Tobacco Documents Online

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SMOKING ^n' HEALTH REPORT OF THE ADVISORY COMMITTEE TO THE SURGEON GENERAL OF THE PUBLIC HEALTH SERVICE U.S DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public IIealth Service I

Public Health Service Publication No. 1103 For sde by the Superintendent of Doeuments, U.S. Government Printing Office Wbebington, D.C., 20402 - Price $1.25 ;i

H 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.

COMMITTEE STAFF ProfessionaI Staff Eugene H. Guthrie, M.D., M.P.H. Sta f;' Director Alexander Stavrides, M.D. Special Assistant to the Director Mort Gilbert~ Editorial Consultant Peter V. V. Hamill„M.D., M.P.H. Medical Coordinator Jack Walden Information Offter Jane Stafford Editorial Consultant Helen A. Johnson Administrative Officer Benjamin E. Carroll Biostatistica.l Consultant SecretariaI and Technical Staff Helen Bednarek Alphonzo Jackson Adele Rosen~ Mildred Bull Jennie Jennings Margaret Shanley Grace Cassid'y Martha King Don R. Shopland Rose Comer Sue Myers Elizabeth Welty Jacqueline Copp Irene Orkin Edith Waupoosee 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 an& 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-healt'h; controversy. The interrelationships of smoking and health undoubtedly are complex. The subject d'oes not lend itself to easy answers. Nevertheless, it has been increasingly apparent thaU answers must be found. As the principal Federal agency concerned broadly with the healthi of the American people, the Public Healthi 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 directionf 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't'he 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 fromi 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 f'rom, 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, tioni of the.highest order. I acknowledge a profound debt of gratitude to the Committee, the many consultants who have giveni their assistance, and the members of the staff. In doing so, I extend thanks not only for the Service but for the Nation as a whole. SURGEON GENERAL V k ar- -9

Table of Contents Page FOREWORD .................. ACKNOWLEDGMENTS . . . . . . . . . . . . . v ix PART I INTRODUCTION, SUMMARIES AND CONCLUSIONS Chapter 1 Introduction ............ 3 Chapter 2 Conduct of the Study . . . . . . . . 11 Chapter 3 Criteria for Judgment . . . . . . . . 17 Chapter 4 Summaries and Conclusions ..... 23 PART II EVIDENCE' OF THE' RELATIONSHIP OFS1bIOKING TO HEALTH Chapter 5 Consumption of Tobacco Products in the United States . . . . . . . . . . . . 3 Chapter 6 Chemical and Physical Characteristics of Tobacco and Tobacco Smoke .... 47 Chapter 7 Pharmacology and Toxicology of Nico- tine . . . . . . . . . . . . . . . . 67 Chapter 8 Mortality . . . . . . . . . . . . . . 77 Chapter 9 Cancer . . . . . . . . . . . . . . . 121 Chapter 10 Non-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pul- monary Emphysema . . . . . . . . . 259 Chapter 11 Cardiovascular Diseases . . . . . . . 315 Chapter 12 Other Conditions . . . . . . . . . . 335 Chapter 13 Characterization of the Tobacco Habitt and Beneficial Effects of Tobacco ... 347 Chapter 14 Psycho-Social Aspects of Smoking ... 359 Chapter 15 Morphological Constitution of Smokers. 381 vil .

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9 I. ACKNOWLEDGMENTS During this study the Advisory Committee on Smoking and Health has had the constant support of individuals, 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 authorityy and completeness of the Report. In this space it is impossible tb ~ assigp priorities or special emphasis to individual contributions or contributors: The Committee, however, doess acknowledge with~ gratitude and deep appreciation-and with~ sincere apologies to any individual inadvertently omitted'-the substantial coopera- tion and assistance ofl the following: ACKERMAN, LAUREN, M.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 Uhiversity b'Iedical Center, New York, N'.Y. ALLEN, GEORGE V.-President and Executive Director, The Tobacco Insti- tute, Inc., Washington, D.C. ALLING, D. W., M.D.-Statistician, National Institute of Allergy and Infeca tious Diseases, U.S. Public Health Service, Bethesda, MdL AMERICAN CANCER SOCIETY, New York, N'Y AMERICAN Tosacco Co., New York, N.Y. ANDERSON, AuGUSTUS E.,, Jr., M.D.-Senior Attending Internist!, Research Laboratory, Baptist Memorial Hospital, Jacksonville, Fla. ANDERVONT, HOWARD B., Sc. D.-Chief'y Laboratory of Biology, National Cancer Institute, U.S. Public Health Service, Bethesda, Mdi ARTHUR D. LITTLE, INC., Cambridge, Mass. ASCARI, WIt.LIAM, Mi.D.-Pathologist; Presbyteriani Hospitial, New York, N.Y. ASIaFORD, THOMAS P., M.D.-Instructor in Surgery, College of Medicine, University of Utah, Salt Lake City, UtahL ASTIN, ALEXANDER W.,, Ph. D.-Researchi Associate,, National! Merit Scholar- ship Corporation, Evanstony I111 AUERBACH, OSCAR, M.D.-Senior Medical Investigator, Veterans Adminis- tration Hospital, East Orange, N.J. BAILAR, JOHN C. III, M.D.-Head, Demography Section, Biometry Branch,. National Cancer Inst'itute; U~S. Public Health Service, Bethesda, Md. B.aTTIST.a', S: P.-Pharmacologist, Arthur D. Little, Inc., Cambridge, Mass. BEARMAN, JACOB, F., Ph. D.-Professor of Biostatistics. University of Min- nesota School of! Public Health, Minneapolis, Minn. BEEBE, GILBERT W'.,,Ph. D.-Statistician, National Acad'emy of Sciences, N'a- tional Research Council, Washington, D.C. ix

BELL, FRANK A., Jr.,-Program Director for the Engineer Career Develop- ment Committee, Offlce of the Chief Engineer, U.S. Public Health Service, Washington, D.C. BERKSON, JOSEPH, 1Vl.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 Medicali Services, California Department of Public Health, Berkeley, Calif. BROWN AND WILLIAMSON TOBACCO CORP., Louisville, Ky. BROWN, BYRON WM.,, Jr., Ph. D.-Associate Professor, Biostatistics Division, School of Public Health, University of Minnesota, Minneapolis, Minn. BUTLER, WILLIAM T., M.D.-Clinical Investigator, Laboratory of Clinical Investrgations, 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 ofl Medicine, University of Utahs Salt Lake Cit'y, Utah. CARRESE, Louis M.-Program Planning, Officer, National Cancer Institute, U.S. Publfic Health Service, Bethesda, Md. CASTLEMAN, BENJAMIN, M.D.-Department of Pathology, Massachusetts General Hospital, Bostony Mass. CHADWICK, DONALD R., M.D.-Chief, Division of Radiolbgical Health, U.S. Public Healtli Service, Washington, D.C. CLARK, KENNET~H, 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 HL, M.D.-Professor of Physiology and Director of the Cardiovascular Research Institute, University of California, San Francisco, Calif. CooN„ CARLETON S., PhL D.-Curator of Ethnology, University of Pennsyl- vania Museum, Philadelphia, Pa, COOPER, W. CLARK, 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 Schooll of Public Health, Cambridge,, Mass. x R

DAWSON, JOHN M.-Statistician, National! Cancer Institute, U.S. Public Health Service, Bethesda, Md.. DIPAOLO, JOSEPH A., Ph. D.-Senior Cancer Research, Scientist, Roswell 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 Hospit'al! Medical School~ London, England •DORN, HAROLD F.-Chief,, Biometrics Research Branch, National Heart Institute, ULS. Public Health Service, Bethesda, Md. DOYLE, JOSEPH T., M.D.-Direetor, Cardiovascular Health Center, Albany. Medical College„ Union University, Albany, N.Y. DUNHAM, Lt7cIA J., M.D.-Medical Officer, Laboratory of Pathology, Na, tional Cancer Institute, U.S. Public HealtL Service, Bethesda, Md. EaERT!, RICHARD V., M.D.-Professor and Head, Department of Medicine, University of _Vrkansas Medical Cent'er, Lit'tle 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. EtsENBERG, 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. FALI:, HANs L., Ph; D.-Acting, Chief, Carcinogenesis Studies Branch,, Na- tional Cancer Institute, U.S. Public Health Service, Bethesd'a, Md. FILLEY, GILES F., M.D.-Associate Professor of Medicine, University of Colorado ~ Medical Center, Denver,Colb. FisxER, RUSSELL SYLVESTER, M.D.-Chief Medical Examiner, State of Maryland, Baltimore, Md. FORAxER, ALVAN G.,, M.D.-Pathologist, Baptist Memoriall Hospital, Jack- sonville, Fla. Fox, BeRVARD H., Ph. D.-Research Psychologist, Division, of Accident Pre- vention, U.S. Public Health Service, WashingKon, D.C. FRAZIER, TODD M., Sc. M.-Director, Bureau of Biostatistics, Baltimore City Health Departmenty Baltimore, Md. G.aRFINxEL, LAWRENCE, M.A.-Chief,, Field and Special Projects, Statistical Research Section, Medical Affairs Department, American~ Cancer Society, Inc., New York, N.Y. "G[LLIAM, ALEXANDER, M.D.-Professor of Epidemiology, The Johns Hop- kins University, Baltimore,, Mdl 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, JOHN. M.D.-Head. Air Pollution Medical Studies, California Department of Public,Health, Berkeley,,, Califl ' Deceased. xi

GOLDSTEIN, HYMAN, Ph. D.-Chief, Biometrics Branch, National Institute of Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, Mdl GRAHAM, SAXON, M.D.-Associate Cancer Research Scientist, Roswell Park Memorial Institute, Buffalo, N.Y. GRF.ENBERG, BERNARD G., Ph. D.-Professor of Biostatistics„School of Public: Health, University of Nbrth~ Carolina, Chapel Hill, N.C. GROSS, PAUL, M.D.-Research Pathologist, Industrial Hygiene Foundation, Mellon Ihstitute, Pittsburgh, Pa. HAENSZEL, WILLIAM-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 andl Social Psy- chology, National Science Foundation, Washington, D.C. HALMSTAD, Dt,vID-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~ call Affairs Department, American~ Cancer Society„ Inc., New York, N.Y. HAMPERL, H., M.D.-Director of the Pathology Institute, University of Bonn, Bonn, Germany. H.aR'nwELL, JONATxAN, L., Ph. D.-Chief'y Research Communications Branch, National Cancer Institute, U.S, Public Health Service, Silver Spring, Md. HAYDEN, ROBERT G., Ph. D.-Research Psychologist, Behavioral Sciences Section, Division of Community Health Services, UIS. Public Health Service, Washington, D.C. HEIMANN, HARRY, M.D.-Chief, Division of Occupational Health, U.S: Public Health Service, Washington, D.C. HEINZEnvIANN,, 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, KATHERINE, M.D.-Medical Director, Laboratory of Pathology, National Cancer Institute, UIS. PublfiaHealth Service, Bethesda, Md. HESTON, WALTER E., M.D., Ph, D.-Chief, Laboratory of Biology, National Cancer Institute, U.S. Public Health Service„ Bethesda, Md. Hicciws, IAN T. T., M.D.-Professor of Epidemiology and Microbiology, University of Pittsburgh Graduate Schooll of Public Health„Pittsburgh, Pa. HocxBAUM, 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 Scientfific Director, Tobacco Indus- try Research Committee, New York, N.Y. HORN, DANIEL, Ph. D.-Assistant Chief for Researchy 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 Studies Branch, Division of Air Pollution, U.S. Public Health Service, Cincinnati, Ohio, HUEPER, WILHELM C., M.D.-Chief, Environmental Cancer Section,, Na- tional Cancer Institute, U.S. Public Health Service, Bethesda, Md, IrsEN, Jox ANNES, Ph. D.-Professor of Medical Statistics, Henry Phipps In- stitute, University of Pennsylvania, Philadelphia, Pa. ISBELL, HARRIS, M.D. Professor of Clinical Pharmacology, University of Kentucky Medical School, Lexington, Ky. ISICRANT„ ALBERT P.-Chief, Developmental Research Section, Division of Accident Prevention, U.S. Public Health Service, Washington, D.C. JANUS, ZELDA-Statistician, National Cancer Institute, U.S. Public Health Service,, Bethesda, Md. JosIE„ G. H., Sc. D., M.P.H.-Chief,, Epidemiology Division, Department of National Health and Welfare, Ottawa, Canada. KAHN,,HAROLn A.-Stathistieian, Biometrics Research, Branch„National Heart Institute, U!.S. Public Health Service, Bethesda, Md. KANNEL, W. B., M.D.-Associate Director, Heart Disease Epidemiology Study, National Heart Institute, ULS. Public Health Service, Framingham, Mass. Ker.ENtEN,, GEORGE, M.D.-Research Associate, Massachusetts Eye and Ear Infirmary, Harvard University Medical School, Bostons Mass. 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 Seiences,Division, Arthur D. Little, Inc., Cambridge, Mass. KESSELNIAN", AvivA-Statisticians National Cancer Institute, UIS. Public. Health Service, Bethesda, Md. KLEINERMAN, JEROME, M.D.-Associate Director, Medicall Research~ Depart- ment, St. Luke's Hospital, Cleveland, Ohio KNIGHT, VERNON, M.D.-Clinical Director, Nathionall Institute of Allergy and Infectious Diseases, U.S, Public Health Service, Bethesda, Md. KNUTTi, RALPH E., M.D.-Director, National' Heart Instithite, U.S. Public Health Service, Bethesda, Md. KOTIN, PAUL, M.D.-Associate Director ofi 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. LnxsoN, 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. LEUCHTENBERGER; CECILIE, M.D., Ph. D.-Professor, Eidgenossische Tech- nische Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland Xill

LEi7CHTENBERGER, RUDOLF, M.D.-Professor Eidgenossische Technische Hochschule, Institut fiir Aligemeine Botanik, Zurich, Switzerlan& LEVIN, MORTON L., M.D.-Professor of Epidemiology, Roswell Park Me- moriall 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 Cootc, M.D.-Scientific Director, Tobacco Institute Re- searchi 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. MxNOS, NICxoLAS E.-Statistician, Division of Occupationall Health, U.S. Public Health Service, Washington, D.C. 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 Medicall Psychology, Department of Medical Psychology, University of Oregon Medical School, Portland, Oreg. McFARLAND, JAIaIES J.,, M.D: Professor of Otolaryngology, School of Medi- cine, George Washington University Hospital, Washington, D.C. McGILU, HENRY C., M.D.-Professor of Pat'hology, Louisiana State Uni- versity School of Medicine, New Orleans, La. McHucH, RICHARD B., PhL D.-Associate Professor of BiostatistScs, 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 HealYh~ Small Grants Committee,,N'ational Institute of Mental Health, U.S. Public Health Service, Bethesda, Md. MEHLER, MRS. ANN-Resear& 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, Epid'emiology 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 an& Chairman, Department of Indus- trial b'Iedicine,, New York University Medical Center, New York, N:Y. ORCHIN, MILTON, Ph. D.-Professor of Chemistry, University of Cincinnatiy 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 Epid'emiological Studies,. Passavant Memorial Hospital, Chicago, 111. PFAELZER, ANNE I.-Concord, Mass. PHILLIP 1bIoRRIS, INC., New York, N'.Y. PICKREN, JOHN W., M.D.-Chiefy Department of Pathology, Roswell Park Memorial Institute, Buffalo, N.Y. PIERCE, JOHN A., M.D.-Associate Professor, Department of Medicine, Uni- versityof Arkansas Medical Center, Little Rock, Ark. POTTS, ALBERT M., M.D.-Professor of' Ophthalmology, University of! Chi- cago Sehool of Medicine, Chicago, Ill. PftINDLE; RICHARD A., M.D.-Chief, Division of Public Health Methods, US. Public Health Service, Washington, D.C. R. J. REYNOLDS TOBACCO Co., Winston-Salem; N.C. REED, SHELDON C., Ph. D.-Professor of Zoology, Departmentl of Zoology, University of Minnesota, Minneapolis, Minn. REMINGTONRAND, LaD:(Ottawa). Roos, CHARLES A.-Head, Reference Services Section,, National Library of! Medicine, U.S, Public Health Service, Bethesda, Md. ROSEN, S.aM[iEL, M.D.-Chief, Pulmonary Mediastinall and ENT Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. ROSENsnATT ,, MILTON B., M.D.-Associate Clinical Professor of Medicine, New York MedicallCollege, and Visiting Physician, Metropolitan Hospital,. New York,N.Y. Ross, JOSEPH,N'I.D.-Associate Professor of Medicine, University of Indiana Schooll 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 Schooly Dallas, Tex. SAVAGE, I. RICHARD, Ph. D.-Professor of Statistics, Florida State University, Tallahassee, Fla. ScHaFFMAN, ZELDA-Special Assistant to Executive Officer, National Cancer Institute, U.S+ Public Health Service, Bethesd'a, Md'. SaHNEIDERMAN,, 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 Diseasesand'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. SELIGMAN, ARNOLD M., M.D.-Chairman, Department of Surgery, Sinai' Hos- pital, Baltimore, Md. 0 I xv

SELTSER; RAYMOND, M.D.-The Johns Hopkins University School of Public Health, Baltimore, Md. SELTZER, CARL C., Ph. D.-Research Associate in Physical Anthropology,. Peabody Museum, Harvard Uhiversity„ Cambridge, Mass. SHAPIRO, HARRY, M.D.-Curator of Anthropolbgy., American Museum of Natural History, New York, N.Y. SHUBIx, 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, Mo:vROE; Ph. D.-Acting Chief, Division of Health Records, The National Center for Health Statistics, U.S. Public Health~ Service, Wash. ington, D.C. SLOAN, MARGARET H., M~D.-Special Assistant to Director, National Cancer Institute, U.S. Public Health Service, Bethesda; Md. SPIEGELMAN, MORTIMER-Associate Statistician, Metropolitan Life Insurance Company, New York, N'.Y. STALLONES, REUEL, M.D.-University of California Schooll 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 HealtL 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, SHERMAN LEONARn-Sociologist, San Francisco Field and Training Station, U.S. Public Health Service Hospital, San Francisco, Calif. TAEUBER, K. E.-Research Associate, Population Research and Training Center, University of Chicago, Chicago, Ill. TOBACCO INSTITUTE, INC., Washington, D.C: TOBACCO INSTITUTE RESEARCH COMMITTEE, New York, N.Y. TOKUHATA, GEORGE, Ph. D., D.P.H.-Chief of Epidemiolbgy, St. Jude Re- search Hospital, Institute of Biology and Pediatrics, Memphis. Tenny and Assistant Professor of Preventive Medicine, University of' Tennessee, Col- lege of Medicine, 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. TbTTEN; ROBERT S., M.D.-Associate Professor of! Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. TURNER, CLAUnE G.-Director, Tobacco Policy Staff, Agriculture Stabiliza• tion~ and Conservation~ Service, United States Department of Agriculture, Washington, D.C. xvi M I

VINCENT, WILLIAM J.-Student, University of California, Los Angeles, Calif. VON SALLMANN, LUDWIG, MsD.-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 IndustrialJ Medicine and Hygiene„ Wayne University College of Medicine, Detroit, Mich. WALKER, C. B., B.A.-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. WE1:vSTEIrr, HOWARD I., M.D.-Director, Division of Medical Review, Foo& and Drug,Administration, Washingtony D.C. WOOLSEY, THEODORE D.-Assistant Director, National Center for Health~ Statistics, U:S. Public Health Service, Washingteny D.C. WYATT, JOHN P., M.D.-Professor of Pathology, St. Louis University Schooll of Medicine, St. Louis, Mo.. 7,E:RZavY, FRED M.,, M.D.-Department of Maternal and! Child Health, The Johns Hopkins School of Public Health, Baltimore, MdL 7.UKEL, WTLLIAni, M.D.-Associate Director, Collaborative Studies, Nationall Cancer Institute, U.S. Public Health Service,,Bethesd'a, Md. 714-422' 0-64'-2' xvii 9

