCLUSION The overwhelming evidence points to the conclusion that smoking-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 existen,ce of predisposing constitutional or hereditary factors. REFERENCES 1. A Report on Personality Factors and Smoking. Part 2. [Eysenck supv] Prepared by Mass-Observation Ltd. August 1962. 27, 24 p. 2. Bothwell, P. W. The epidemiology of cigarette smoking in rural school children. Med Offr 102: 125-32,1959. 3. Cartwright, A., Martin, F. M., Thompson, J. G. Distribution and devel- opment of smoking habits. Lancet 2: 725-7; 1959. 4. Davis, R. Cigarette smoking motivation study. Research Services, London, 1956. 5. Earp, J. R. The student who smokes. Yellow Springs, Antioch 1931. 64 P. 6. Eysenck, H. J., Tarrant, M., Woolf, M., England, L. Smoking and personality. Brit Med J 1: 1456-60, 1960. 7. Haenszel, W., Shimkin, M. B., Miller, H. P. Tobacco smoking patterns in the United States. Public Health Monog No. 45: 1-111, 1956. 8. Hammond, E. C. Report to the Surgeon General's Advisory Committee on Smoking and Health. 9. Hammond, E. C., Percy, C. Ex-smokers. N Y J Med 58: 29569,1958. 10. Heath, C. Differences between smokers and nonsmokers. AMA Arch Intern Med 101: 377-88,1958. 377 11. Horn, D. Behavioral aspects of cigarette smoking. J Chronic Dis 16. 383-95. 1963. 12. Horn. D. Modifying smoking habits in high school students. Children 7: 63-5. April l%O. 13. Horn. D.? Courts, F. A., Taylor. R. M., Solomon: E. S. Cigarette smokina among high school students. Amer Public Health 49: 1497, 1959, 14. Kissen, D. M. Emotional factors cigarette smoking and relapse in pul. monarp tuberculosis. Health Bull 18: 38-44, 1960. 15. Kissen. D. M. Psycho-social factors in cigarette smoking motivation. Med Offr 104: 365-72. 1960. 16. Lawton. M. P. Psycho-social aspects of cigarette smoking. J Health Hum Behav 3: 163-70,1962. 17. Lawton. M.. Goldman. A. Cigarette smoking and attitude toward the etiology of lung cancer. J Sot Psycho1 54: 235-48, 1961. 18. Lawton, M., Phillips, R. The relationship between excessive cigarette smoking and psychological tension. Amer J Med Sci 232: 39742. 1956. 19. Lilienfeld, A. Emotional and other selected characteristics of cigarette smokers and nonsmokers as related to epidemiological studies of lung cancer and other diseases. J Nat Cancer Inst 22: 259-82, 1959. 20. Lynn. R. M. A study of smokers and non-smokers as related to achieve- ment and various personal characteristics. [Abstract J In: Res Prog No. 464, p. 164, 1948. 21. McArthur, C. C. The personal and social psychology of smoking. In: James, G.. Rosenthal, T. eds. Tobacco and Health. Springfield, Ill., Thomas, 1961. p. 201-9. 22. McArthur. C.. Waldron, E., Dickinson, J. The psychology of smoking. J Abnorm Sot Psycho1 56: 267-75. 1958. 23. hlatarazzo, J. D.. Saslow, G. Psychological and related characteristics of smokers and non-smokers. Psycho1 Bull 57: 493-513,196O. 24. Matarazzo. R. M.. Matarazzo, J. D.. Saslow, G., Phillips, J. S. Psycho- logical test and organismic correlates of interview interaction pat- terns. J Abnorm Sot Psycho1 56: 329-38, 1958. 25. Moodie. W. Smoking. drinking, and nervousness. Lancet 2: 188-9, 1957. 26. Sackrin, S.. Conover. A. Tobacco smoking in the U.S. in relation to income. L-SDA Market Res Rep Xo. 189, 1957. 27. Salber, D.. MacMahon. 8. Cigarette smoking among high school stu- dents related to social class and parental smoking habits. Amer J Public Health 51: 1780-9, 1961. 28. Salber, E., Worcester, J. Ch ange in women's smoking patterns. Cancer. In press as of September 1963. 29. Salber. E. J., Welsh. B.. Taylor, S. V. Reasons for smoking given by secondary school children. J Health Hum Behav 4: 118-29, NO. 2, Summer 1963. 30. Salber, E. J., and others. Recreational activities and attitudes toward smoking: A study of school children. Pediatrics. In press as of Sep- tember 1963. 378 31. Salber, E. J., Goldman, E., Buka, M., Welsh, B. Smoking habits of high school students in Newton, Mass. New Eng J Med 265: 969-74,1961. 32. Salber, E. J., MacMahon, B. S mo k ing habits of high school students related to intelligence and achievement. Pediatrics 29: 780-7, 1962. 33. Schonfeld, J. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 34. Schubert, D. Volunteering as arousal-seeking. [Abstract] Amer Psycho1 15: 413, 1960. 35. Seltzer, C. Masculinity and smoking. Science 130: 1706-7, 1959. 36. Strachey, J., ed. Sigmund Freud three essays on the theory of sexuality. In: Inst Psycho-Analyt Lib. London, Hogarth, 1962. No. 57, p. l-130. 