Introduction,. Summaries,, and Conclusions :.wrr~ , . _._ ... ,,4 ..-« _ .. .. _+. .-..--.,

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Chapter 1 Realizing that for the convenience of all' types of serious readers it~ would be desirable to simplify language, condense chapters and bring opinions to the forefront. t'be Committee offers Part I as'sueh a presentation. This Part includes: (a) ani introduction comprising, among other items, a chro- nology especially pertinent to the subject of this study and to the establish- ment and activities of the Committee, (b)! a short account ofl how the study was conducted, (c) the chief criteria used in making jNd=ments, and' (d) a brief overview of the entire Report. HISTORICAL NOTES AND CHRONOLOGY In the early part of the 16th century, soon after the introductSon, of' tobacco into Spain and England by explorers returning from t'he New World, controversy developed from differing opinions as to the effects of the human use of the leaf and prodhcts 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-smeliing, lbathsome custom, harmful to the brain and' lungs. The chief question was then as it is now: is the use of tobacco bad or `rood for health, or devoid of effects on health? Parallel with~ the increas- ing prodtiction and use of t'obacco, especiall~, with the constantly increasing smoking of ci-arettes, the controversy has become more and more intense. Scientific attack upon the problems has increased proportionately. The design, scope and penetration of studies have improved, and the yield of significant results has been abundant. The modern~ period of' inuestigatiom of smoking and healthis include& within the past sixty-three years. In 1900 an increase in cancer of the lung was notedl particularly by vital statisticians, andl their data are usually taken as the st'arting point for studies on the possible relationship of smoking and other uses of tobacco t'o cancer of the lung and of cert'aini other organs, to diseases of the heart and blood vessels (cardiovascular diseases in gen- eral; coronary artery disease in, particular) „ and to the non-cancerious (non- neoplastic) diseases of the lower respiratory tract (especially chronic bronchitis and! emphysemal . 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 eonspicuous. Since then a: areat variety of investigations have been carried out. Many of the chem- ical compounds in~ tohacco, andd in tobacco smoke havebeem isolatedl and tested. Numerous experimental studies in lower animals have been made by exposing them to smokeand'~ to tars, gases and various constituents in tobacco~ and tobacco smoke. It is not feasible to~ submit human beings to 5 -4::-. v-.::.e";:,:,.: ik'AM .._

experiments that might produce cancers or other serious damage, or to expose them to possibly noxious agents over the prolonged periods under strictly controlled conditions that wouldl be necessary for a valid test. Therefore, the main evidence of the effects of smoking andl other uses of tobacco upon the health of human beings has been secured through clinical and pat!holbgical observations of conditions occurring in men, women and children in the course of their lives, and by the application of epid'emio- logiealand statistical methods by which a vast array of information has been assembled and analyzed~ Among the epidemiolbgical 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 value for the work ofl this Committee. These are (!l ) retro- spective studies which deal with data from the personal histories and medical and mortalityrecords of human individuals in groups; and (2)~ prospeetit;estudies, in~ which men and women are chosen randomly or f'rom~ somee special group; such as a profession, and are follbaed from the time of their entry into the study for an indefinite period, or until they die or are lost on account of other event's. Since 1939 there have been 29 retrospectiive studies of lung cancer alone which have varying degrees of completeness andl validity. Following, the publication of several notable retrospective studies in the years 11952-1'956, the medical evidence tending to link cigarette smoking to cancer of the lung, received particularly widespread attention. At this time, al'so, the criticali counterattack upon retrospective studies and upon conclusions drawn from them 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 be discussed further in Chapter 3, Criteria for Judgment, and in other chapters, especially ChapterII, Mortality, and Chapter 9, Cancer. Durin- the decade 1950-1960, at various dates„statements based upon the accumulated evidence were issued by a number of organizations. These included the British Medical Research Council; the cancer societies of Den- mark,'orway; Sweden, Finland, and the Netherlands; the American Cancer Society; the American Heart Association; the Joint Tuberculosis Couneit of' Great Britain; andlthe Canadian Nationall Department of' Health and~''Velfare. The consensus, publicly declaned, was that smoking is an important health hazard, particularly with respect to: lung cancer and! cardiovascular disease. Early in 1954. the Tobacco Industry Research Committee (T:I.R.C.) was established by representatives of tobacco manufacturers.. growers, and ware- housemen to sponsor a program of research into questions of tobacco use and health~ Sincethen, under a Scientific Director and a Scientific AdvisoryBoard composed of nine scientists w,homaintain t'heirrespecthve institutional affiliations, the Tobacco Industry Research Committee has conducted a grants-in-aid program, collected information, and i'ssued reports. The U.S. Public Health Service first became officially engaged in an appraisal of the available data on smoking and health~ in~ June; 1956, when, under the instfigation of the Surgeon General, a scientific Study Group on 6

the subject was established jointly by the National Cancer Instfitute;, the National Heart Institute, the American Cancer Society, and the American Heart Association. After appraising 16,independent studiesearried on in five countries over aperiod'of 18 years, this group concluded that there is al causal, relationship between excessive smokingoflcigarettesandilungcancer. Impressed by the report of the Study Committee and by other new evi- dence. Surgeon General Leroy E. Burney issued a statemea on July 12, 1957, reviewing the matter and declaring, than "The Public Health Service feels the wci_ht of the evidence is increasingly pointing, in one direct'2on;, that Axcessive smoking is one of the causative factors in ltmg cancer." Again, in a special article entitled "Smoking andlLung,Caneer A St'at'ement of the Pi ublicHealthService;"published in the Journall of the American Medicall 1ssociation on November 20', 1959. Surgeon Generall Burnev referred too his statement issued in 1957 and reiterated the belief of the Public HealthServ,ice that: "The weight of evidence at present implicates smoking as the. Eirincipal factor in the increased incidence of lung cancer," and that: "Ciga- rette smoking particularly is associated with an increased chance of de- Nelbpinn lung cancer." These quotations state the position of the Publfc. Flealth Service taken in 1957 and 111959 ont'he question of smoking and health. That position has not changed in the succeeding, years, dhring «hichseveral units of the Service conducted extensive investigations on t-moking and airpollution; and theService maintained a; constant scrutiny '?freportsandlpublications in this field. ESTABLISHi~-TENT OF THE COMMITTEE The immediateantecedent's of the establishment of the Surgeon Gen- eral's Advisory Committee on Smoking and Health: began in mid-1961. On June t of that vear, a letter was sent to4hePresident' of the I:Tnited States: qi;ned' bvt'he presidents of the American CancerSociety; the American Public Health Association: the American Heart Association; and theNa- tional Tuberculosis Association. It urged the formation of a Presidential'commission t~o~ study the "widespread implications ofl the tobacco problem."' On January 4, 11962, representatives of the various organizations met with Surgeon General Luther L. Terry: who shortly thereafter proposed to the Secretary of Health, Education, and Welfare the formation ofi an advi- sory committee composed of "outstanding experts who would assess avail- able knowledgein this areai [smoking vs. health] and make appropriate rec- ommendations, . . ." On April! . 16. the Surgeon General sent a moredetail'ed' proposal t'o: theSecretarv for the f'ormation of the advisory group, calling for re-evaluation ofl thePublficHealth Service position taken by Dr. Burnev in the Journal of the American Medical Association. Dr. Terry felt the need for a; new look at the Service's position in the light of' a number of significant': develop- ments since 1959 which emphasized the need f'or further action. He listed t'heseas: 7

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 technicall guidance by the Service from the FederalTrad'e Commission on labeling and advertising of tobacco products. 7~. Evidence that medical opinion has shiftedsianificantly against smoking~ The recent study and report cited by Surgeon General Terry was the highlay important volume: "Smoking and Healt'h+-Summary and Report of the Royal College of Physicians of London on Smoking in Relation to Cancer of the LunT and Other Diseases." The Committee of the Royal College ofiPhysicians dealing with these matters had beem at its work of appraisal of data since April 1959. Its main conclusions, issuedi: early in 11962, 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- ina and health. The President, later in the same day at his press conference acknowledged the Surgeon General's action andl approved it. On July 2-1, 1962; the Surgeon General met' with, representatives of the American Cancer Society, the Americani College of Chest Physicians, the American Heart Association, the American Medical Association„the.Tobacco Institute, Inc:. the Food' and Drug Adtninistration, 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 follbws: Phase I-An objective assessment of the nature and magnitude of the health hazard, t'o, 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 recognize'that different competencies would be need'ed& 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 working in the fields of biology and medicine, 8 ~,.

with interests and competence im the broad range of medical sciences and with capacit'yy to evaluate t'he elements and factors in the complex relation- shi'p between~ tobacco smoking and health. During, thenext' month, these lists were screened' by the representatives of' organizations present at t'he July 27meetiiig. Any organization coul& veto any of the names on the list, no reasons being required. Particular care was taken to eliminate the names of any persons who had1'aken a public position on the questions at issue. From the final list~ of! names the Surgeon General selected ten men who agreed to serve om the Phase I commit'tee. which was named The Surgeon General's Advisory Committee on; Smoking, and Health. The com- mititee members, their positions, and their fields of competence are: Stanhope Bavne-Jlones, M.D., LL.d., (Retired ), Former Dean, Yale School (4 Medicine (19351-40), former President. Joint Administrative Board. Cor- nell University.., New York Hospital Medical Center (1947-52) ; former President. S'ociety of American Bacteriologists (19291. and American Society of'~ Pathology-andl Bact'eriolog,v(11940). Field: Nature and Causation of Di-~ea<e in Human Populations. Dr. Bavne-Jones served also as a special consultant to the Committee ~ta fl'. Walter J. Burdette, M.D:, Ph. D., Head of Department'of Surgery; Uiti- versitv of Utah Schooli ofl Medicine. Salt Lake City. Fields: Clinical & Trxperimental Surgery; Genetics. William G. Cochran. NI.A., Professor of Statisttics., Harvard University. Field: Mathematical Statistics, with Special Application to Biological Prohl lerns. Enunanuel Farber. M.D., Ph. D., Chairman, Department of Pathology; 1 niversitw of Pittsburgh. Field: Experimental and Clinical Pathology. Louia F. Fieser, Ph. D.. Sheldon Emory, Professor of Oiganic ChemiEtry; i{arvard University. Field: Chemistry of Carcinogenic Hydrocarbons. Jacob~ Farth. MLD., Professor of Pathology. Columbia University. and I)iiector of Pathology Laboratories, Francis Delafield Hospital, New York. N.Y. Field: Cancer Biology. John B. Hickarn, M.D., Chairrnan, Department of Internal Medicine; Uni- versity of Indiana, Indianapolis. Fields: Internal Medicine, Physiology of Cardiopulmonary Disease. Charles LeMaistre, M.D., Professor of Internal' Medicine, 'I1heUniversity of Texas Southwestern Medical'School, and Medical Director, a'oodlaNN n Hos- pital, Dallas, Texas. Fields: Internal Medicine, Pulsnonary Diseases,. Preventive Medicine.. Leonard M.. Schuman, M.D.. Professor of Epidemiology, L niversity of 1linnesota School of Public Health, Minneapolis. Field'i:~ Health and Its. Belationshipto the Total Environment. Maurice H. Seevers, :11.D.,,Ph. D.. Chairmam Department of Pharmacology. Fniversity of Michigan, Anni Arbor. Field': Pharmacology of Anesthesia and Habit-Forming Drugs. Chairman: Luther L. Terry,, MI.D., Surgeon General of the United! States Public Health Service.

Vice-Chairman: James M. Hundley, M.D., Assistant Surgeon General for Operations, United States Public Health Service. Staff 1)irector 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.

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i 4

Chapter 2 CONDUCT OF THE STUDY The work of the Surgeon General°s Advisory Committee on Sinoking and llealth was undertaken, organieeds and pursued with independence, a deep sense of responsibility, and with full appreciation of the national' importance 4 the task. The Committee's constanfl desire was to carry out in its own way. with the best obtainable advice and cooperation from experts outside it; membership, a thorough and objective review and evaluation of available information about the effectsof the use of various forms ofl tbbaccoupon the hvalth ofl human beings. It desired that the Report of its studies andijud'g- nwnts should! be unquestionably the product of its lhbors and its authorship. With an,enormous amount of' assistance from 155 consultants, from members and associates of the supporting staff, and' from several organizations and institutions. the Committee feelsthat, adocument of adequate scope, integrity, and individualitv has been produced. It is emphasized, however, that the ;,untent and judgments of the: Report are the sole responsibility of the Committee. at the outset, the Surgeon General emphasized his respect f'or the freedom 4 the Committee to proceed with the study and! to report as it saw fit, and he i4ecl,t*ed all support'; possible from the Unit'ed! S'tatesPublic Health~ Service,. ['he Service; represented~ chiefly by his office, the National Institutes oflH'ealth, the National Library of Medicine, the Bureau of State Services, and the Na- tionall Center for Health~ Statistics, furnished the able and devoted personnel :hat constituted the st~aff at the Committee's headqparters iniWashington, and provided an extraordinary variety and volume of supplies, facilities an& re- ~:ources. In addition, the necessary financial support! was made available by the Service. It is the purpose of this sectioni 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 9-10, 1962,, but this had to be 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 internali environments and make-up of humani beings. It 1Nas soon found to be impracticable to attemptito d'o all of this in any reason. able length of time, and certainly not under the urgencies of the existing sit~uation., The finallplan was to give partieularattention to the cores of prob- lems of the relationshipof uses of tobacco, especially the smoking of ciga- rettes, to the health of men and women, primarilyy in the United States, and 13 a

to deal wit6 the material from~ both a general viewpoint and on the basis of So dlsea.~e categories. u1 . As may be seen in a glance at the Table of Contents of this Report, the main topical divisions of the study were: ~ fs • Tobacco and tobacco smoke, chemical and physical characteristics ~ rr (Chapter 6). f al • Nicotine, pharmacology and toxicology (Chapter 7). • Mortality, general and specific, according to age, sex„disease, and smok- n ing habits, and other factors (Chapter 8). M • Cancer of the lungs and': other organs; carcinogenesis; pathology, and ti epidemiology (Chapter 9). • Non-neoplastic diseases of the respiratory tract, particularly chronic r bronchitis and emphysema. with some consideration of the effects of 11 air pollution (Chapter L0) . i • Cardiovascular diseases, particularly coronary artery diseases (Chapter ~ 11). • Other conditions. a miscellany including gastric and duodenal ulcer, peri'natal disorders, tobacco amblvopia, accidents (Chapter 12)~. • Characterizatiom of' the tobacco habit and! beneficial effects of tobacco (Chapter 13). 1 • Psycho-social aspects of smoking, (Chapt'er 14)1_ ~ • Morpholbgical constitution of smokers (IChapter15). As the primary duty of' the Committee was to assess information about th ki * " ki d h l i h l h f' ng an ma ng e smo ea t rement was t at o , a major genera requ information available. That requirement was met in three ways. The first and most im>>ort'ant was the bibliographic service provided by the National Lihrary ofl Medicine. As the annotated monograph by Larson, Haag; and ~ ~ Silket'te-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 souree_ the National Library of Medicine wasrequested to compile a bibliog- raph}• (by author and by subject), covering the world literature from 1958 to the present. In compliance with this request, the National Libr~ary 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 locathoni 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 need'ed for study by members of the Conimitt'ee. In addition, the members drew upon the libraries and bibliographic services of those institutions ini which they held academic positions. A considerable volume of copies of reports and a number of special articles were received from a variety of additional sources. Alll of the major companies manufacturing cigarettes and other tobacco products were invited to submit statements and any information pertinent to the inquiry.. The replies which 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

sourc.e-, much valuahle information was obtained; son-ie of it new and hithertoo unpublished. In addition to the special reports prepared under contracts. manv,con- flerencesv seminar-like meetings. consultations. visits and correspondence madeavailablp to the Committeeal lar,e amount of material and ai consider- able amount ofwell-inform4and well-reasoned opinion and' advice. To deal in depth and! discrimination with thetopics listedlabove. the Com- mittee at it's first meeting formed subcommittees with much overlapping in~ ineneber=hip. Tihesesubcommitteesw-eretihe main forces engaged in collec- tion. analn-.sir. and evaluation ofl data from published reports. contractual' r,,ports. discussions at confierences: and from sorne new prospective studies"'Programmecl and carried out generously at' the request of theCommittiee.'Iiir~e will' heacknowledged more fully el~esclier~einthisReport. The first i1,rmulations of conelusionswere made by these subcommittees. andl these~ MT(' submittled tot'he fulll Committee for revision and adoption after debate. 1t the beginnin,, and until the Committ'eebegan to meet routinely in I vo4uti~e session, it had the adkantage of attendance at its meetings of oh- -t•r%,0rsfrom otlier Federalagencies: There were representatives fromthet,~)llhm,inr• a=encies: EsecutiveOffice of t'hePresident ofl the United States. Fr~_lural Trad!* Commission. Department of Commerce. Department ofA-ri- ~ulturc. and theFood and Drug~ Admiilistration., Serving as moret'hani ob- ~~r~f n, and reporters to their agencies. when thev were present or by «,rittrn communication, they supplied the Committee with much useful infii,rmatlion. Thcre were an uncountednuunber of inectiii_s of subcommittees and other i0 ~=er gatherings. Petweeni Aovemlier 119f>2 and December 1963, the full t:ommi'ttee heldlnine sessions each lasting from two tof'ourd'aysin Washing- h,u or Bethesda. The main matters consi'deredl at the meet6n_sin October. \on-ember, and December196.3' were the review and revision of chauters. l is f l i ' ca scrut !IN o cone us ons; andlt he innumerabldtilf thi eeas oecompos- t:iun and editin~ of this comprehensive Report. 714-422 0-64-3' 15 - ~.._._.~_.,~:.~....

U37sss93

Chapter 3 Criter ia f or Judgment

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Chapter 3 CRITERIA FOR JUDGMENT Tn makinl- critical appraisals of datal and! interpretations andin, formulat- iv, its own conclusions; the Surgeorr General's Advisory Committ'ee on ~'mfokinaand, Health-its individual members and it's subcommittees and the (`ommitt'eeas a: whole-made decisions or judgments at three levels. These I,~velswere: I. JIudgment as to the validity of a publication or report. Entering intoo 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. designand scope of the investigation, adequacy of facilities and resource;, adequacy of controls. 11. Judgment as to the validity of the interpret'ations placed by investigators upon their observations and dlita. and as to the logic and justification of their conclusions~ 111. Judgments necessarv for theformulatiion of eonclhsions within the. Committee. The priniary reviews. analyses and evaluations cnfl publications and unpub- lil,hed reports cont'aining, data,, interpretations and conclusions of authors ~+eremadeMv inditi,idual members of the Committee and'. in sonreinst'ances„ hn- consultants. Their statements were next reviewed and evaluated by a; ~.ubcoinmittee. This was followedlat aniappropriaUe time by the Committee's cniticali consideration of a~ subcommittee's report. and bvy decisions as to the selection of material for inclusion inithe drafts of the Report, together with drafts oftheconelusionssubmitted bv subcommittees. Finallv; after re- peatedlcritical reviews of drafts ofi chapters. conclusions were formulat'ed and ,idopted by the whole Committee. setting forth the considered j udbmcnt of the Committee. It is not the intention of this section to present an essay on decision,making. Nor does it seem necessary to describein detail the criteria used' for making, scientific judgments at each of the three levels mentioned above. All mem- bers of the Committee wcre schooled in the high standards and criteria im- plicit ini making scientific assessments; if any member lacked even: a small part of suchi schooling he received it in good measure from the strenuous debatesthat tookptaceat' consultations and at meetings of the subcommittees and the whole Committee. CRITERIA OF THE EFIDEDIIOLOGIC METHOD It is advisable, however., to discuss briefly certain criteria which; although applicable walU judgments involved in this ReportL were esper_iallysignificant for judgments based upon the epidkmiologicmethod. Im thisinquir~ythe. 19

epidemiologic method was used extensively in the assessment of causal fac- tors in the relationship of smoking to health among human beinrs upon whom direct' experimentation could not be imposed: Clfinieal; pathological and ex- perimental evidence was thoroughly considered and' often served to suggest an hypothesis or confirm or contradict other findings. When coupled witL the other data, results from the epidemiologic studies can provide the basis upon which judgments of causality may be made. Iwcarrying out studies through the use of this epid'emiologic 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, thenithe 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, goesbey.ond any statement of statisticali probability. To judge or evaluate the causal significance of the association between theatt'ribute or agent and the disease, or effect upon health, ai number of criteria must be utilized, no one oflwhichiis 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 associationi d) The temporal relationship of the association e) The coherence of the associationi 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 ofl this inquiry were constantly and inevitably aroused in the minds of the members because they were preoecupied! with~ the subject of theirinvestigat'2on-"Smoking, and Health." Without summarizing the more important concepts of causality that have determined human attitudes and actions from, the days even before Aristotle, 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 rregard to causality an& 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 (variable man)' and a complex agent (tobacco and its products, partic- 20.

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Summaries and Conclusions 0 w ~ U1 M 0 0

Contents Pa e g A. BACKGROUND AND HIGHLIGHTS .......... 25 Kinds of Evidence . . . . . . . . . . . . . . . . . . 26 Evidence From the Combined Results of Prospective Studies . 28 Other Findings of the Prospective Studies ...... 29 Excess Mortality . . . . . . . . . . . . . . . . . 30. Associations and' Causality . . . . . . . . . . . . . . 30 The Effects of Smoking; Principal Findings 31 Lung Cancer . . . . . . . . . . . 31 Chronic Bronchitis and Emphy sema . 31 Cardiovascular Diseases . . . . . . . . . . . . . . 32 Other Cancer Sites . . . . . . . . . . . . . . 32 The Tobacco Habit and Nicotine . . . . . . . . . . . 32 The Committee's Judgment in Brief . . . . . . . . . . 33 B. COMMENTS AND DETAILED CON'CLUSIONS .... (A Guide to Part II of the Report). 33 Smoke . . . . . . . . . . . . . . . . . . . . 33 Characterization of the Tobacco Habit . . . . . . . . . . 34 Pathology and Morphology . . . . . . . . . . . . . . . 34 Mortality . . . . . . . . . . . . . . . . . . . . . . 35 Cancer by Site . . . . . . . . . . . . . . . . . . . . 37 Lung C an cer . . . . . . . . . . . . . . . . . . . 37 Oral Cancer . . . . . . . . . . . . . . . . . . . . 37 Cancer of the Larynx . . . . . . . . . . . . . . . 37 Cancer of the Esophagus . . . . . . . . . . . . . . 37 Cancer of the Urinary Bladdler . . . . . . . . . . . 37 Stomach Cancer . . . . . . . . . . . . 38 Nbn-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pulmonary Emphy sema . . . . . . . . 38 Cardiovascular Disease . . . . . . . . . . . . . . . . . 38 Other Conditions . . . . . . . . . . . . . . . . . . . 39 Peptic Ulcer . . . . . . . . . . . . . . . . . . . 39 Tobacco Amblyopia . . . . . . . . . . . . . . . . 39 Cirrhosis of the Liver . . . . . . . . . . . 39 Maternal Smoking and Infant Birth Weight ..... 39 Smoking and Accidents . . . . . . . . . . . . . 39 Morphological Constitution of Smokers . . . . . . . . . 39 Psycho-Social Aspects of Smoking . . . . . . . . . . . . 40 List of Tables 1. Deaths from selected disease categories, United States, 1962 . 26 2. Expected and observed deaths for smokers of cigarettes only and mortality ratios in seven prospective studies ..... 29 24 Chemistry an& Carcinogenicity of Tobacco and Tobacco

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 l.ung 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' die& 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: Ini the short period since 1955, deaths from lung cancer rose from less than 27;000 to the 1962 total of 41,000. This extraordinary rise has not been recorded for cancer ofl 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 1940, to 396,000 im 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 1.-Deaths from selected disease categories, United'Sta2es, 1962~ Cause of death' Degenerative andiarteriosclerotic heart disease, including coronaryy disease (420„ 422) -------------------------------------------------- Hypertensive heart disease (440-3)!______-_ ---------------- Cancer oflune~(16'2-3)-.-____________________________________________ Ciirhosia ofliven (581)---------------------------------------------- i3ronchitis and emphysema (502, 527.1) :________________________-_--- Stomach and duodenal ulcers (51I1-1) -.__-_------------------------- Cancer~.ot bladder.(181)--------------------------------------------- Cancer~of oral cavity(140-8)------------------------------ Caneer ofesophacns (180)------------------------------------------- Canoer of larynx (lCll.. ----------------------------- A11 above causos------------------------ ------- All othcr cauxrs --------------------------------------------------- .alllcrausc.s.---------------------------------------------------- •International Statistical Cl9ssiflcationmumbers in parentheses. 'Potal 577;918 6'2.17fi 41, 376 21,824 15,104 12, 22S 8,081 fi. 481 5, 0R4 2,417 752,691 1,004,027 1, 7.56, 720 Males ' 349,604 26. ,654 35,312 14; 329 12,937, 8, FL'iB 5,,R7.5 4,920 3,973 2;172 Females 229,314 35,522 fi, 0fi4 7,495 2,167 3.392'. 2. Sbr' 1,561 1, 115 245 994, 79 ~ 761.931 Nearly 70 million people in~ the United States consume tobacco regularly. Cigarette consumptioni in the United States has increased markedly since the turni of the Century, when per capita consumption was less than 50' cigarettes a year. Since 1910, when cigarette consumptioni per person (15 years and older) was 138;it rose to1,365 in 1930, to 1,828 in 1940: to 3,322 in 1'950, and to a peak of 3,986 in 1961. The 1955 Current Population Survey showedl that 68 percenC of the: male population and 32.4 percent of the female population 18 years of age andl 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 eapit'a consumption of cigars declined f'roum 117 in 1920 to 55 in 1962. Consumption of pipe t'obacco; which reached a peak of 21/Z 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 withi increased deat'hs in a; number of majpr disease categories. It was in this setting that the Committee began its work to assess the nature and magnitude of the health hazar~d attributable to smoking. KINDS OF EVIDENCE In order to judge whether smoking and ot'her tobacco uses are injurious to health or related to specific diseases, the Committee evaluated three main kinds of scientific evidence: 1. Ani.mal experirnents:-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 aompoundh) have been~ established as cancer-produoing (carginogenic). Other substances in tobaccoo and smoke, though not carcinogenic themselves, promote cancer production or lbwer the threshold to a known~ carcinogen. Several toxic or irritant gases contained in tobacco smoke produce experimentally the kinds of non-cant cerous damage seen in the tissues and cells of heavy smokers. This includes 26

f,uppression of ciliary action that normally cleanses the trachea and bronchi, damage to the lung air sacs, and to mucous glands and goblet eells which produce mucus. 2. Clinical aad 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 thanl two layers of basal ce115), and presencee of atvpical cells-are much more common in the lining, laver (epithelium) (if the tracheal 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 changesregularly found at autopsy in patients with chronic bronchitis are more often present in the bronchil of smokers than non-smokers. Pathologicallchanges in the air sacs and other functional tissue (,f the lung (parenchyma) have a remarkably close association with past hi.~torv of cigarette smoking. 3. Population studies.-Another kind of evidence regarding ani associatfion, bo«-een smoking and disease comes fYom epidemiological studies. In retrospective studies; the smoking histories of persons with a specified! liQea~e (for example, lung cancer), are compared with those of appropriate control groups without the disease. For lung cancer alone, 29suchiretrospec+ tiN e 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- prnrtionatelymore cigarette smokers are found among the lung cancer patients than in the controll populations without lung cancer. Extensive retrospective studies of the prevalence of specific symptoms and signs-chronic eough, sputum production; breathlessness, chest, illness, and decreased lungf'nznctuon-consistently show that these occur more often in cigarette smokers than in non-smokers. Some of these signs and symptomss 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 epid'emiological evidence on the relation of smoking and mortality comes from seven prospective studies which have beenl 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 tbt~aldeath rates and death rates by cause to be computed for smokers ofi 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 overalll 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 aonclhisions. 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 relationl to the disease is the crucial question. For such judgments all three

lines of evidence are essential, as discussed in more detail on pages 26-27 of' this Chapter, and in Chapter 3. The experimental, clinicali and pathological evidence, as well as data from population studies, is highlighted in Section B of this Chapter, which im 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 RESULTS 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 1,123,000' men who entered the seven prospective studies and who provided usable histories of smoking habits (and other characteristics such as age), 37,3911 men died during the sithsequent 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 114, disease cate- gories for which the mortality ratio of cigarette smokers to non-smokers was 11.5 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 lfisted'in the table as well as for the 14 disease categoriess shown. ) In the combined results from the seven studies, the mortality ratio of cig- arette smokers over non-smokers was particularlyy high for a number of diseases: cancer of the lung, (10:8) , bronchitis and emphysema (16.1), can- 28

at the earlier ages (40-50) represented in these studies, and declines witli I than for non-smokers, even for men who smoke 10'or more pipefuls a day` and f'or men who have smoked pipes more than 30 years. who have been smoking more than 30' years and who inhale the smoke tq some degree. The death rates for pipe smokers are little if at all higher smoking more thani 5 cigars daily, death rates are slightly higher. There is some indication that these higher death rates occur primarily in men less than 5 cigars a day are about the same as for non-smokers. For men also investigated! in the seven studies. The death rates for meni smoking Possible relationships of death rates and other forms of tobaeco, use were increasing age. Excess Mortality A Several of the reports previously published on the prospective studies ' included a table showing the distributioni of the excess number of deaths ' of! cigarette smokers among the principal causes of death. The: hazard' must be measured not onlyy 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 too the excess number of deaths of cigarette smokers over non-smokers, with lung, cancer uniformly in~ second' place. For all seven stud'1es combined,, coronary artery disease (with a mortality ratio of 1.7) acaounts 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 f'or more than 85 percent of the higher death rate among cigarette smokers, they are of particular interest topulilic health authorities and the medicall profession. ASSOCIATIOnS AND CAUSALITY assessment! . of causal factors in the relationship of smoking to health~ among human beinns upon whom direct experimentation could not be imposed.Clinieal. pathological„and experimental evidence was thoroughly considered: an& often served'to suggest an hypothesis or confirm or contradict other findings. Whern coupled with the other data, results, from the epidemiologic. The array of information fromi the prospective and retrospective studies of ~ smokers and non~smokers,clearlv establishes an association between cigarette ~smoking and substantially higher death rates. The mortality ratios ini Table ~ 2 provide arr approximate index of the relative strength of this association, _~ for all causes of death and for1I4disease categQries. In thisincluiry theepidemiologic method was used' extensively ini the ~ 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 lea& 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 deat'h, rates of females. The total number of excess deaths causally related too cigarette smoking in the U.S: population cannot be accuratel, estimated. In view of the continuing and mounting evidence from many sources, it is the judgment of the Committee that cigarette smoking contributes sub- stantiallv to mortality from certain specific diseases and to the overall death rate. Lung Cancer Cigarette smoking is causally related to lung cancer in men; the maYni- tudeof the effect of cigarettesmoking, 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 dav, and is diminished by dis- continuing smoking. In comparison with~ non-smokers: average male smokers of cigarettes have approximatelv a 9- to 10-fold risk of developing lung cancer and heavy smokers at leasta 20-fold risk. The risk of developing cancer of the lung for the combined' group of pipe smokers, cigar smokers, an& pipe and cigar smokers is greater than for non-smokers„but much1essthan for cigarette smokers. Cigarette smoking, is much more important thani occupational exposures in the causation of lungcancerin the generallpopulation,. 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- chitisand emphysema. Arelationshipexist's between cigarette smoking andemphysema; 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 bulkofithe population ofl the L nited! States, the relative importance of cigarette smoking as a: cause of chronic broncho~pul'tnonary, disease is muchi greater than atmospheric poll'ution or occupational exposures. 31 714-422 0-64-4

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 coronaryy disease is not proveni 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 uncert'aintyremains. 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, an& 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 associationi exists between tobaccoo use and cancer of! the esophagus, and between cigarette smoking and cancer of the urinary bladder in mens but the data are not adequate to decide whether these relationships are causaL Data oni an association between smoking and cancer of the stomach are contradictory and incomplete. THE TOBACCO: HABIT AND NtCOTIN'E The habitual use of tobacco is related primarily to: psychological and social drives, reinforced and perpetuated by the pharmacological act'ions of nicotine. Social stimulation appears to play a major role in a young person's early and first experiments with smoking. Nb 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 begjnning, 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 smalll d'oses 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 beneficiall 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. rs

,l i 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 Uhited 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 en& of this section in bold-faced type for convenience of reference. In the interest of conciseness, the documentation and most of the discussioni are omitted from this condensation. Together withi the tables of contents which appear at the beginnina of, each chapter ini Part II, it is intended as a guide to the Report. CHEMISTRY AND CARCINOGENICITY OF TOBACCO AND 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 prodticed by the application of tobacco extracts, smoke, or condensates to the lung or the tracheobronchiall tree of experimentall animals with the possible exception of dogs (Chapter 9, p. 165). Bronchogenic carcinoma has been produced in laboratory animals by thee administration of polycyclic aromatic hydYocarbons, 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 variet'y (Chapter 9, pp. 166-1$7)l. Seven polycy,clic hydrocarbon compounds isolated from cigarette smokee have been established to be carcinogenic in laboratory animals. The resultss of a number of assays for carcinogenicity of tobacco smoke tars present a puzzling anomaly: the total tar fromi cigarettes has manyy t'imes the carcino- genic potency of benzo{a)'pyrene present in the tar. The other carcinogens . known to be present in tobacco smoke are, wit'h, the exception of dibenzo(a,i) pyrene,,much less potent'thanibenzo(a)pyrene and'.they are present in smaller amounts. Apparently, therefore, the whole is greater than the sumi of the known parts. This discrepancy may possibly be due to the presence of cocarcinogcns 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 lo:

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 mamalso (Chapter 9, pp. 146-148') . Genetic factors play a: significant role in the development of pulmonary adenomas ini mice. It is possiblc that genetic factors can influence the smok- ing habit and the response in man to carcinogens ini 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 showni 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. 611 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 13i p. 354) . The tobacco habit should be characterized' as an habituation rather than~ ani ad'diction. Discontinuation of smoking, although possessing the difficul- ties attendant upon extinction ofany conditioned reflex, is accomplished best by reinforcing, factors which interrupt! the psychogenic drives: Nicotinee substitutes or supplementary medications have not been, proven to be of majpr benefit in breaking the habit (Chapter 13„p. 354). PATHOLOGY AND MORPHOL,OGY Several types of epithellal changes are much more eommoni 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 nucleiL 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 menwhosmoked, 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 atypical cells than do men. Older men smokershavsmore:atypicalcells 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 epitheliall hyperplastic ]ksions withi many atypical 34 i

I cel.ls, as seen in the bronchi of cigarette smokers, are probably premalignant (Chapter 9,,pp.167-173 ) . T yping o f Tumors.-Squamous and oval-cell carcinomas (Group I of Kreyberg's classification) i comprise the predominant types associated with the increase of lung cancer in the male population. I'n several st'udies, adenocarcinomas (Group fI)have 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 histologicali types as an index of the magnitude ofl increase in lung cancer is of' limited value (Chapter 9, pp. 173-175). Functional and Pathological Ch.angvs.-Cigarette smoke produces signif- icant funtional alterations in the trachea, bronchus, and lung. Like several other agents, cigarette smoke can~ reduce or abolish ciliaryy motility in experi- mental animals. Postmortem examination of bronchi from smokers showss a decrease in the number of ciliated cells, shortening of the remaining cilia,, and changes ini goblet cells and mucous glands. The implication of these morphological observations is that functional impairment would result. In animal experiments, cigarette smoke appears to affect the physical characteristics 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 elearance mechanism breaks down under the stress of protracted hi~h-level exposure to cigarette smoke, and smoke components accumulate in the lungs of experimental animals (Chapter 10, pp. 269-2 70) . The chronic effects of cigarette smoking upon pulmonary function aree manifested mainly by a reduction in- ventilatory function~ as measured by the forcedlexpiratory volume (Chapt'er 10, pp. 289-292 ). Histopathological alterations occur as a result of tobacco: smoke exposure in the tracheobronchiall tree and in the lung par~enchyma 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 ofl smokers than non-smokers. Cigarette smoke produces significant functional alterations in the upper and lower airways to the lungs. Such alterations could he expected to interfere with the cleansing mechanisms of the lung. Pathologieali changes in pulmonary parenchyma, such as rupture of alveolar septa (partitionsofl the: air sacs)~ and fibrosis, have a remarkably cl'ose association with past history of cigarette smoking. These latter changes cannot be related! with certainty to emphysema or other recognized diseases at the present time (Chapter 10, pp. 270-275) . MORTALITY The death rate for, smokers of cigarettes only, who were smoking at the time of entry into the particular prospective study. is about 70 percent higher than that for non-smokers. The death rates increase with the amount smoked.. For groups of inen smoking less than 10, 10-19, 20-39, and 40 cigarettes and over per day, respectively, the deathi rates are about 40 percent, 70 per- 35

cent, 901percent„ and 120percent higher than for non-smokers. The ratio of the death rates of smokers to non-smokers is highest at the earlier ages (40- 50) represented1n these studies, and declines with increasing age. The same?-7 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 mor- tality ratio fbr al given amount of smoking, was greater for inhalers than for t' non-inhalers. Cigarette smokers who had stopped smoking prior to enrolb ment in the study had mortality ratios abouti 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. 96). Death rates of cigar smokers are about the same as those of non-smokers for men smoking less tham 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 deat4 rnate occurs primarily in meni 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, eveni with men smoking 10 or more pipefuls per day and with meni 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 o f Deatii.-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 an& 2.0. The explanation of the moderate elevations in mortality ratios in this large group of causes 35 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 alfio 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). Im all sevem 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 number of cigarettes smoked per day, and is diminished byy 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, but much less than for cigarette 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 be established. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of iobacco use, their causal implications cannot at present be stated (Chapter 9, pp. 204-205). Cancer o fthe Larynx Evaluation of the evidence leads to the judgment that cigarette smoking is a significant factor in the causation of laryngeal cancer i n 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 o f 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 from chronic bronchitis. A relationship exists between pulmonaryy 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 froni 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 adkninist'ration cause acute cardiovascular effects similar t'o~ those induced by stimulation of the autonomic nervous system, but these effects do nott account well for the observed association between cigarette smoking and coronary disease: It is est'ablished 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 welll 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-age& and elderly males in the United States. Other factors such as high blood pressure, high serum eholesterol~ 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' stYongly enough to be a major reason for taking countermeasures against'~ them. It is al5o more prudent to assume that the established association bet«-een 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 arteryy 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). [ Cirrliosis o f the Liver 4 Increased mortalitv of smokers from cirrhosis of the liver hass been shown in the prospective studies. The data are not sufficient to support a direct or causal association (Chapter 12, p. 342). Maternal Smoking and In. f ant 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 an}- influence on the biological fitness of the newborn (Chapter 12, p. 343). Smoking and Accidents Smoking is associated with accidental deaths from fires in thee home. No conclusive information is available on the effects of smoking on traffic accidents (Chapter 12, p. 345). MORPHOLOGICAL CONSTITUTION OF SIVLOKERS The available evidence suggests the existence of some morpholog - M ical differences between smokers and non-smokers, but is too meagerYo permif a conclusion (Chapter 15, p. 387). 39 IN

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 studies has shown a single variable whi&is found solely in one group and is completelyy 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- ing-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 ). 40 i

PART II Evidence of the Relation Between Smoking and Health ~.#..