37. Straits, B., Sechrest, L. Further support of some findings about the characteristics of smokers and non-smokers. J Consult Psycho1 In press, 1963. 38. Thomas, C. B. Characteristics of smokers compared with non-smokers in a population of healthy young adults including observations on family history, blood pressure, heart rate, body weight, cholesterol, and certain psychologic traits. Ann Intern Med 53: 697-718, 1960. 39. Todd, G. Statistics of smoking. 2d edition. Research Paper No. 1. The Tobacco Manufacturers' Standing Committee. London, 1959. 379 Chapter 15 Morphological Constitution of Smokers Contents PHYSIQUE OF SMOKERS Page ................ 384 SOMATOTYPE CLASSIFICATION ............ 38:( MASCULINITY ..................... 383 BODY WEIGHT. .................... 384 PROSPECTZVE STUDY ................. :I85 CONCLUSION ...................... :<87 REFERENCES. ..................... X8; 382 Chapter 15 MORPHOLOGICAL CONSTITUTION OF SMOKERS PHYSIQUE OF SMOKERS Several studies deal with the relation of morphological constitution and smoking. In 1929 Diehl (2) reported a study of the physique of smokers as compared to non-smokers in a group of freshmen at the University of Minnesota. Measurements of height and weight were obtained at the time of the freshman entrance examination, and smoking habit was determined from a questionnaire item based simply on whether the student did or did not smoke. No significant differences were found in height, weight, and height/weight ratio between the 445 smokers and 441 non-smokers. How- ever, the design of the study limits the reliability of the information. SOMATOTYPE CLASSIFICATION A more satisfactory but still limited study was reported by Parnell (4) in 1951. Using Sheldon's somatotyping technique, Parnell contrasted the classifications of smokers and non-smokers of 308 Oxford undergraduates. In smokers the most frequent somatotypes were the dominant endomorphs and endomorphic mesomorphs; the least frequent was the dominant ecto- morph, with the dominant mesomorph in the middle. For the non-smokers the most frequent somatotype was the dominant ectomorph, and the meso- morphic ectomorph; the least frequent were the endomorphs and the endomorphic mesomorphs, and again the dominant mesomorphs were in the middle. MASCULINITY In 1959 Seltzer (5 j presented information on the relationship between physical masculinity and smoking in a group of 247 Harvard College students who had been followed for more than 15 years for smoking habits, as well as other information. From the smoking data, the subjects were classified into three groups, non-smokers, moderate smokers and heavier smokers. When the subjects were sophomores, they were rated with respect to a body- build complex known as the masculine component, which referred to the element of masculinity as indicated by external morphological features. In measuring this element, the more the pattern of anatomical traits tends 7 14-422 O-64-26 383 toward the extreme masculine form, the stronger is the masculine component. the greater the departure from the extreme masculine type towards th; feminine build, the weaker is the masculine component. The results of this study showed a statistically significant association between the strength of the masculine component and smoking habits. More specifically, it was found that weakness of the masculine component is significantly more frequent in smokers than in non-smokers, and most frequent in heavier smokers. Furthermore, it was indicated that the subjects with weakness of the masculine component showed a constellation of personality and behavioral traits that were, for the most part, not inconsistent with the findings of Heath (3) in his study of the differences between smokers and non-smokers, Although these findings were suggestive, they were recognized by the author as being preliminary and tentative in nature and requiring further confirma. tion. Furthermore, the series on which these results were obtained was relatively small and represented a highly selected population. BODY WEIGHT Thomas (7)) in her study of precursors of hypertension and coronary artery disease in more than 1,000 students at The Johns Hopkins University School of Medicine compared the group of non-smokers with the group of smokers for body weight among other characteristics. The group of 297 non-smokers included occasional smokers as well, and the 321 smokers in- cluded all smokers except non-smokers, occasional, ex-smokers, and unknown. Pipe, cigar, and mixed smokers were included in the smoker category. The relationship of body weight to smoking habits was analyzed