03'765619

I

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 44 uk~ .: 4~' -.-__ :.

Chapter 5 CONSUMPTION OFTOBACCO PRODUCTS IN THE UNITED STATES The U.S. Department of Agriculture estimates that~ the total number of persons ini the United States, including overseas members of the Armed Forces, who consume tobacco on a regular basis is close to 70 million (11). Consumption of! tobacco prod'ucts 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 3,958. Per capita cigar consumption re- mained steady at slightlv over 100 in the first two d'ecades of the century, but started to decrease in 1921. The figure for 1920 is 1117, and for 1962 it is 55. Per capita consumptionof'pipe tobacco remained steady until'the mid-1!940's. In 1945 the figure was 1.59 pound's, but in 1962 it was just over half a pound (0S6)i. Consumption of chewing tobacco showed a de- cline during about the same period, from 1.09 pounds per, capita in 1945 to 0.50 ini 1962. Consumption ofl snuff has showni very little change (2) (Table 1). TABLE 1-Consumption of tobacco produets per person aged 15 years and over in the UhitedStates for selected years,,1900-1'962 1" •eu I All tobacco, ' Cigarettes, pounds number Cigars, ~ nu nbc•r Ripetohacoo, pounds Che~ing tobaccu; pounds Snue, pounds LLNbI-------------- 7.42 49 111 1.63 4.10 0.32 L910!--------- ----- 8.59'~ 138'. 113 2.58 3199. .50 L920j _-------__ 8, 66 '. 611 117 1.96 3:06 .50 1930, ---_----------. 8.88I I 1,365 72 1.87 1.90 .46 L940--------------- 8.91 1,828 56.1 2.05 1.00 .38 1950 - _------------ 11. 59 , 3,322 50. .94 .78 i .36 1960--------------- 10.97 3,.888 57. .59 ' .51 .29 1961-- ------------ 11.15 3,986 56. .59 .51 .27 Lt62--------------- 10.85 3,958 i 55 .56 .50 .26 Struroe: Department.of,Agriculture;Economic Research Service. Starting in 1950, production of filter tip cigarettes began t'o, rise. Un« official estimates for 1950 show that only about half of one percent of! ciga- rettes produced were filter tip. In 1952, unofHcisli estimates show 1.3 per- cent of cigarettes produced were filter tips. In 1956 the figure had! reached 27.6 percentL From 1959 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 ini 1958'to 54.6 percent produeedl in1962(3)(;Table 2)1.

TAU[.E2.-Estinlatedoutput offiIter-tip cigarettes and percentage of total cigarette production, United, States, 1950-1962' 1-ear Filter cigare (billio ,tip, ttes ns) Percent of totall Year Filtff cigare (billio -tip trtes ns) PercenV of total 1950------------------ 2.2 0. 6 ~1957------------------ 16h13 38.0 1951i------------------ 3.0. 0:7 1958'----------------- 213. 0 46,3' 1952`----------------- 5.6 1.3 1959------------------ 238.8 4R:7 1953'---------- -------- 12: 4 2.9 1960.------------------ 25t3. 0 50:9 195t! 36. 9' 9.2 191i1--- ------ -- 277, 1 52.5 ----------------- 195 i- ---------------- 77. 0 18:7 ----- -- 19i;2-' ---------------- 292.5 54. 6' 193~6----------------- 116.9 27.6 'Data [ron11195'Sthrough 1962 are official estimates from Censusof3Yansifaeherera- Source: U.S:,Departmentof Agriculture; Economic Research Service: REFERENCES 1. U.S. Department of'~ Agriculture. Special report to the Surgeon General's Adt°isory, Committee on Smoking and Health. 2. UIS. Department of Agriculture. Economic Research Service. Tobaccoo products. Conbumption per capita. 115 y-ears and over, United States, 1900=62. 3. U.S. Departnlent' ufAgriculture. Economic Research~ Service. Thetobacco sit~uation.March 1962, .lkirch 1963, September11963. 4.6

Chapter 6 Chemical and Physical Characteristics of 'I'obacco and Tobacco Smoke 714-422 0-64-5

Contents' Page CHEMISTRY OF' TOBACCO . . . . . . . . . . . . . . . 49 COMPOSITION OF CIGARETTE SMOKE . . . . . . . . COMPOUNDS OF THE PARTICULATE PHASE 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 . . . . . . . . . CARCI\OGENIC HYDROCARBONS AND HETEROCY- CLICS IN TOBACCO SMOKE . . . . . . . . . . . . . COCARCINOGENS . . . . . . . . . . . . . . . . . . . . MECHANISM OF THE FORMATION OF CARCI\OGI-;\S. THE GAS PHASE . . . . . . . . . . . . . . . . . . . . EFFECTS ON CILIARY ACTIVITY . . . . . . . . . . . PESTICIDES AND ADDITIVES . . . . . . . . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . List of Tables' TABLE 1. Major classes of compounds in the particulate phase of cigarette smoke . . . . . . . . . . . . . . TABLE 2. Carcinogenic polycyclic compaunds isolated from cigarette smoke . . . . . . . . . . . . . . . . TABLE 3. Polycyclic hydrocarbons isolated from tobacco smoke . . . . . . . . . . . . . . . . . . . . TABLE 4. Some gases found in cigarette smoke .... ... 48 50 55 58 59 60 61 61 62 63 51 56 58 60

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 t'obacco as a curative agent. The species Nicotiana 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. alkaloid5, 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 inclndess the alkalbid nicotine and the related companion substances nornicotine, myosmine, and anabasine. These nitrogen-containing substances are all ;V CHa N H Nicotine /\ I H Nornicotine Myosmine Anabasine basic and hence extYactable with acid. Seven members of a second group of compounds fairly distinctive to tobacco have been isolated and charac- terized (1962-63):byD. L. Roberts and R. L. Rowland(i36). They are de- scribed as isoprenoids, since the structures are divisiblb into units of isoprene, the building principle of rubber, ofl the red pigment of the tomato, and of the yellbw pigment of! the carrot, as illustrated in the f'ollowing formulas: HaC~ C /CHa C"'C/C 1 HaC CElia C~r~~C'i C\('i C~~C .17 OH I I C C/C-"C,C C/C ~ C Isoprenoidltobacco component 4 Isoprene unit's Althoueh none of the 7 isoprenoid' components of tobacco has been isolated from another source, the hydrocarboni cernbrene from a pine exudate has the same ll4-membered ring with the same complement of an isopropyll group at Cl and methyl groups at G, Ce, and C=, (9). 49

COMPOSITION OF CIGARETTE SMOKE Cigarette smoke is an heterogeneous mixture of gases, uncondensed vapors, and liquid particulate matter (32) 1. As it, enters the mouth the: smoke is a concentrated aerosol with millions or billions of particles per cubic centimeter (25, 30). The median size of' the particles is about 0.5 micron (1). For purposes of investigating, chemical composition and biolbgical 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. The large quantities of material required for investigation of the chemical components are prepared on smoking machines (25) in which large numbers, of' cigarettes are smoked simultaneously in a fashion designed to simulate average smoking habits,, and a yellbw-brown 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.component's of the gas phase. The amounti of tar from the smoke of one cigarette is between 3 and'40 mg„ the quantity varying,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. each) 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 stilllanotlier study (3!1') 34,000' 70-mm. cigarettes were smoked mechanically on a constant puff-volume typee machine with which 35-ml. puffs, each of two seconds duration, were taken at one minute intervals from eachi cigarette. Eight puffs were required t'o smoke each cigarette to an average butt length of 30 mm. The smoke wass 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 t i

Proceduresfor 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 with that of an authentic sample and include one or more of the following: Rfl vallue observed in a paper chromatogram (41) ; order of elution from alumina; mass spectrometry. C0NNIPOIJNDS OF THE PARTICULATE' PHASE OTHER THAN HIGHER POLYCYCLICS This brief summary is based largely on the comprehensive review by. Johnstone and Pliinmer of the Medical Research Council at Ezet'er Uni- versitv, England! ( 241. It should be noted that water constitut'es 27 percent ofl the particulate phase. The major groups of compounds included are shown in Table 1. ALIPHATIC AND ALICYCLIc HYDROCARBONS rllnlost all ofl the possible hydrocarbons, C1 through, C4, saturated and unsaturated, straight-chain and branched-chaini have been reported to bee present in tobacco smoke. Intermediate, normally liquid' paraffins are pres- ent. All the CtG through Cg3 n-alkanes have been identified, as well as the Czr andCz,-C33isoparaffins. T,~BLE 1.-ll7ajor classes of compounds in the particulate phase o f cigarette smoke Class Pe p lat rcent in articu• e' phase Aciils----------------------------------- 7. 7-12 8 (,lveoroll,glgcol. alcrol ols---------------- 5. 3-8. 3 Aklehctiles anrl ketonas - -------------- 8.5 A9iphntic hydrocarhons,---------------- 4. 9 A'rom.uic h}..clror.ubons.---------------- 0i 44 I'hvnol -- - ---------------------------- 1 L 0-3. 8 Numher of compounds 25 18 21 64' 811 45 254 Toxic actibn on lung Some irritant Possible irritation Some irritant Some irritant Some carcinogenic Irritant'and possldlycocarcinogenio TERPENES AND ISOPRENOID HYDROCARBONS Isoprene;, the basic', unit of the terpenes and of higher terpenoids has been identified in cigarette smoke (i34) as have its dimers, dipentene and' 1',8-p- rnenthadiene. The triterpene squalene, consisting of six isoprene units and shown to be present in smoke (47,) is of, interest because of the possi- bility of its being cyclized to polycyclic compounds and because of its ready

H,c CH3 CH3 CH3 CH' CH, CHa CHJ Squalene reaction with air to form hydr~operoxides (which would be destroyed! during attempted isolation)'; a hydroperoxide der~i'ved from cholcsterot has been shown to be.carcinogenic (cancer-causing)i„ at least under certain conditions of administration ( 12). Phytadfienes, products of the dehydration of the diterpene alcohol phytol, are also present ini smoke and subject to air oxida- tion to hydroperoxides. H3C Phytol ALCOHOLS AND ESTERS CHsOH A wide variety of mono- andl dihvdric alcohols, both aliphatic andl 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. (i0.44 percent ). Grossman et al (13 ) found that pyrolysis of solhnesol at 500° C. gives isoprene, its dimer dipentene, and other terpenoid products and concluded that the alcohol is the sour~ceofl terpenoid compounds which are important factors in the flavor of tobacco smoke. 1 Ethylene glycol and g14-cerol have been found present ini 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 ethyll estersofl the Cz, C3, and C4 fatty acids, are present in smoke. Higher fatty acids are f'ound'lioth as free acids and as esters. STEROLS Stigmasterol„ /3:sitosterol, and y-sitosterol have been isolated from, to- bacco smoke. Indeed the: sterol fract'ion, is reported (,29) to constitute approximately 0:15 percent of whole, tar. The sterols are of interest as possible precursors of polycyclic aromatic hydrocarbons and because of, thee evid'ence, noted above, that sterol hydroperoxides can be carcinogenic. ALDEHYDES AND KETONES Most common aldehydes of lbw molecular weight (acetaldehyde, pro- pionaldehyde, acetone, methyl ethyl ketone, etc.) have been found present 52

i CHv CHa. 5Q0°3, "Ilj~ Isoprene CH: H3C-"C'~"CHs HaC" I Dipentene Solanesol (major, product) H,C-*' C CHs H,C HiC HIC HSC HaG HJC CHa CHs CHa in tobacco smoke, as have such dicarbonyl compounds as glyoxal and di~ aceqL Dipalmityl ketone exemplifies ket'ones of high molecular weight isolated from tobacco smoke. Dipalmityl ketone ACIDS A large number of volatile and nonvolatile acids of 1'owmolecular weight are present in~ tobacco smoke. Fatty acids of chain length C13 t'o C,g are reported to constitute 1 percent of the whole tar and the bulk of these acids are present in the free: form 146). Unsaturated f'atty 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 identifi- cation~ of complex tobacco phenols such as rutin and chlorogenic acid. The presence of simple phenol's in tobacco smoke was established as early as 1871. The phenol content of smoke became of increasing importance with OH HO Rutin O II' Ao"' CH = CHCO CO2H' HOi H OH Chlbrogenic 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 fromi one cigarette contains as much as 1 mg. of phenols (7)~. In addition to simple alky]phenols, 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 threee polh,cyclic heterocyclic compounds have also been identified in smoke (45)) and will be discussed later since:the three polycyclic compounds are carcino- genic. A pentacyclic compound related' to xanthene, namely 1,8,9-peri- naphthoxanthene, has been identified in smoke (45). 1,8,9-Perioaphthoxanthene 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 ,

It is estimated that't the main-stream smoke from one cigarette contains about 150 µg. of metallic constituents, which are mainly potassium (90 percent ), sodium (5 percent ); and traces ofi aluminum, arsenic, calcium, and copper. Arsenic is reported' to be present to the extent of 0.3-1.4 µg. ini the smoke of one cigarette. The inorganic compounds are most likely chlorides, but metals themselves may be present. Apparently beryllium is present ini tobacco in trace quantities, but is not volatilized in the smoking process (48). Nickel is present in cigarettes in trace amount's and may occur in main-stream smoke to a small extent, probably as the chloride (31). Spectrographic analysis has shown the presence of chromium in smoke at a levell of less than 0.06 µg. per cigarette. This level appears too low to represent a hazard (48). NONCA'RCINOG'ENIC ARO1iATIC HYDROCARBONS The aromatic hydrocarbons present in tobacco smoke have received ani enormous amount of attention since some of them are carcinogenic. Noncarcinogenic hydrocarbons of smoke containing one to three rings include benzene. toluene and other alkylbenzenes, acenaphthene, acenaph- th,,lene. fluorene, anthracene, and phenanthrene. Hydrocarbons of estab- IMhed carcinogenicity to mice all containi from four to six condensed rings. Hos,ever„ no less than 27 hydrocarbons containing four or more condensed ring$ which have been t'ested for carcinogenicity with negative results have been isol'atedl from tobaacosmoke tar. As methods of! separation an& identification improve, it is almost certain that additional hydEocarbons will be foundi present in smoke, because ahnost every conceivable ring system has been demonstrated to be present and the number of possible alkylated polycr~-clics isv.ery 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 coalltar distillates of established carcinogenicity to mice, discovered that dibenzo(a,h)anthracene(for f'ormul'a, seeTable 2 i preparedi by sN nthesis evokes skin cancer when applied to the skin of mice (11). The hvdrocarbon~ was recognized as different! from the carcino- gen of coal tar because its fluorescent spectrum did not match the character- istic three-banded spectrum of the tars. In 1933 Cook and co-workers (11) isolated the coal t'ar constittrent responsible for the characteristic fluorescence and identified iU as benzo,(a):pyrene. It is one of the most potent of all the carcinogens now knowns . ..~.::a..,_,. ~:.

TABi.E2.---Careinogenic Polycyclic Compounds Isolated'FromC'igarette. Smoke Compound Structure Carcino- Amount reported, genicity µg/1000 cigarettes 1. Benzo(a)pyrene + + + + 16 (ave. of 10 reports) 2. Dibenzo(a,i)pyrene I I 11I +++i, 0.02-10 (2 reports) 3. Dibenzo(a,h)anthracene I 1I 11 1 ++ 4 (1 report)', 4. Benzo(p)phenanthrene ~ ~ + not stated .5. Dibenz(a,j)acridine + 2.7 (,1 report)', l 6. Dibenz(a,h)acridine 7. 7H-Dihenzo(a;g)carbazole 56 + 0.1 (1 report) + 0.7 (1 report), 1

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 ofi hydrocarbons in the same relative order of potency. A compilation (and its supplement) prepared by J. L. Hartwell (16)~ of the National Cancer Institute lists 2108' compounda 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 idontified in tobacco smoke have already been documentedl in the Hartwell report and can be assigned a rating as very potent ( + . + + ) , potent ( -i- + + )~, moderately carcino- genic (+-f- ), or weakly carcinogenic ( i-- ) i( 31) . Many other such com- pounds studied are reported ini the Hartwell survey and in another by :A-rthur D. Little, Inc. (131). The rating assigned to dibenzo (ia,i) pyrene is based oni experiments with over 10,000 inbred mice in which one subcutaneous injection in the groin of 0.5 mg. of hydiocarbon in tricaprylin produced 50 percent sarcomas at the injection site in 14 weeks and 98 percent tumors in 24 weeks (20). Benzo(ia)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 caroinogenieity, are: benzo(j)fluoranthene and dibenzo~(a,1)pyrene. Identification of benzo(a)pyrene is reported in 19 separate investiga- tions; the amount giveni in the table per 1000 cigarettes (170! mm. long, weighing about 11.0 g, eac4 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 actuadly present. Wynder and' Hoffman~ (50) investigated this point by adding a know n amount of radioactive Cl}-labelled benzo (a) pyrene to a smoke condensate and applied the usual procedtire 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 (ia) pyrene finally isolated indicated a loss of 35-40 percent of carcinogen during proc- essing, The 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 tlie:other carcinogens in smoke are also at' least 1.5 times the reported amounts. Relatively littlie 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.

TABLE 3.-Polycyclic hydrocarbons isolated from tobacco smoke (µg. per 1000 g. of tobaea» consumed] Hydrocarbon Cigarett es Cigars Pipes ~ ----- Benzo(a)DSrene ---------------------------------------------- 9 34 85~ AeenaPhttiylene---------------------------------------------- 50 16 291 Anthracene------- ------------------------------------------- 109 119 1,100 Pyrene------------------------------------------------------- 125' 176 755 COCARCINOGENS Assays of'tobacco smoke tars for carcinogenicity are done by applying, a dilute solutiom 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. Appliea- 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 t'otal tar from cigaretrtes 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 erot'on oil, which itself is noncarcinogenic except in certain strains of mice (4a), on the action of hyd'rocarbon 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 potentiating 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)ianthracene, identified'in cigarette smoke, is very 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 forme& from un- sat'urated 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 dibenzo('a,i)'p~~-rene per 1000 cigarettes (Table 2) is 0.02µg. and another is 10pg. However: it is not necessary to wait for an exact balance of the two sets of data to draw a conclusiom from eachL The isolation, experiments, taken 58

alone, indicate that cigarette smoke contains a number of identified chemicals which are carcinogenic to mice. The bioassays suggest that cigarette smoke probably contains components which, acting 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 fattry acids, bo& of which, as previously mentioned, enhance the activity of known carcinogens: Cellulose acetate filters now in use remove 70-806 percent of acidic constituents of tobacco smoke. MECHANISM OPTHE 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 (44) reports formation of benzo(a)pyrene and pyrene on pyrolysis of stigmasterol, a smoke com- CHaCHi Stigmaeterol Benzo(a)pyrene -F 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)pyrene (50):. Hurd and co-workers (22) by careful experimentation have elaborated plausible mechanisms for the formation of polycyclic aromatics by pyrolysis of materials of lbw molecular weight at temperatures in the range 800-900° C: Posttilated radical intermediates are: (a) CHs=C=CH •*1 CHs-C-=CH (b) CH-CH=CH s-~ CH=CH--CH (c) CH=CH-CH=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

I It 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 benzti(a) pyrene. The: observation (2)that treatment of tobacco with copper nitrate decreases the benzo (la) 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 GAS PHASE The gas phase accounts for 60 percent of total cigarette smoke. Hobbs et aL (34, 35Y found that 98.9 mole percent of the: gas phase is made up of the following seven~ components: N1t'rogen----------------------------- 73 mole percent OxygeR------------------------------ 10 Carbon~dioxide----------------------- 9:5 Carbon-monoxide--------------------- 4:2' Wdrogen---------------------------- 1. Argon------------------------------. 0i6 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 which have been identified as present ini trace amounts. Some of these are listed in Table 4 (1). TABLE 4. Some gases found in cigarette smoke Compound Carbon Monoxifle--------- _____________ Carbon Dioxide __.____________________ Methane, ethane;,propane,~butane~, etc. A'cetM1lene, ethydene; propylene, etc_____ Formaldrhyde:_________________________ Acetalt3e}lyde--------------------------- Acroleini ------------------------------ Methanol - ----------------------------- Acetmie . - - - - - - - ______- - __________ - Mcthyl ethy~iiketone____________________ Ammonia - ---------------------------- Nitto~en.l)iokide_______________________ 11eth}rl Nitnte __ _ _______ r[cdtogen 8ulfele ______________________ Hy tiogen Cy-anide_____________________ Methy] Chloridc-__-____________________ Concentra- tion (PPm). 42, 000 92,000 87,000 31,000 30 3,200 150 ' 700 ; 1,100 1 500 1 300 250 2~ 40 1,600 1:,200 Sate level for induxtrial I expasure' (PPrn) i 100 -------~--- Toxic action on IunK Unknown \mie None None Itritant~ Irritant IrritanU Irritant Irritant Irritant. Irritant Irr it ant Uhknowni Irritant Rl,spiratory enzyme pocson, Uilknowni 'Thevalues,listed refer.to time-weiqbted average concentrations forr a normal work day. 60 .,..^,- :.

® 9 EFFECTS ON CILIARY ACTIVITY* An important line of investigation was opened up by the report by Hilding (18) that cigarette smoke is capable of inhibiting the transport activity of ciliated cells such as found in the respiratorytract, It has been suggestedl (10; 17) that failure of ciliary function to provide a constantly moving stream of mucus enables environmental carcinogens to reach the epithelial cells. Kensler and Battista (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 80'percent and trap about 40~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 partSculhte 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 inhibitron~ of ciliary transport activity. Assays ofl known components of the gas phase showed the following compounds to possess such activity: hydFogerc cyanide, formaldehyde. acetaldehyde, acrolein, an& 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 11933 showed a range of 7.5-26A parts of As_0,3 per million, wit'h an average value of 13:9' ppm. (6). Coghill and Hobbs (8) found that main-stream smoke per of cigarettes containing 7.1 µg. of arsenic per cigarette contains0:031 ugr puff. This amount would be equivalent to.0.25 µg, of arsenic per cigarette (8 puffs), and hence a smoker consuming 2.5 packs of such cigarettes per day might inhale 12:5 µg. of arsenic per day. By comparison, analysis of the atmosphere of New York City over a 12-year period indicated an~ average contea ofl 100-400µg0 of arsenic per 10 cubic meters, which isan~ 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 tobaeco~ crop resulted! in a sharp de- *Thiss topic is dlscussed morefully, in Chapter 10.. 61 I

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 As20, (14). It seems unlikely that the amount of arsenic derived even f'rom unfiltered cigarettes is sufficient to present a health hazard. Chemicals recommended by the Department of Agriculture for the control of t'obaeco insects are: malathion, parathion„Endosulfan, DDT, TDE, endrin, 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 level§ approximating 013 percent and 1 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'rrum. Gl'yceroli and methylglycerol are looked on with disfavor as humectants be- cause on pyrolysis they yield the irritants acrolein and methylyglyoxal. Additives have not'been usedlin the manufacture of domestic~British cicarettessinee the Customs and Excise Act, of 11952, Clause 1176, and probably longer,, inasmuch as Section 5 of the Tobacco Act, ofl 1842' imposed a widespread prohibition on, the use of additives in tobacco manufacture. SUMMARY Of the several hundred compounds isolated from the tobaeco, 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 biologieal'properties, it is necessaryto deal separately with the particulatee phase and gas phase of smoke. Components of the particulate phase other tham 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. Sevem polycyclic compounds isolated from cigarette smoke have been established 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 subst'ancesisolat'ed from it. The difference may be associated! in part with the presence in tobacco smoke of cocarcinogens, 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., Nelsonj N. SpecialI report to the Surgeon General's Ad- visory Committee on Smoking and Health. 2. Alvord, E. T., Cardon, S. Z. The inhibitiomof formation of 3,4-benzpy- rene. Brit J Cancer 10: 498-506, 1956. 3. Berenblum„ L„ Shubik, P. The role of croton oil applications, associated withi 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-streami cigarette smoke. Agriculture and' Food Chem 9(3) : 193-7, 1961. 5. Campbell, J. M.,, Lindsey, A. J. Polycyclic hydrocarbons in cigar smoke. Brit I Cancer 11:1192r5, 1957,. 6. Carey, F. P., Blodgett, G., Satterllee, H. S. Preparation of samples for determination of arsenic: Oxygen-bomb combustioni met'hod. 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. Cogbill, E: C., Hobbs, M. E. Transfer of metallic constituents of ciga- rets to t'he 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 hydrocarbont J Amer Chem Soc 84: 2015-6, 1962.. 10; Falk, H. L.,, Tremer, H. M., Kotin, P. Eflect: 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. Fieser, L. F., Greene, T. W., Bischoffs F., Lopez, G., Rupp, J. J. [Com- munication to the editor] A carcinogenic oxidation product of choles- terol. J Amer Chem Soc 77: 3928-9;,1955. 13. Grossman, J. D., Deszyck, E. J., Iked'a, R. M., Bavley; A. A study of pyrolysis of solanesol. Chem Industr 1950-1962. 14. Guthrie, F. E., McCants, C. B., Small„ H. G., Jr. Arsenic content of, commercial tobacco, 1917-1958. Tobacco Sci 3: 62-4, 1959. 15. Hadlbr, H. L, Darchun, V., Lee, K. Initiation and promotion activity ofl certain polynuclear hydrocarbons. J N'at Cancer Inst 23: 1383-7, 1959. 16. Hartwell, J. L. Survey of'~ compounds which have been tested for car- cinogenic activity. Fed'erall Security Agency, 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 prodirced 12. 714-422 0-64-6 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 actioni ofl cow's lungs, the deposition of t'ar in the bronchial tree and removaliby ciliary action. New Eng J Med 254: 1155-60; 1956. 19. Holsti, P. Tumor promotfingeffects of somelonachaim fatty acids in experimental skin carcinogenesis in the mouse. Acta Path Microbiol Scand46: 51-8, 1959. 20. Homburger, F., Tregier, A. Modifyina,fact'orsin carcinogenesis. Progr Exp Tumor Res 1: 311-28, 1960. 21. Hurd, C. D., Macon, A. R. Pyrolytic formati'on of arenes. 4'. Pyrolysis of benzene, toluene and radioactive toluene. J Amer Chem Soc 84: 4524A-6, 1962 . 22. Hurd'y 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 ChemiSoc 84: .1509-L5, 1962. 23. Hurd! C. D., Simon, J. I. Pyrolh-tic formaYioni of arenes. 3: Pyrolysis of pyridine, picolines and methylpyrazine. J Amer Chem Soe84: 4519-24; 1962. 24. Johnstbne,, R. A. W., Plimmer, J. R. The chemical constituents of to- bacco and tobacco smoke. Chemi Rev 59: 885-936, 1959. 25. Keith, C. H., Newsome, J. R. Quantitative studies on cirarette smoke. 1. An automatic smoking machine:Tobacco 144: (113')~ 26-32. Mati~- 29, 1957. 26. Keithy C. H., Newsome, J. R. Quantitatia-e: 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 lungcancer. Brit '1led~ 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- masterol in cigarette smoke. Science 125: 991-2, 1957.. 30. Langer, G., Fisher, N. A. Concentration and particle size of cigarette- smoke particles. AM.V Arch Ifidustr Health 13: 3 72-8; 1956. 31. Liggett & Myers Tobacco Coi Arthur D. Little, Inc. Special repor6 to the Surgeon General's Advisory Committee on Smoking and Health. 32. Lindsey„A. J. Some observations upon the chemistryy of tobacco smoke. In: James, G., Rosenthal, T., eds. Tobacco and health. Springfield,. Ill!, Thomas, 1962. Chapter 2, pi 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: 557-611, 1958. 34. Osborne, J. S., Adamek, S., Hobbs, M. E. Some components of' gas phase of cigaret smoke. Anal Chem 28: 2111-5, 1956. 64

35. Philippe, R. J., Hobbs,, M. E. Some components of the gas phase of ciaaret smoke. Anal Chem~ 28,: 2002-6, 1956. 36. Roberts, D. L., Rowland, R. L. Macrecyclic diterpenes a and B-4, 8, 13-Duvatriene -L,3-diolsfrom tobacco. JI Org, Chemi 27: 3989-95, 1962. 37. Row1'andL R. L., Rodgman, A., Schumacher, J. N., Roberts, D. L., Cook, U! . 0., W'alker, W. E. 1963~ I In press)~. 38. Satterlee,, H. S. The problem of arsenic in American cigarette tobacco. New Eng JMed 254: 11-19-5:1, 1956. 39. Setala, H. Tumor promotin=, and co-carcinogenic effects of some non- ionic lhpophilic-hydlrophillc (surface active) agents. _lcta PatL Microbiol Scand f Suppl No. 115) p. 1-93~ 11956. 40. Shubik, P., Hartwell, J. L. Supplement 1, Department of Health, Edu- cationi and Welfare, PHS PubNoI 1k19;1957. 41. Tarbell, D. S., Brooker, E. G., Vanderpooly A., Conway, W., Cl'aus, C. J., HalL T. J. A system for paper chromotography of 3,4-benzpyrene, some derivates and other polycyclic aromatic hydrocarbons. J Amer Chem Soc 77: 767-8, 1955. 42. Touey, G. P., Mumpower, R. C. t1'leasurement of' the eombustion-zone temperature ofcig,arett'es. Tobacco 141: (8Y 18-22, Feb~ 22, 1957. 42a. U.S. Department of Agriculture. Insecticide recommendations of the. Entomology Research Division for the Control of Insects Attacking, Crops andlLivestock for 1963. Handbook No. 120, Agricultural Re- search Service and Federal Est'ensioni Service, 19631 43. Van Duuren, B. L. Identification of! some polynuclear aromatic hydro- carbons in cigarette smoke condensate. J Nat Cancer Inst 21: 1-16, 11958. -1=1. Van Duureny B: L. Some aspectsofl the chemistry of tobacco smoke. In: James, G., Rosenthal. T. eds. Tobacco and health. Springfield, I11L, Thomas, 1962. Chapter 3, p. 33-47. 45. Van Duuren, B. L. The polynuclear aromatic hydrocarbons in cig- arctte smoke condensate. 2. J\at Cancer Inst 21: 623-30, 1958'. 46. Van Duuren, B. L,. Schmitt, F. L. Ikolatiom and identification of some components of cigarette smoke condensate. J Org Chem 2° : 473-5,. 1958. 47. Van Duuren, B. L., Schmitt', F. L. Isolation and identification of squalene f'rom~ cigarette smoke condensate. Chem Industr, 1006-7„ 1958. 48. Williams, J. F., Garmon, R. G. Beryllium in cigaret tobacco. Tobacco Sci 5: 25- 7; 1961. 49. Wynder, E. L., Fritz, L.,, Furth, N. Effect of concentration of benzopy rene in skin carcinobenesis: J Nat Cancer Inst 19': 361-70; 1957. 50. Wynder, E: L., H'offinann, D. Present status of laboratoryy studies on tobacco carcinogenesis. Acta Path .llicrobiol Scand 52: 119-32, 1961. 51. Wynder, E. L.,, Hoffman, D. A study of tobacco carcinogenesis. 7. The role of higher pol~cyclic hn drocarbons. Cancer 12: 1079-86, 1959. 65

03765F43

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Contents Pa~e GE\ ERAL PII AR'~i ACOLOGIC ACTION OF NICOTINE ON NERVE CELLS . . . . . . . . . . . . . . . . . . . . 69 EFFECTS O-.N THE CENTRAL NERVOUS SYSTEM ... 69 CARD IOV'ASCULAR EFFECTS . . . . . . . . . . . . . . 70' GASTROINTESTINAL EFFECTS . . . . . . . . . . . . . 71 DISTRIBUTION AND FATE . . . . . . . . . . . . . . . 71 CHRONIC TOXICITY . . . . . . . . . . . . . . . . . . 73 SUAI MARY . . . . . . . . . . . . . . . . . . . . . . . 74 REFERE\ CES . . . . . . . . . . . . . . . . . . . . . . 75 Figure FicuREL Summary diagram of routes for the metabolism of nicotine in mammals . . . . . . . . . . . . . . . . . 72 68' O W ~ C: C11

Chapter 7 GENERAL PHARMACOLOGIC ACTION OF NICOTINE ON NERVE CELLS The pharmacology andl chronic toxicity of nicotine, in dosage comparable to the amounts that man may absorb from smoking or other use of tobacco. are pertinent to an evaluation of health hazard. The most notable action ofl nicotine involves a direct effect on sympathetic and parasympathetic ganglion cells (18~):. This~ usually occurs~ as aJransient excitation, follo« ed by depression, or even~ paralysis with effective doses. The: ganglia are rendered more sensitive to acetVlcholine initially and thus make preganglionic impulses more effective. Paralysis is associated with diminished sensitivity of'ganglia to acetylcholine and concomitant reduction in~ the intensity of postganglionic discharges. Similar effects occur at the neuromuscular junction, resulting in a curariform action in skeletal muscle with adequate doses (16). In~ the central nervous system, as in gangli'a, primary stimulation is succeeded bv depression. Furthermore, nicotine like acetylcholinediseharges epinephrine from the adrenal glands andl other chromaffini tissue (20; it also releases, antidiuretic hormone from the posterior pituitary bystimulatingthesupraopticohy.pophyseall system (3'). Nicotine also augments various reflexes by excitation of chemoreceptors in the carotid bod'y (10) . The pharmacological response of the whole organism at any one time therefore, representing as it does the algebraic sum of stimulant! and de- pressant effects resultina, from manM1- direct, reflex,, and chemical'mediaton influences on autonomic nervous transmission and excitability of virtually all or~gan systems, defies accurate description. The wide variation in smoking habits leads to everyy concei'vable pattern of fluctuating bl'ood levels of nico- tine during, the day. This suggests strongly that nieot7ne+sensitive eelk may be shifting continuously from excitation to depression. Such, activity prob- ably accounts for the unpredictable effects observed in different individual5 and in the same individual at different times. Using the classic pharma- cological approach, it is therefore virtually impossible to make reliable state- ment's regarding the effect of smoking on the many organ systerns: In order to characterize the biological effects oflnicotine iniman, it thus becomes neces- sary to place heavy reliance on, symptoms and signs derived from clinical and epidemiological studies. EFFECTS ON THE CENTRAL NERVOUS SYSTEM The action ofi nicotine on central nervous systemi functions has recently, been reviewed (20). Very litt'le of the reported, work involves human 69 l :~,.,>.v, - ~__,.. ._ . . .u.: . .,... : .,, ,..,. ~...~ .,., .... .,.

experimentation, and most of it is with doses much larger than are asso- ciated with the act of smoking. It suffices to note here that moderate doses of nicotine elicit marked! increases in respiratory, vasomotor, and emetic activity, and still larger doses lead to tremors and convulsions, both in ani- mals and man. The amounts absorbed even in heavy smoking may, produce transient hyperpnea through carotid' and aortic arch reflexes (5). The increase in blood pressure which is commonly observed' is partly central in origin. Nausea and emesis are more pronounced' in~ the novice smoker but may occur even in~heavy smokers with excessive use of tobacco. Electro- encephalographic (EEG) studies in the intact rabbit (21): indicate that nico- tine, in doses of 0.5 to 3:0 milligrams per kilogram, produced an "arousal, reaetion"' involving, the hippocampus. In a later stage of the same reaction there appeared a discharge pattern similar to that noted in convulsions. Lesions ini the septum~ abolished the "arousall reaction," chlorpromazine and evipan abolished' the discharge patterm None of the congeners of nicotine, including lobeline, produced similar patterns. Knapp and Domino (12) found! that concentrations of nicotine ('10 to 20 µg/kg), a levell commonly reached' in man by smoking, prod'uced EEG arousal patterns in four species of animals, the rabbit, cat, dog, and monkey, after neopontine transection. These effects did not appear to be related to fluctuations in blood pressure or to catecholamine or serotonin levels. In a study of electrical activity (as measured by electroencephal'ogram) in 25 human subjects before andl after smoking one cigarette, Lambiase and Serra (15) noted an 80 percent depression~ in~ voltage and an acceleration in frequency of' the alpha rhythm which remained unchanged in form during the recordings. These alterations were more consistent in~ subjects over 35 years of age and were attributed tb carbon monoxide and nicotine resulting in cerebral anoxia and/or release of epinephrine. Hauser et al. (9), who studied the EEG'changeson cigarette smoking, in healthy young, adults, ob, tained highlyy variable: responses usually toward an increase in the dominant alpha frequency of 1 or 2 cycles per second. Some subjects showed sim- ilar changes when puffing a glass cigarette stuffed with cotton and others when puffing specially prepared nicotine-free cigarettes. They concluded that the effects noted were more likely to represent a psycho-physiologic response to the act ofl smoking than to any substances present in cigarette smoking. Bickford (1) arrived at a similar conclusion. Wide gaps of information exist in this area and it is not meaningfull to attempt inferences concerning correlations of electrical events in the central nervous system and subjective effects of smoking from the type of evidence currently available. CARDIOVASCULAR EFFECTS The cardiovascular effects of nicotine are described in Chapter lil, Cardio- vascular Diseases. 70 J

GASTROINTESTINAL EFFECTS Most but not all experimental and clinical evidence supports the populkr view that smoking reduces appetite (6, 17 p. 27;1). This reduction has been attributed both to direct effects on gastric secretions and motility and! to reflexes arising, from local' effects on thelaste buds and mucous membraness in the mouthi The unpredictable and temporary elevation of blood sugar is probably too small to contribute significantly (17,, p. 326). Nicotine effects on the hypothalamus, comparable to the appetite reduction produeed by other stimulants like amphetamine, and psychological mechanisms may play significant roles (23). Hunger contractions are inhibited but gastric movements of digestion do not appear to be influenced signifieantly by mod'erat'e smoking, (4!). Nausea, often associated with, vomiting, is by f'ar the most common symptom related to thegastrointestinall tract. This effect probably origi- nates centrally in the medull'aryemetic chemoreceptor tTig,aer zone (14). It is now generally agreed that nicotine stimulates peristalsis but the mechanism is a complex one, probably involving local„ central and reflex actions. Schned'orf and Ivy (21)' found wide individual variation in gastro- intestinal passage: time in medicall student smokers and non-smokers but gained the impression that smoking, tends to augment motility of the colon. These effects are probably reltited to actions on the parasympathetic ganglia in the bowel. The summative effects of alll of these pharmacological actions on the whole intestinal tract do not produce a consistent' pattern. Excessive smoking may be associated with diarrhea, constipation, or alternating pat', terns between the two extremes. The only consistency is that symptomss attributable to nicotine effects on the gastrointestinal tract': are very common. DISTRIBUTION AND FATE Nicotine is actively and rapidly metabolized by man and other mammals, the metabolites being in large measure excreted im the urine. If any tissue storage occurs, it is in such small quantity as to elude current analytical r alka- hichi t l l l h t bl i Ni in i h n neu ra o e mo ecu e w er uns a es. sa rat n cot e tec line conditions undergoes a variety of changes. A review•ofthe current concepts of the known and suggested pathways for the metabolism of nicotine is show•n~ in Figure 1 (18). The main intermediate appears to be ( -)-cotenine which yields y-( 3-py.ridyl) -y-methylamino butyric acid. Cotenine has low toxicity and lacks the potent pressor activity of nicotine. Dogs reeeiving, 150 mg/kg"'dayorally for 108 days exhibited no weight loss or other obj'pctive signs (2). Man has ingested 500'mg orally at 8-hour !i intervals for 6 days, without! untoward effects. No evidence has been pre. sented' that the other known metabolites of nicotine carry any significant i systemic toxicity. 71