on the basis of percentage of overweight and underweight calculated from standard tables. Thomas found the percentage distribution of overweight and underweight was similar for smokers and non-smokers except at the upper end of the distribution curve. There was an excess of smokers who were 30 percent or more overweight, and the subjects who were 4Q percent or more overweight were all regular smokers, The non-smokers had also a greater frequency of individuals with 10 percent or more underweight than the smokers. The difference between smokers and non-smokers with regard to this body weight classification was found to be statistically significant. The subjects were also compared for the ponderal index (height over the cube root of weight), with the smokers showing an excess of the unusually heavy body builds. In the introduction to her paper on the characteristics of smokers com- pared with non-smokers (of which the weight analysis was a part), Thomas wrote: "The finding that smokers, especially heavy smokers, have a higher mortality rate from coronary heart disease than do non-smokers makes it important to determine whether those who smoke are fundamentally different from those who do not smoke, or whether smokers and non-smokers are essentially alike. If alike, th en smokers and non-smokers may be considered as a single population with a uniform life expectancy. If, however, smokers have constitutional differences from non-smokers, the two groups might have 384 inherently different mortality rates, and one group could not serve as a control for the other in statistical studies." After detailing the significant differences noted in her data between smokers and non-smokers, with regard to history of parental hypertension, heart rate, pulse pressure, body weight, and other variables, Thomas concluded that "It cannot be determined from the present data whether those individual characteristics which are more often found among smokers than non-smokers represent true constitutional differences or are due to the effects of smoking. The differences observed in the parental histories indicate that smokers and non-smokers have a somewhat different heritage, and suggest that at least some of the variations found in individual traits may be genetic in origin." In a study of 167 adult male factory workers of Neapolitan parentage but of American birth and upbringingt Damon (11 reported on morpho- logical correlates with smoking. The original series contained 213 volunteers but 46 dropped out for various reasons, and the age range was most extensive from 20 to 59 years of age. Damon's non-smoker category con- sisted of subjects not currently smoking and had never been regular smokers. Cigar and pipe smokers were combined with cigarette smokers, and the statistical analysis was based on the biserial correlation coefficient. As a result of his analysis, Damon found that smoking was associated at the 5 percent level with bi-iliac/biacrominal breadth. subscapular skinfold, ectomorphy, and physical activity; and at the 1 percent level with weight, height/cube root of weight, endomorphy and somatotype group. Smokers of all grades had very similar levels of activity. On the other hand, the most active and the least active men smoked more than those of average activity-a finding which reflects a curvilinear regression of smoking on activity. Damon concludes: "The results show a consistent and significant tendency . . . for lean men to smoke more than stout or fat (but not mus- cular) men . . . higher cholesterol levels among smokers . . . contrary to findings previously reported, smokers in this series were no less masculine in physique, were no more active and consumed no mnre alcohol than non-smokers." PROSPECTIVE STUDIES The most extensive study of morphology as related to smoking habits is Seltzer's prospective study of 922 H arvard alumni 13 years out of college, whose physical characteristics were recorded when they were under- graduates (6) . The investigation was concerned with the morphological characteristics of different classes of non-smokers, cigarette smokers, pipe smokers, and cigar smokers, in a selected male population in order to ascertain the extent to which different smoking classes are phenotypically and genotypi- tally conditioned. The morphological material consisted of a series of anthropometric measurements taken in the fall of 1942 as part of the routine Harvard College medical examination. A total of 12 measurements were obtained of various parts of the body, from which 10 body ratios or indices were