~ lV SUMMARY DIAGRAM OF ROUTES FOR THE METABOLISM OF NICOTINE IN MAMMALS (Some hypothetical intermediates are shown in brackets.) Nicptine y-(3-Pyridyl}y-methylnminoGu[yrnlde6yde _1110 y-(3-Pyridyl)-y-rnethyk.minobutyria Acid / ~ I N('11j N - Innmethylnicotinium lon 'Hydrozynicotine' / Hydroxycutinine 'Ketonmidx• FIGORE 1. COOH y-(3-Pyridyl)-y-oco-6utyriq Acid 3-Pyridylacetic Aid Source: n4cKennis, Herbert H., Jr. (18) CHj coo sVyss4eo

CHRUNIC TOXICITY Evaluation of the chronic: toxicity of tobacco smoke may be considered in several categories: (a) the systemic t'oxiaity, of nicotine or its congeners, (b) the systemic toxicity of other constituents of smoke or tobacco, carbon monoxide andl other compounds, (c) specific organ toxicity incertain~ suse ceptible individuals, such as those with Buerger's disease and allergic re- sponses, (d )! lbcal effect of irritants on mucous and pulmonary membranes by tars, phenols, the oxides of nitrogen, and' others. The latter three types of potentiall toxicity are discussed in Chapter 9; Cancer, and Chapter 10; IWon-Neoplastic Respiratory Diseases. It might appear that! the least difficult problem in this group of variables would be to assess the chronic toxicity, of nicotine since we are deali'ng with a comparatively simple organic compound of known composition and re- actionL Whereas there is a voluminous literature of studies involving chronic exposure to nicotine or tobacco smoke in many animal species (17, pp. 501-5Ud),, most of these are poorly designed and controlled and are of little value for extrapolation to man. For example;, in the best~ nicotine experiments involving life span studies, the daily dose of nicotine was near the: maximal tolerated dose (just subeonvulsive), which is greatly in excess of any human smoking exposure: Even though some authors (11) observed weight loss and degenerative vascular changes in rats under these severe conditions, others (22) noted some weight lbss but no~ histologic change. In life span experimentsim rats, with tobacco smoke in amounts approxi- mating human smoking exposure, very litt'le systemic toxicity was noted (8, 13). Even though animal experimentation is inadequate, especially in lon-term effects of nicotine on large animall species, existing, data permitss a tentative conclusion that the chronic systemic toxicity of nicotine: is quitee low in small to moderate dosage. The clinical literature is devoid of human, datai concerning chronic expo- sure to nicotine albne, and the general statement's regarding the chronic toxicity of nicotine f'or man represent inferences drawn from chronic expo- sure to tobacco in various f'orms, including industrial poisoning. Repeated exposure to tobaecoin excessive amounts is reported to induce amblyopia; arrhythmias, digestive disturbances, cachexia and a wide variety of other signs and symptoms. But the effects of excessive dose are of littleconcern here. The questioni is whether prolonged exposure to nicotine, in the quan- t'ities absorbed systemically fromi smoking or other tobacco use, produces toxic effects which result in unpleasant symptoms, dangerous signs, specific degenerative disease, or shortening of the life spanI. Unfortunately even a tentative answer to this question must be obtained indirectly andl by making certain assumptions. Inasmuch as nicotine is systemically absorbed' from all routes of administration, smoking, chewing, snuffing, or "snuffl dipping," it appears logical tb~ assume that if the amounts of! nicotine absorbed in the various methods ofl use:are of the same order of magnitude, any toxic effects observed should also be in this order of magnitude. There appears to be general, agreement that this is so. Calculations indicate that the nicotine *Asmall amount of snuff is placed in the groove between the tieeth, and the lower lip or beneath thet'onnue and held there from 30~ minutes to severall hours. fll 73 lil 'i

absorbed (40-60 mg) from 6 cigars uninhaled equals that from 30 eiga- rettes inhaled (19). Chewing tobacco may yield 8 to 87 mg in 6 to 8 hours (244; in chewing snuff, 20-60 mg of nicotine (7). The following, variables play a role in the amount of nicotine absorbed (47,p. 8)1: To sum up, the rate and amount of absorption of nicotine by the smoker depend' to a greater or less extent upon the following factors: 1. Length of time the smoke remains in contact with the mucous membranes ; 2. pH of the body fluids wit'hi which, the smoke comes in contact;, 3. Degree and depth of inhalation; 4. Degree of habituationi of the smoker (?') ~ 5. Nicotine content of the tobacco smoked; 6. Moisture content'~ of the tobacco smoked'; 7. Form in which tobacco is smoked' (cut [cigarettes] or uncut [cigars] )(?); 8. Length of butt; 9. Use of' holder or filter; 10. Alkalinity or acidity of the tobacco smoke (?); 11. Agglbmeration of smoke particles (more important in eigarette- smoking) . There is no,acceptable evidence that! prolonged exposure to nicotine creates either dang-erous functional'i chanbe of an, objective nature or degenerative disease. The minor evidences of toxicity, nausea, digestivedisturbances and the like, are similar in kind and degree with all forms of use. The fact that the over-all death rates of pipe and cigar smokers show little if any increase over non-smokers is very difficult to reconcile with a concept of high nicotine toxicity. Im view of the mortality ratios of pipe and cigar smokers, it follows logically that the apparent increase im morbidity and mortality among cigarette smokers relates to exposure to substances in smoke other than~ nicotine. Unfortunately, there are no useful mortality statistics in those wlio che%v, snuff, or "dip" tobaccoi and! the literature regarding in- dustrial exposure is so~confusing that little help is available here. The type of projection made above, however unsatisfact'ory, is not inconsistent with the animal toxicity data as well as the fact that nicotine undergoes very rapid! metabolism to substances ofl lbw toxicity. The evidence therefore supports a conclusion that the chronic toxieity of nicotine in amounts ordinarily ob- tained in eommomflorms of tobacco use is very low indeed. SUMMARY The pharmacological effects of nicotine at dosage levels absorbed from smoking (il-2 mg per inhaled cigarette) are comparatively small; the response ini any point in time represents the algebraic sum of stimulant and depressant actions from direct, reflex, and chemical mediator influences on the several organ systems. The predominant actions are central stimulation and/or tranquilization which, vary with the individual, transient hyperpnea, 74:

peripheral vasoconstriction usually associated with a rise in systolic pr~essure, suppression of appetitite, stimulation of' peristalsis andl wit'h larger doses. nausea of central origin whic4 may be associated with vomiting. Nicotine is rapidly metabolized by man and certain other mammals. The primary pathway through (-)-cotenine to y- ( 3-pyridyl )-y,methylamino- butyric acid is described in detaill The known metabolites have very low toxicity. The rapidity of degradation to non-toxic metabolites, the result's from chronic studies on animals, and the low mortality ratios of' pipe and cigar~ smokers when compared with non-smokers indicate that the chronic toxicitv of nicotine in quantities absorbed from smoking and other methods of to- bacco use is very loxv and probablly does not represent a significant health problem. REFERENCES 1. Bickford, R. G. Physiology and drug action: An electroencephalo- graphic analysis. Fed Proc 19: 619-25, 1960. 2. Borzelleca. J. F.. Bowman, E. F., McKennis, H., Sr. Studies on~ the respirator}~- and cardiovascular eff'ect's of (- l~-cotenine: J Pharma- col Exp Ther 137: 313. 1962. 3. Burn, J. H., Tiuelbve, L. H., Burn, I. The antidiuretic action of nico- t7neandlof smoking. Brit Med J 1: 403-6, 1945. 4. Carlsom A. J., Lewis. J. HI. Contributions to the physiology of the stomach. 14. The influence of smoking and of pressure on the abdo- men (constriction of the belt)', on the gastric hunger contractions. Amer J Physiol 34: 149=54, 1914. 5. Comroe. J. H.. N'adel. J. The effect of smoking and nicotine on respira- tion. In: James. G., Rosenthall T. eds. Tobacco and health. Spring- field, Thomas. 1962. Chapter 17, p. 233-43. 6. Eff'ect of smokinr on appetite and on peripheral vascular disease. [Queries and minornotes] JAMA 119: 534, 1912: 7. Gaede. D. Sur wirkung des schnupftahaks. Naunvn Schmicdeberg Archiv Exp Pa& 1'.3O--45, 1944. 3. Haag, H. B:, Weatherby, J. H., Fordham, D., Larson, P. S. The effect on rats of daily-life span exposure to cigarette smoke. Fed Proc 5: 181, 1946. 9. Hauser, M. Schwarz, B. E., Roth. G., Bickford, R. G Electroenceplialo• graphic changes related to smoking. Electroenceph Clin Neuro- physiol 10:57,6, 195& 10. Heymans, C.,, Bouchaert. J. JL, Dautrebande, L. Sinus carotidien et reflexes respiratories. 3. Sensibilite des sinus carotidiens aux sub- stances chimiques. Action stimulante respiratorie reftexe du sulfure de sodium. du cyanure de potassiumi de la nicotine a de la l4beline. Arch Int Pharmacodyn 40: 54-91, 19311. 11. Huepery, W. C. Experimental studies in cardiovascular pathology. 7. Chronic nicotine poisoning in rats and! dogs. Archi Path (;Chicago) 35: 846-56, 11943. 75 r

12. Knapp, D. E., Domino, E F: Action of nicotine on ascending reticular activating system. Int J Neuropharmacol 1: 333-51, 1962. 13: Kuchle. H. J., Loeser, A,,, Meyer, G., Schmidt, C. G., Strurmer, E. Ta- bakrauch. Ein beitrag zur wirkung von tabakfeuchthaltemittein. Z Ges Exp Med 11$:554-72, 1952, 14. Lal£an, R. J., Borison„ H. L. Emetic action of nicotine andi lobeline. J Pharmacol Exp Ther 121: 468-7~6, 1957. 15. Lambiase, M., Serra, C. Fumo e sistema nervoso. 1. >1'Iiodificazioni dell'attivita elettrica corticale da fumo. Acta Neurol (Napoli) 12: 475-93, 1957. 1'6. Langley; Ji. hi'. 0n the reaction of cells and of nerve-endings t'o certain poisons; chiefly as regards the reaction of striated muscla to nicotine and to curari. J Physiol (London), 33: 374-413, 1905. 17. Larson, P. S., Haag, H. B., Silt~ette, H'. Tobacco. Experimental and clinical~ studies. Baltimore, William & Wilkins, 1961. 932 p. 18. McKennis; H., Jr. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 19. Nicotinecontent of snrokefrom cigarsan&cigarets. [Queries and minor notes] JAMA 130: 825, 1946. 20. Rapela., C. E., Houssay„ B: A. Accian d'e la nicotina sobre la secrecion de adrenalina y nos adrenalina de la sangre venosa suprarrenal del perro. Rev Soc Argent Biol 28: : 219=24,, 1952. 21. Schnedorf, J. G., Ivy, A. C. The elTect' of tobacco smoking on~ the ali- mentary tract. An experimental study of man~ and' animals. JAMA 122: 898-904, 1939. 22. Silvette, H., Hoff, E. C., Larson„ P. S., Haag H. B. The actions of nico- tine on central nervous system f'unction. Pharmacol Rev 14: 1'37-73,, 1962. 23. Stumpf~ C. Die wirkung von nicotin auf die hippocampustatigkeit des kaninchens. Naunyn Schmiedeberg Archiv Exp Path 235: 421-36, 1959. 24. Thienes, C. H. Chronic nicotine poisoning. Ann NY Acad Sci 90: 239, 1960. 76 x_n..

Chapter 8 Mortality

Contents Page PROSPECTIVE STUDIES OF MALE POPULATIONS ... 81 Data on Smoking History . . . . . . . . . . . . . . . 82 Adjustment for Differences in Age Distribution ...... 82 RESULTS FOR TOTAL DEATH RATES . . . . . . . . . 85 Mortality Ratios for Current Smokers . . . . . . . . . . 85 Mortality Ratios by Amount Smoked . . . . . . . . . . 85 Mortality Ratios at Different Ages . . . . . . . . . . . 87 Age at Which Smoking was Started . . . . . . . . . . . 89 Mortality Ratios by Duration of Smoking ... ..... 90 Inhalation of Smoke . . . . . . . . . . . . . . . . . . 91 Ex-Cigarette Smokers . . . . . . . . . . . . . . . . . 92 Ex-Cigar and Pipe Smokers . . . . . . . . . . . . . . . 94 EVALUATION OF SOURCES OF' D ATA . . . . . . . . . 94 The Study Populations . . . . . . . . . . . . . . . . . 94 Non-Response Bias . . . . . . . . . . . : . . . . . . 96 Measurement of Smoking History . . . . . . . . . . . . 98 Stability of the Mortality Ratio . . . . . . . . . . . . . 98 OTHER VARIABLES RELATED TO DEATH RATES ... 99 MORTALITY BY CAUSE OF DEATH . . . . . . . . . . 101 Results for Cigarette Smokers . . . . . . . . . . . . . . 102 Mortality Ratios for Cigarette Smokers by Amount Smoked . 106 Cigars and Pipes . . . . . . . . . . . . . . . . . . . 107 The Contribution of Different Causes to Excess Mortality .. 108 SUM MARY . . . . . . . . . . . . . . . . . . . . . . . 108 Total Mortality . . . . . . . . . . . . . . . . . . . . 108 Cigarette Smokers . . . . . . . . . . . . . . . . . . 108 Cigar Smokers . . . . . . . . . . . . . . . . . . . 112 Pipe Smokers . . . . . . . . . . . . . . . . . . . . 112 Mortality by Cause of Death . . . . . . . . . . . . . . 112 APPENDIX I Appraisal of Possible Basis Due to Non-Response .... 113 APPENDIX II Stability of Mortality Ratios . . . . . . . . . . . . . . 117 Assumptions . . . . . . .. . . . . . . . . . . . . . 117 The Binomial, Approximation . . . . . . . . . . . . . 118 The Normal Approximation . . . . . . . . . . . . . . 119 REFERENCES . . . . . . . . . . . . . . . . . . . . . . 120 78 

i Figure FiGURE 1. Death rates (logarithmic scale) plotted against age for current cigarette smokers and non-smokers, U.S. veterans study . . . . . . . . . . . . . . . . . . . . . . . . . List of Tables Page 88 TABLE 1. Outline of prospective studies of smoking and mortality. 83 TABLE 2. Mortality ratios of current smokers by type of smoking . . . . . . . . . . . . . . . . . . . 85 TABLE 3. Mortality ratios for current smokers of cigarettes only, by amount smoked . . . . . . . . . . . . • • 86 TABLE 4. Mortality ratios for current smokers ofl cigars only, by amount smoked . . . . . . . • • • • • • • . . 86 TABLE 5. Mortality ratios for current smokers of pipes only, by amount smoked . . . . . . . . . . . . . . . . 87 ' '1'AsLE 6: Mortality ratios by age group for current smokers of cigarettes only, men in 25 States . . . . . . . . . 87 TasuE'7. Increase in natural logarithm of death rate per ],000, man-years for each, 5-year increase in age, 6 prospec- tive studies . . . . . . . . . . . . . . . . . . 89. TABLE 8. Mortality ratios by age at which smoking was started and by amount smoked for current, smokers ofl cigarettes only . . . . . . . . . . . . . • • • • 89 TABLE 9. Mortality ratios for current smokers by type of smoking and by length of time smoked . . . . . . . . . • 90 TABLE 10. Mortality ratios for smokers of cigarettes only by inhalation status and amount of smoking ..... 91 TABLE 11. Mortality ratios for ex-smokers and current smokers of cigarettes . . . . . . . • • • • • • • • • • • • 93 TABLE 12. Mortality ratios for ex-smokers of cigarettes only by number of years since smoking was stopped and by amount smoked . . . . . . . . • • • • • • • • 93 TABLE 13. Mortality ratios for ex-cigarette smokers by number of years of smoking, U.S. veterans study ..... 93 TABLE 14. Mortality ratios for ex-smokers of'~ cigars only, and pipes only and for current cigar and pipe smokers . 94 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 . . . . . . . • • . • • • • • • • . 95 TABLE 16. Percentages of' usable replies in five studies ..... 96 TABLE 17. Mortality ratios for cigarette smokers by population- size of city . • • • . • • . . • . . . . . . • • 99 TABLE 18. Age-adjusted death rates per 1,000 (over approximately 22 months) for variables that may be related to mortality . . . . . . . . • • • • • • • • . • • 100 714-422 0-64-7 79

Page TABLE 19. Total numbers of expected and observed deaths and mort'alityy ratios for smokers of cigarettes only in seven prospective studies . . . . . . . . . . . . 102 TABLE 20. Expected and observed deaths and' mortality ratios for current smokers of cigarettes and' other (three studies): and for ex-cigarette smokers (four studies) . 105 TABLE 21. Mortality ratios for coronary artery disease for smokers of cigarettes onlyy by amount smoked ....... 106 TABLF 22. Lung cancer mortality ratios for current smokers of cigarettes only by amount smoked . . . . . . . . 106 TABLE 23. Expected and observed deaths and mortality ratios for current cigarette smokers, for selected causes of death, by amount smoked, in six studies ..... 106 TABLE 24. \ umbers of expected and observed deaths and mortal- ity ratios for cigar and pipe smokers, in five studies . 107, TABLE 25. Percentage of totalinumber of excess deaths of'cigarettee smokers due to different causes . . . . . . . . . 108 TABLE 26. Numbers of'expected and observed d'eaths for smokers of cigarettes only, and mortality ratios, eac6 prospec- tive study and! all studies . . . . . . . . . . . . 109 TaBLE'27. Age-adjusted death rates (per 1,000 person-years) for 1951respondents, 1957 respondents, and non- respondents in L.S: veterans study . . . . . . . . 114 TABLE 28. Illustration of calculation of non-response bias . . .. 115 'hABLE 29. Mort'ality ratios in respondents and computed vahtres for the complete population . . . . . . . . . . . 116 1'ABLE 30. Proportions and death rates for Berkson's example .. 116 80. 1=~

Chapter 8 PROSPECTIVE STUDTES OF MALE POPULATIONS The principal data on, the death rates of smokers of various types and of nonsmokers come from seven large prospective studies of men. In such studies, information about current and past'~ smoking habits, as well as some supplementary information (e:g., on age), is first obtained from the members of the group to be studied. Provision is also made to obtain death certificates for all members of the group who die during subsequent years. From these data, over-all death rates and death rates by cause are computed for the different types of smokers, usually in five-year age classes. These seven studies comprise all the large prospective studies known to us. The first started in October 1951: the latest, in October 1'959. In brief, the seven~ groups of men are as follows: (11) British doctors, a questionnaire having, been sent to all members of the medical profession in the United Kingdom by Doll and Hill, 1956 (15). (2), White American men in nine states. These men were enrolled by a large number of American Cancer Society volunteers, each of whom was asked to have the questionnaire filled' in by 10 whitee men between the ages of 50 and' 69. Hammond and Horny 1958'. (10). (3)', Policyholders of U.S. Government Life Insurance policies,, available to persons who served' in the armed forces between 1917 and 1940. Dorn, 1958' (6). (4) Men~ aged 35-64 in nine occupations in California who were sus- pected of being,subject to a higher than usual occupational risk of developing lung cancer. Dunn, Linden and Breslbw, 1960 (7). (5) Calif'ornia members of the American Legion and their wives. Dunni Buell and Breslow (8)'. (6) Pensioners of: the Canadian Department! of Veterans Affairs, i.e., vet- erans of World Wars I and II and the Korean War. Best, Josie and Walker, 1961 (2) ~. (7) American men in~ 25 states; enrolled by volunteer researchers of the American. Cancer Society,, each of whom was asked to enroll about 10 families containing, at least one person over 45. Hammond, 1963 (11). ItI will be noted'that the studies cover different types of population groupss in three countries. Study (2), often referred to as the Hammond and Horn study, terminated after 414 months' fo]lowup, and the data discussed here for this study are essentially the same as those already published (10). All other studies have accumulke& substantial' amounts of' data beyond that which has been publishedL The authors and agencies responsible for 81 O C.~ ~ ~ CR OD

the studies supplied' tlieir latest available data for this report. The tables in~ this Chapter are based on the new compilations. Table I shows for each study the approximate number of subjects from whom usable replies about smoking habits were obtained, the date of en- rollinent, age range, number of,months followed~ total number of deaths, and the number of' person-years of exposure. The number of subjects studied (usable replies) ranged from around 34,000~ in the British doctors study to 448,000 in the nLw American Cancer Society study. The number of months of follbw-up varied from~about22 to 120. Although several' of the studies obtained some data: on women, only the California Legion study (8)i and the new American Cancer Society study (11) include large numbers of women. No tabulations on women are as yet available from these prospective studies. The exact description of the type of smoking and the amount smoked at all times throughout a man's past life would necessitate an amount of detail and an accuracy of memory that was not considered practicable in these studies. While the information~ collected on smoking habits varied! from study to study, all studies asked for data on the current amount and type of smoking as of the date off answering the questionnaire. These amounts were usually expressed as the number of cigarettes, cigars or pipes per day. In~ the case of subjects who had stopped smoking previous to the date of enrollment (ex-smokers ), most studies obtained data on the maximum amount previously smoked'per day. The category described as non-smokers sometimes included also those men who had smoked an insignificant total amount during their whole previous lifetime. As regards type of smoking, cigarettes, cigars and pipes appear in all seven combinations. Since results for the "mixed" categories are difficult to interpret and sometimes involve relatively small numbers of subjects, the analysis here concentrates on the following types: Cigarettes only Cigarettes and other Cigars only Pipes only In some instances the last two categories have been combined' when the num- bers of subjects are too small to give reliable dhta for the separate types. ADJUSTMENT FOR DIFFERENCES IN' AGE DISTRIBUTION Since the death rate of any group of men is markedly affected by their age distribution, it is essential, when comparing the death rates of two groups of men, to ensure that their age distributions are comparable. A standard meas- ure for this purpose is the age-specific death rate, in which the rate is com, puted for a group of men whose ages all lie within~ a relatively narrow span, say 50~-54 years. This measure is particularly appropriate when it is desired to examine how the relative death rates in two groups change with age. 82 i

TABLE I.-Outline of prospective studies of smoking and mortality Authors --- Doll & Hill (5) - -- - - llammon l & Horn (10) -- Dorn (6) - Dunn, Linden, Bmslow (7) . . . Dunn, Buell, Breslow (8) . . _ _ . Best, Josie, Walker (2) . Hammond (11) 8ubjects British doctors -- i Wbite men in 9 States -- - U.$. veterans Californix occu- pationul groups ~ - California Ameri- can Legion mcm- bers - Canadian pensioners (veterans and de-. penilonts)-- Men in 25 States Number of usnble replies 34,000 188,000 248,000 fi7,0(10 Ofi,0(10 78,000 448,000 Date of enrolllnent Oct. 1951 Jan.-Mar. 1952 Jan. 1954 nand Jan. 1957. Nov. 1953 and May 1957. May-Nov. 1957 Sept. 1955-July, 1950) Oct. 1959-Feb. 19fi0. Age range 3,4-7,5{- 50-fi0 3tF75_-f- 35-1i9 35-75+ 35-75+ 35-89 Mont.hs followed 120 4-4 78 About 46 About 24 72 About 22 Number of deaths 4,534 11,870 24,519 1,714 1,704 9,070 11,612 Person-years of exposure 269,000 61'~i,pW 1,312,0110 222,000 119,000 383,000 620,000 099S9LE0

Several methods of adjustment for differences in age distribution are available for populations that have a wide range of ages. For comparing the death rate of a group of smokers with that of the non-smokers in the study, the measure most frequently used in previous publications is a type of mortality ratio, obtained as follows: In each five-year age class, the age- specific death rate for non-smokers is multiplied by the number of person- years in the group of smokers. This product gives an expected number of deaths, which represents the number of deaths of smokers that would be expected to occur if! the age-specific death rate were the same as for non- smokers. These expected numbers of deaths are added over all age classes, and their total is compared with the total! number of observed deaths in the smokers. The mortality ratio is the ratio (total observed deaths in the smokers)/(total expected deaths)~. A mortality ratio of 1 implies that the over-all deatL rates are the same in smokers and non,smokers after this adjustment for differences in age distribution. It does not imply that: the death rates of smokers and non•smokers were the same at each specific age. A mortality ratio higher thani 1 implies that the group of smokers has a higher over-all death rate than the non-smokers. Another common method of adjustment: for age is to use some age- distribution as a standard, for instance the combined age-distribution of all' persons in the study or the age-distribution of the ULS. male population as of a certain Census year. The age-specific death rates for a certain group: (e.g., smokers) are multiplied by the number of persons of that age in the standard distribution. These products are added and finally divided by the total standar& population to obtain, an age-adjusted rate for the group. A mortality ratio of smokers to non-smokers is then computed as the ratio of the age-adjusted rates for smokers and non-smokers: Mortality ratios com- puted in different ways will of course give somewhat different results an& experts in this field do not regard any one method as uniformly best. In this report we have used the ratio of observed: to expected deaths, as described in, the previous paragraph, primarily because this measure is the most'common~ one in previous publications from these studies. Both methods of adjust- ment run the risk of concealing a change in the relative death rate with age:. For instance, the over-all mortality ratio might be unity if smokers hadihigher death rates than non-smokers prior to age 60,,but lower death rates thereafter. Smokers and! non•smokers may differ with regard to variables other than age that are knowni or suspected to influence death rates, such as economic level, residence, hereditary factors, exposure t'o occupational hazards, weight„ marital status, and' eating and drinking habits. In the summary results to be presented in subsequent sections, as in: most results previously pub- lished, the death rates of! smokers and non-smokers have not been adjusted so as to equalize the effects of' these disthirbing variables. This issue will be discussed later in this chapter. A further compllexity in interpreting the results comes from interrela- tionships among the variables that describe the habit of smoking, As will be seen, the death rates of a group of cigarette smokers vary with the amount smoked; the age at which smoking was started, the duration of smoking, and the amount of' inhalation. In trying, to: measure the "net"' effect of one of these variables, such as the number of cigarettes smoked' per day, we 84

should make adjustments so that the different groups of smokers being compared are equalized on all other relevant aspects of the practice. This can be done at best only partially. Most', studies measured only some of the variables on which adjustment is desirable: When the data are subclassi- fied in order to make the adjustments, the numbers of d'eaths per subclass are small, witL the consequence that the adjusted d'eat'h rates are somewhat unstable. Consequently, like previous reporters om these studies, we have used our judgment as to the amount of subclassification and adjustment to: present. The possibility that part of the differences in~ death rates may be associated with smoking variables other than the one under discussion cannot be excluded, RESULTS FOR TOTAL DEATH RATES. MORTALITY RATIOS FOR CURRENT' SMOKERS Table 2'showsthe mortality ratios to non-smokers for men who were smok- ing regularly at the time of enrollmentL For males smoking cigarettes only, the over-all d'eath~ rate is higher than that for non-smokers in all sthdies, the increase ranging from 44 percent for the British doctors to 83 percent in the men in 25 states. For smokers of other forms of tobacco as well as cigarettes t'he increases in death rates are in all cases Ibwer than for the smokers of cigarettes only. For smokers of cigars only, or of pipes only, three of the studies show small increases in over-all death rates; ranging from 5 percent to 111 percent. The study of inen in 25 states, however, gives slight decreases for both types, as does the British stYldy for the two types combined. TABLE 2-1Vlortal'ity ratios of current smokers by type of smoking Study g roup I ~ Type of smoking Briti doct sri ~ ors Men Stat in 9 es U.S, era vet- ns Canad veter ian 34en in ans State 25 s Ci arettes onl 44 1 1.70 1179 1.65 1183 ' y ________________________ g Cigarettes and other . 1.05 I 1. 45 1i 46' 1. 73 1'. 54'. . _ _______ Ci ars only' r 1. 10 110i 1.11 0.97 g ------------------------ Pipes only.--------------------------------- I 0.95 t 1. 05 1.06 1.10 i 0. 8e I The California occupational and Legion sttrdies give mortality ratios of 1.78 and 1i58 respectively, forr all cigarette smokers (current and ex-smokers). MORTALITY RATIOS BY An1OUNT SMOKED For smokers of cigarettes only who were smoking at the time of entry, the mortality ratio increases consistently witL the amount smoked im each of the seven studies, with one exception4 or the California occupational st'udy, which includes ex-cigarette smokers as well as current smokers (Table 3)~. 85

For smokers of cigars only who were smoking at the time of entry,, four of the studies give a breakdown int'o two amounts of smoking (Table 4). Mem smoking less than five cigars per day have death rates about the same as non-smokers. For men smoking higher amounts there is some elevation of the death rate. When the results are combined by adding the observed and expected deaths over all four studies, an over-all mortality ratio of 1.20 is obtained for the five-or-more group. This over-all increase is statistically significant at the 5 percent level.* I TABLE 3'.-lblortality ratios for current smokers of cigarettes only, by amount smoked Cigarettes per British Men in 9 U.S. California California Canadian Men in 25 day doctors States veterans ' occupa- Legion•' veterans States tional' I Less.than 10---.-- 10-20------------- 21-39--- 40 and over -- --- - '1.06 1.31. s1.62 11.50 . 1133 . 1168. 1193 2:.20 1..35 1.70 1.99. 2.22 L 44 l' 2,1,. ~. / 1. 55 1.79 J } 1.88 2.27°'1.~I`.. s1.84 1. 83 ~ .85 J 1:45 l 1.75 ( 1.90 l 2.20 *Current and ex=ciRarette smokers combined. ~"Less than 10" is "lessthan 5" plus"9bout yJ"; "10-20" is "about 1"; "21-39" is "about 13¢"t 3 Less than 1 pack. 3 20-34':. + 35 plus: , 5 More thanil pack., 6 About 1 pack. T More thani 1 pack... TABLE 4.-Mortality ratios for current smokers of cigars only, by amount smoked Number per dag 1 H---------------------------------------- 5 or more--------------------------------- s 1-2. ~ 3 or more. Men in 9 States 1. 00 1.20 U.S: vet- erans 0. 99'. 1,24 Canadian veterans s 1.12 21.26 Men in 25 States 0.93 1.10 o ver-an results 1.00 1.20 I 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 dgy)' two studies show increases of 15 and 12 per- cent in deathi rates, but the other two studies show little or no increase. The over-all mortality ratio of 1.05 does not differ statistically f'rom, unity. The *Statistical significance throughout this report' refers to the 5 percent llvel, 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 popullitions having the same deathirate. If this proba- bility is less than 0.05 (5 percent)' the observed increase in the death rate of smokerss relative to non-smokers is said to be statistically significant at the 5 percent level. The results of significance tests willl be quoted only for mortality ratios in whichithe numherof deaths raises 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 5.-1llortality ratios for current' smokers of pipes only, by amcuntt smoked Pipes per day. 1-9----- ----------------------------------- 10or more--------------------------------- Mmin 9 States 1.00 1.15 Study U.S. veterans Canadiann veterans 1.03 1.12 Men in 25 States. 0.92 0.76' O cer-all ratio MORTALITY RATIOS AT DIFFERENT AGES 1.01 1.05 As indicated previously, the mortality ratios presented in previous tabless for different! groups of smokers represent' a kind of' average over the age- distribution of the smokers concernedy and do not necessarily apply to smokers ofl 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 70i 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- sistentlyy 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 agee 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, thee absolute excess also increases steadily with increasing age. A more thoroug)1 investigation of the relation between death rates and age for different groups of smokers has been made by Ipsen and Pfaelzer (14). If the logarithm 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 6.-IYlortality ratios by age group for current smokers of cigarettes only, men in 25 States Number of cigarettes per day Age at start of st udy 40-49 50-59' 60'-69 70-79 80-89 1-9---------------------------------------- 2. 27 1.44 1.40 1.40 1.08 10-19 - - ------------------------------ 2.12 1.94 1.60 1.50 1.65 20-a9-------------------------------------- 2,22 2.05 1.78 1.48 1.16 40i---------------------------------------- 3.06 ' 2.37 1.68 1.28 0.~58 All amountk------------------------------- 2.33 106 . 1.70 1.47 1.22 87 I

veterans study, Figure 1 shows the points and fitted lines for non-smokerss 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, thiss would imply that the mortality ratio of the smokers to the non-smokers wass 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 CURRENTICIGARETTE SMCKERS AGE IN YEARS 88 FIGURE 1.

the. slope is slightly less. steep for theeigarette 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 f!rom~ six of the studies. The salient features are as f'ollows: (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 theslopes are closer to those for non-smokers. TABLE 7-lncrease in nadurallogaritkm of deathrateper I;00© man-years f or each 5-year increase in age, 6 prospective studies, British Men~in 9, U.S. Calitornia California ' Men in 25 Type of smoking doctors States veterans occupa I-egion I States r tional I Non-smokers----------------- .593~ .474 ' .499. .489. .502 ~ .490 Cigarettes by arnount per day-, .492 ' .427 ~ .448 .436 '. .476 . . 438 1-$ --------------------------- .536: .484 '' .490 .401 .567 .445 10-20'------------------------- .551 .457 ' .454 I .461 . .471 .441 21-39!-.----------------------- .477 .420 .46i~ .447~ .449~. .401 40+--------------------------- .401 .345 ------------ ------- - .~401 Cigars Pipes-------------- ------- 598 } { .466~ ~ I 521 .483 .458 ------ i-------- ~----------- ----------- ------------ .457 I .458 I "CigareEtes" includes "cigarettesand otrier^an&currenti and ez-smokers. 2 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 dataa on the d'eathi rates of current smokers of cigarettes only,, classified by the age at which, the person started'' to smoke. Since in bothi studies the. men, who start, to smoke early tend to smoke greater amounts per day thani men' who start later in life, the mortality ratiosto non-smokers are preonted separately for different amounts of smoking (Table 8). TASIlE' 8.-Mortality ratios by age at whichsmoking was started and by amount smokedtor currentsmokers of,cigarettes only Age started to smoke Number of cigarettes per day Over- all 1-9 10-20 21-39 40+ ratio U:S. veterans: Under 20------------------------------ 1.,60~ 1.89 2.16 2.45 1.98 20-24'------------- -------- 1.40, 1.72 1.87~ 2.23 1.72 25 or over-- --------------------------- 1,15 1.50 1.47 1. 11, 1.39 Men in 25 States: Under15____________ ___ 1179 1 2.23 2 2.! 21 2.15 2.17 15-19__________________________________ 1.75 1 1.83 22.101 2.38 1.99 20-24---------------------------------- 1.25 1 1.52 ' ~ 1.62 1. 93 1. 59 25~or over------------------------------ 1.03' 1 I.36 ~ 1.45 1.56 1.34 1 10-19 cigarettes per day. I 20i39 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. This 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. The comparison of mortality' ratios for difl'erent! lengths of time smoked is of interest in relation to two questionss raised by Dorn (6) in an earlier analysis of'~ the U.S. veterans' data. Is theree 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 yeare, with a further rise for those smoking ]bnger 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 d'urations 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 tham 30 years. TABLE 9:-Rlortality ratios for current smokers by type of smoking and by length' of time smoked Number of years smoked Type of smoking Cigarettcs only____ C igarettes an d oUier ----------- Cigars only __----_ Pipes.only-------_- ti . S: , veterans Canadian veterans Men in 9 States <15 15-24 2.5-34'. 35+}- <15 15-29 ~30+ <25. 25-34 i 35-f- 0.92 1.52 1.50 . 1. 8s 1.52 1.41 li L 73'. 1.46 i 1,74 1.78 1.07 1.41 1. 33'. 1.49 1l 24 1.27 1i22 0.92 0!94 0.95. 1. 12 1i06' 0.81 1i 31 1.01 1.34 0.97 1. 07. 1i36', 0l93 1109: 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'andl 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 OF SMOKE In two: of the studies the subjects were questioned as to whether they inhaled. In the stud!y of men in 25 states each subject was asked to place himself in one of the four classes: do not inhale, inhale slightliy, inhale moderately, inhale deeply. In the Canadian veterans study the subjjecUsimpUy classified himself as an inhaler or non-inhaler. For current smokers of cigarettes only in the UIS. 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 Canadiam 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 ani increase in the degree of inhaling for a fixed amount of smoking is in general accompanied by an increase in the mortality ratio. Therelation of inhalation to mortality appears quite marked: for instance, non-inhalers who smoke 20-39 cigarettes daily have mortality rathos no higher than moderate or deep inhalers who smoke 1-9 cigarettes d'aily. With the very heavy smokers (40+ ) the figures in Table 10 suggest that the mortality ratio~ may remain the same for non~, slight4 and moderate inhAers. The ratios of 2.05 (non-) and 1.97 (slig)it)! are, however~, based on only 26 and 411 deaths, respectively. TABLE 10: Mortality ratios for smokers of cigarettes only byinhalation status and amount of smoking Degree of inhalation 1-9 Cigarettes per day 10-19 20-39 Overall ratio 40+F Alen in 25 States: None- 1 29 1.46 1.56 2.05 1149 ----'---------------------------- Slight--------------------------------- . 1.29 1.fi8 1. 54 1.97 1168 Moderate - -------------------------- 1.61 1. 82 1'. 84 2.01 1183 Deep----------- ----------------------- 1.88 1. 76 2.18 2.50 2,20 Canadian veterans:~ None------ ----------------- 1.05 2 1.11 1 1.03 1.08 8ome---------------------------------- 1. 35 21.50 31.71 1:52 I Aanountsare lifetime maximumamounts smoked. 7 10-20 cigarettes per day. 3 Over 20 cigarettes 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 smoked. Ipsen and Pfaelzer (14) have shown that the logarithms of the 16 death rates at age 61, (approximately 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 themseNves 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 11.0 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 f'romi 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 rellevant 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 illhess: 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 st'opping (12). This factor would tend to make mortality ratios for ex-smokers higher than those for current smokers. Finally, 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 1L-Mortality ratios for ex-smokers and current smokers of cigarettes British doctors Men in 9 UIS. I States veterans i Canadian veterans Men in 25 States Ex-cigarettes ------------------------------ 1.04 1.40 1.41 1,42 1.50 Current cigarettes_________________________ 1.44 1.70 1.79 1165 1.83 ~ Ex-cigarettes and other_ _____ _ _______ ______ 1: 21 1.29 1. 211 1'. 18 1.511 Current cigarettes and other______________ 1.05 1.45 1.46 1.23 1.54 TABLE 12.-Mortality ratios f or ex-smokers o f cigarettes only by number o f years since smoking was stopped and by amount smoked Study Ciearettes Number of years stopped Current per dayI <1 1+-4 1-9 5-9 10+ smokers <19 2 04 1.30 1. 08 1.61 Men in 9 Stetes I ---------- l 20+ . 2,69 . 1.82 1.50 2:02' <19 1 60 62 1 1i 46 0 81 3 1. 13 Men in 25 States________-__ l 20+ . 2.80 . 2.01 1151 . 1.22 2.01 I These data are from Hammond and Horn, 1958: TABLE 1'3.-Mortality ratios f or ex-cigarette smokers by number o f years o f smoking, U.S. veterans study Cigarettes per day 1 Number of,years of smoking 1-20 ---------------------------------------------------- 20 - ---------------------------------------------------- 1-20 ---------------------------------------------------- 20+---------------------------------------------------- <15 I, 1&24! . 25-34 35+ 1.05 1.08 1125 1.58 1.12 1.18 1.41 I 00 2.00 Age at which smoking was stbppe& <45 45-54 55+ ~ 1.09 1i 24 1. 51 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 tham that for current smokers. Thereafter the ratio drops steadily as the intervall since smoking was stopped increases. In the UIS. veterans study, further breakdowns are available by the numbers of' years during which the ex-smokers were smoking an& 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