computed. When the morphologic data were collected, there was no 385 prior consideration or knowledge of their ultimate use in this correlative study with the subjects' subsequent smoking histories. Information With respect to the smoking habits of these Harvard men was obtained in the fall of 1959 through the medium of a questionnaire (81 percent response). The questionnaire covered approximately 16 years of smoking history and the subjects at the time of completing the questionnaire averaged 35 years of age, a period of maximum lifetime smoking experience. . AS far as smoking categories are concerned, an attempt was made to obtam groupings as nre. cisely differentiated as possible. The primary ClaSSifiCatiOn separated the subjects into non-smokers and smokers. The non-smoker was defined as a person who had never smoked at all or had attempted an occasional smoke during his lifetime. Individuals who smoked occasionally but not every day were excluded from the non-smoker category. The smokers were subdivided into exclusive groupings of cigarette only, cigar only, and pipe only in accordance with the form of tobacco used. All who regularly used more than one form of tobacco were omitted from this particular classification. For the analysis of degree or rate of cigarette smoking, there was a breakdown into five subgroups from occasional to 2f packs a day. The prospective nature of the study, with the availability of the physical measurements made during the college years, had the special advantage of representing a level of morphological status undifferentiated by individual variations resulting from modes of habit, diet, physical activity, health and disease of the subsequent adult years. The analysis was divided into three parts: comparison of non. smokers and smokers, variations among smokers according to form of smok. ing, and variations among smokers as related to degree or rate of smoking. The comparison of 234 non-smokers and 688 smokers showed that the two groups were significantly differentiated both in morphologic dimen- sions and proportions. ln every instance, the smokers had larger mean dimensions than the non-smokers, and in all but one instance these differences were statistically significant. Smokers were consistently greater than non- smokers in height, weight, and in the dimensions of the head, face, shoulders, chest, hip, leg, and hand. Similarly, the smokers of cigarettes only, pipes only, and cigars only had larger mean dimensions than those of the non-smoker category. In addition, in eight out of ten bodily indices or proportions the smoker types showed mean deviations from the non-smoker that were all in the same direction and indicative of the same trend. A consistent graded pattern of differentiation into a specific order of arrangement of non-smokers, cigarette only, pipe only, and cigar only smokers, in that order, was found. Thus, for example, in the case of weight, the cigarette only smokers were 4.37 pounds heavier than the non-smokers, the pipe only smokers 6.59 pounds heavier, and the cigar only smokers 10.41 pounds greater mean body weight. Analysis of the data dealing with amount of cigarette smoking did not show a regular significant body build differentiation according to rate or degree of smoking, but there were suggestions of a positive linear trend from the lightest smoking category to the "1 to 2 packs daily" followed by a downward trend of the maximum "2f packs daily" smokers. Of all the morphological studies, this prospective study appears to present the best data available. Nevertheless, the Harvard students comprise a highly selected sample. 386 CONCLUSION The available evidence suggests the existence of some morphologic differ- ences between smokers and non-smokers, but is too meager to permit a conclusion. REFERENCES 1. Damon, A. Constitution and smoking. Science 134: 339, 1961. 2. Diehl, H. S. The physique of smokers as compared to non-smokers. A study of university freshmen. Minnesota Med 12: 421, 1929. 3. Heath, C. W. Differences between smokers and non-smokers. AMA Arch Intern Med 101: 377, 1958. 4. Parnell, R. W. Smoking and cancer. Lancet 1: 963, 1951. 5. Seltzer, C. C. Masculinity and smoking. Science 130: 1706, 1959. 6. Seltzer, C. C. Morphologic constitution and smoking. JAMA 183: 639,1963. 7. Thomas, C. B. Characteristics of smokers compared with non-smokers in a population of healthy young adults, including observations on family history, blood pressure, heart rate, body weight, cholesterol and certain psychologic traits. Ann Intern Med 53: 697, 1960. 387