I. 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 cor- 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 pre- sented. The same is true for ex-pipe smokers wi& the exception of the Canadian study. The interpretation of this result is not clear to us. According, to Ham- mond and Horn (10) and Dorni (6), the explanation may be that a sub- stantial 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 U.S. veterans data indicates that mortality ratios run highest in ex-smokers who smoked~ heavily and for a long time. TABLE 14.-Mortality ratios for ex-smokers o`, cigars only and pipes only and for current cigar and pipe smokers Type of smoker British Men in U.S. Canadian ' Men in doctors 9 States veterans veterans 25 States ]yx-cigar----------------------------------- ------------ 1.65 1.30: 1.17 i 1.24 Current ciKar- ---------------------------- ------------ 1.10 1.07 1.11 0.97 Fx-pipe----------------------------------- 11.12 i 1.29 1.,38' 1.01 L 23 Current pipe------------------------------ 10.95 I 1.05 1.06 1.10 0.86 I Pipe andicigar 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. Any answer to the question "to what general popula- tions of men can the results be applied?", must involve alr 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 environmentali 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 al11 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 d

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 hand these studieshave 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 occupationall 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 ] 960 for the comparisoni is arbitrary, but the white male rate clianged! little between 1955 and 1960:)'. In all studies the death rates for non~smokers are markedly below thosee of U.S. white males in 1960. Even, the smokers of one pack of cigarettes or more daily have death rates that average slightly belbw the U.S: white male figure. To some extent this is to be expected, since hospitalized and other seriously ill persons are not recruite& in such studies. The sizes of the differ- ences appear, however, surprising for the studies with United States popula- tions. Hammond and Horn (10)1, 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. They 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 /or current smokers o f cigarettes only (aged 35 and over) i, by amount smoked, in seven studies and f or U.S. white males Study 1Con- Current smokers of cigarettes only U.S. white smokers Less than 1 pack 1 pack or more males, 1960 British doctors---------------------------------------.-- 15.8 19.2 23.2 22. 9 Men in~,9~States------------------------------------ ---- 1 14.4 122.4 127:1. 122,6 U.S. veterans----------------------------------------- 1220 18.1 23:9 22.9 California~~.occupational---------- ______________________ 110.51 i 14.2 1 18.0 122,6 Cahfornia legion ------------------------------------ -- 11. 3 16.4 16:3 219 Canadian veterans------------------------------------- 14.1 22.1 242 72.9 Men in~25.States__________________ - 2 12.9 ~ 18. 5 3 19:2 22.9 I Ages 50-69; ' These figures may be too low by about 1.7 percent, since the person•years used' in the computation included some contribution by men who ~bad not been fully traced. 95 7 f 4-422 0-64-8

5 to 15 years. The U.S. veterans' study population also: came mainly from the middle and upper socio-economic classes (6). Another reason might be a failure to trace all d'eaths: 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 deathi 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 percentl 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! unusuallyy healthy groups of non-smokers. In the case ofi 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 maj or 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 o f usable replies in five studies Britisti ~ doctors 68 LT.S. veterans. Californi a occupa- tional 68,95 1 85 California Legion 56 Canadian veterans 57 In the ULS. veterans study, 68' percent'~ replies were obtained from the 1954 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 Americani 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 96 I

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 t'hat 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 forr smokers oflcigarettes are as follows: 1954 1957 Non- respondents respondents: respondents(6$ percent) (17 pereent)(~15 percent)i 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 mortalit'y ratio in the whole population with that found in the original 68 percent. To consider how much of an over- est'imate 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 andl 1.44 f'or 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 d'on'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-respond'ents, 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 im 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 ass 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 substantially 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 orwit'hout 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 somee period of time "ex-smokers" or "cigarette and other" sanokers, 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 ciprettes per day, two types of errors of measure- nient 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 efEect' 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 smoke& 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'i of the studies to t'he effect'that the general result of errors in reporting smoking, history is t'o depress the mortality ratios of smokers relative to non-smokers, so that reported' ratios willl tend to be underestimates so far as this source of error is concernedl STABILITY OF THE MORTALITY RATIO The sampling distriliution 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 60-

plus non.smoker deaths may be regarded as a binomial' proportion with mean .kR/(1+hR)i where R is the true mortality ratio, X is the ratio of the expected smoker deaths to the observed non.smoker deaths and the samplee 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 giveni 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 number~s of deaths. The estimate has a: positive mathe- matical bias, negligible with large but not with smalll 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 slightl!y younger than the combined population of the st'udy. This is not in~ our opinion a seri- ous objection, but may sometimes be relevant ini 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 25-State study, no attempt was made to measure these variables apart from urban,r~ural residence, and previous reports on thesee studies give little discussion of this problem. For urban-rural residence, Doll and Hilll (5) found that the proportions of smokers of different amounts in the study population were about the same in rurall areas, small cities and large cities. In~ three studies the mortality ratios of cigarette smokers weree 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 25-State study, over 20 other variables that may be associated with death rates were recorded. The study population was broken down int'o: subgroups for many of these variables separately: for instance, into smokers who have long-lived parents an& grandparents and those: whose parents and TABLE 17.-Mortality ratios f or cigarette smokers by population-size o f city Population-size Study. O ver 50,000~ 10;000- 50;000 Small towns Rural Men.in 9~States---------------------------------------- 1.48 1i62 1.50 1.152 iP.S. veterans ------------------------------------------ 1. 54'. 1151 1.42 1.59 Menlin 25 States--------------------------------------- 1.89 12,02 ------------ 1.74 I Includes towns of less tban 10,000. 99

grandparents were short-lived. Inclhlded among these variables were reli- gion„ educational levely native or foreign birth, residence: by size: of town and occupational exposure, use of aleohol, 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 as 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 d'ay who inhaled moderately or deeply)~ have higher deathi rates thani 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 meni from short-lived families, and are somewhat TABLE 18!-Age-adjusted death rales per 1,000' men (over approximately 22months)f or i•ariablesthatmay be relatedto' mortality Type of smoking None ------------------------------------- Cigarettes '-------------------------------- None-------------------------------------- Cigarettes '- ------------------------------ :rione----------- --------------------------- Cigarettes,V `------------------------------- None-------------------------------------- Cigarettes I -------------------------------- Long4ived parents and grandparents 14i S 27.1 Single 2fi. 0 ~ 50.1 No high school 22.7 35.2 None Shortdived~ parents and grandparents 21.1 44.8 Married 18. 9 33.0 No previous serious disease 11.5 22.3 Use tran- quilizers Educational level Some high !IIiRh school I school I gradhate. 20. 0 34.5 16: 9 35.5 Degree of eaceroi'se2 Slight 23.8 34.1 14.7 25.5 Previous serious disease 42:5 65:0 Do not use tranquilizers 29.1 !' 18.2 52.4 1 31.8 Some college College graduate 18.3 34. 2' ' 15.8 29:4. IIeavy 11.0 20.8 9,5 19.7 I Smokers of~morethania.pack per day«-ho,inlialed rnoderatelyor deeply. , 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. Moderate: r t 100

higher for single: than for married men. The size of the excess death rate for users of tranquilizers compared to men who d'o noti use them is perhaps surprising (29.1 against 18.2 and 52.4 against 31.8). However, the tran- quilizers in question~ required a doctor's prescription, so that some mem in this group are presumably under medical attention for illness. 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 associationi 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 deathi rate declining, steadily with additional degrees of exercise. In particular, the two "no exercise" groups show marked elevations in death rates. These groups, however, amouM 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 correlatiom 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 additiony Hammondl (1'1) 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 non-smokers. 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 constitutfional; 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 discussiom of this point appears in the next section. MORTALITY BY CAUSE OFDEATH In all seven studies the underlying cause of deaths as specified in, the Inter- nationall StatisticaU 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 physiciamfor all cancer deaths; this 101

procedure was also follbwed' in the British doctors' study for all certificatess 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 FOR CIGARETTE SMOKERS I For 24 causes of death, plus the "alllot'her causes" category, Table 19 shows summary data over all seven studies.* In~ four of the studies the data are those for current smokers of cigarettes 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 TnsLE19,-Totalnumbers of ' expected and observeddeatJisand mortality ratios f or smokers of'cigarettes only 1 inseven prospective studies Underlping cause of death Expect'ed~ i Observed, Mortality ratio Median mortality ratio Non-smoker deaths - Cancer of lun¢~(162-3) ~--_---____ 170.3 1;R33 I 10.,8' 11.7 123 _ Bronchitis and emphysena (502: 527.1) }__ 89.5 546 6. 1 7.5 59 Cancer of larynx (161) _------------------- 14.0 75 5 4 5.8 8 Cancer~~oforaloavity(140-.-8). ______________ 37.0: 152~ 4.1 ~ ~ 3.9 27 Cancer~of esophaeus(d50) .-- -------------- 33:7~ 113 3:4. I 3.3 Stomach and duodenal ulcers(540-1)------ 105.1 ~, 294 2:8 5.10 67 ~ Other circulatoryy diseases (451-f68)~-------- 254.0 ~ 649: 2:6 2:3~ '~. 170 Cirrtiosisofliver(581)------------------ ___ 169.2 379 2.2 2.1 96 Cancer of bladder (181) -------------------- 111.6 216 1.~9 2.2 92 Coronary artery disease (420)-------------- 6;430:7 11,177 1,7 1.7 4,731 Other heart diseases (421-2, 430~)--------- j 526.0 868 li 7, 1.5 398 Ilypertensive~heart disease,(444-3)._------- 409.2 631. 115 1.5 334 (7enerallarteriosclerosis (450)--------------- 210.7 310 115 1.7 201 Cancer of kidneyy k180)--------------------- 79.0. 120 P.5 1.~4 59 All other caneer--------------------------- 11061.4 1,524 I 1.4 1.4 742 Cancer of stomach (151)-------------------- 285.2 I 413 1.4 L 3 203 Influenza, pneumonia (480-493)_----------- 303.2 415. 1.4 1.6 169 AB otiiercauses--------------------------- 1,.508. 7 1j 946 1.3 1.3 1,036 Cerebral vascular lesions (330-4) ---------- 1,461.8 1j 844 1.3 1.3 11 ~9 Cancer ofiprostate (177)'_------------------ 253.01 318 1.3 1.0 198 Accidents,suioides, violence (800-999)_---- 1,063.2 1,310 1.2 1.3 627 Npphritis (592-4)-------------------------- 156.~4 173 1.1 ' 1.51 ~ 98 Rheumatio~~heart~disease (490+416)--------- 290;6'. 309~ 1.1 1.1 185 Cancerofreetum(154)-__----------------- 20Z8' 218~ 1.0 ! 0.~9~ 150 II intestines (152-3) 422:6 395 0.9 ~ 0!9'~ 307 Allcausen---------------- I 15;653:9 2fi;223' 1.68~ 1.65 ,I I Currenti cigarettes only for four studies:i all cigarettes (current and ex-) for the two California studies and the study of men in 25 Btates. 2 "Bronchitis and empriysema'."includes "other bronchopulmonary dlscasesl"for men in nine States and Canadian veterans. *The individual resultsfor the seven studies are shown for reference purposes Table 26, 102 im

the resulting mortality ratios, arrange& 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 adavis- 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 hibhly desirable. As an~ alternative measure of the combined mortality ratio, the median of thee seven 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 mediany of course, gives equall weight to small and! large studies. AlthougK 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 alll 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 incliides aortic aneurysm, phlebitis of the lower extremities, and pulmonary embolism. For three of these causes-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 additionall breakdown for two of the causes listed in Table 19. For the rubric 527.1 (emphysema without mention of bronchitis), these sthrdies give mortality ratios of 13.1 and 7.5, respectively. For ulcer of the stomach they give 5.11 and 4:3, whereas for ulcer of' the dtiod'enum 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 liverr„ with a ratio of 2.2, down to a ratio of 1.2 for the miscellaneous class which; contains accidents, suicides and violent deaths. This 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, there 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. The 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 othercirculat'ory diseases (;2:0)~. 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 1.7) are omitted, since they receive d'etaile& consideration~ elsewhere in this report, the numbers of expected and observed deaths for this group as al whole are as follows: Expected Observed Mortality Ratio 8,241.3 10,789 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 Mortality Ratio 7,164.01 9,699 1.35 In either case the excess of observed over expected' deaths is close to 2,500 or about 25 percent of~the totaliexcess in observed deaths ini 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 oh- 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 flrom~ non-response might account for a mortality ratio of 1.3. Relatively high mortality ratios in certaini 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 previouslyy 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 & quantitative estimate of the difference in d'eath~ rates that might be attributable to such constitu- tional and genetic factors. Studies reporte& ini Chapters 14 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 com- 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 com- 104. ..<

TABLE 2O.-Expected and observed deaths and mortality ratios for current smokers of' cigar'ettesand other (threes'tudies)1 and for ex,cigarette smokers, ( fburstudies) 2 Underlying cause of death Cigarettes and other Ex-cigarette Cancer of lung (162-3)'.-_____-_ Bronchitis and emphysema (502,.527:1) 3 ----------------- Cancer of larynx (161), ._ Cancer of oral cavity (140+8) _ - Cancer oCesophaeus (150) i _ _ _ _ Stomaoh and duodenal ulcers (540-1) --------------------- Other circulatory diseases (451-468)'- ----------------- Cirrliosis of liver (581)--------- Cancer of bladder (181),___-___ Coronary artery disease (420)_ Other heart diseases (421-2, 430-'k)----------------------- Hypertensive heart disease (440~3) --------------------- General arteriosclerosis (450)-_ Cancer of kidney (180)________ All other cancer _ ------------ Cancer of stomach (151) _ ____ Influenza, pn un:onia (480+493)_ All other causes _____________ Cerebral vascular lesions (330- 4)'-------------------------- Cancer of prostate (177) __ A'ccidents, suicides, violence (800-999) ------------------- Nephritis~(59211). -._____-____ Rheumaticheart disease (400- 416): ------------------------- Cancer of'.rectum (154)-_ _ C9ncer ofiintestines (152-53)-.. All oauses,--__________________ Number of deaths : Mortality Number ofideaths Mortality Expected Observed ratio E'xpectad Observed ratio 60.9 ' 510 9.4 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 2.0 111 57 4.4 5.4 6 1.1 23.0 99 4.3 13.0 40 3.11 99.0 227 2.3 45.8 93 2: 0 57.3 85 1.5 22.4 271 1.2 58. 2 73' 1.3 29.8 311 1.0 2; 335. 0 3,262 1.4 1j 245 0 1, 731' 1.4' 225.9 321 1.4 124.1 178 1.4 144.4 174 1.2 93.0 133 1.4 106.8 146 1.4 63.7 75 li 2 25. 0 37 1.5 13. 9' 25 118 2719 339 1.2 199.3 239 II2 101.0 139 1.4 ' 51.4 66 1.3 199.2 '. 153 0: 8 55: 1 55 1.0 769:3 790 1.0 308.1 357 1.2 634. 0 ~ 605 1.0 300:1 321 1.1 97.1 118 12 52.0 57 1. 1 287.1 316 111: 169.6 159 0.9 30.17 44 114 21.7 23' 1. 1 96.~ 0. 86 0,9 47.9 59 1.2' 89:7 64 0,7 . 43.3 38 0.9' 149.6 ' 164 1.1 85.8 97 1.1 5,~ 941. 1 8,062 ' 1.4 3; 045. 5 4,107 1.35 1 British doctors, U.S, veterans and Canadian veterans. 2 British doctors„men in nine States, U.S. veterans, and Canadian veterans. '"Bronchitis and'emphysema" includes "ottier broachopulmonary diseases" for men in nine States and Canadian veterans, 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 substantiali 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, ini 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 he subject to medical investsaation. Hammond! (13) has suggested that the explana- tionimiglit lie in the effect of cigarette smoking inidecreasing the quantity of oxygen per unit volume ofblaod, 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

MORTALITY RATIOS FOR CIGARETTE SMOKERS BY AMOUNT SMOKED For coronary artery disease and lung,cancer, the mortality ratios are given j 11 smokers (~current and ex-smokers combined) show a less marked trend. studies. The two California studies, in which the data are for all cigarette In Table 21 an increasing trend with amount smoked appears in all five by amount smoked in Tables 21 and 22 for current smokers of cigarettes only: TABLE: 21. Mortality ratios f or coronary artery disease f or smokers o f cigarettes only by amount smoked Number oUpacks per day British doctors < --------------------------------------- 1.0 1.2 3~t`1--------------------------------------- 1.5 1.9 1-2`--------------------------------------- 1 7 2:1 Ocer 2 ---------------------------------- 2.4 I More than one pack. TABLE 22.-Lung cancer mortality ratios for current smokers of cigarettesonly by amount smoked Number of packs per day E 3!i ° ------------- -------------------------------------- Sz-1---------------------------------------------------- 1 -2 ----------------------------------------------------- Over 2------------------------------------------------- I Over one pack. The trends in lung cancer mortality ratio with amount smoked are steep in all four studies. The two California studies also show marked trendss for all cigarette smokers combined. For the six causes of death (other than lung, cancer) ~ that were pointed out in Table 19 as having unusually high mortality ratios„ the numbers of deaths permit a breakdown~ only into two amounts smoked. The results from six studies are shown~ in Table 23. Data were not available from the TABLE 23.-Expected and observed deaths and mortality ratios for current cigarette smokers, for selected causes of death, by amount smoked, in six stud zes Causes of death i Bronchitis and emphysema:-- Cancer ufilaryna-------------- Canccr oforal cavity-----_--- Cance~r ofiesopfiagus.--------- Stomach and duodenalulc.^rs- Other circulatory-----_------ Caneer of4hee bladder---_---- 106 One pack or less More than one pack Number of deaths Mortality Number of deaths Expected Observed ratio 11 E apccted O hserved 44.6 225 5.0 17.2 147 3:8 19 5 3 4 1' 31 18: 8 53 . 3.2 . . 14. 8 60 13.2 401 3.0 9.7, 48 32:5 110 3. 4 31i2 91, 98.5 253 2.8' 60.4 175 57:3 80 1.4 23.7 73 Mortality ratio

men in the 25-State study. Cancer of the bladder is included in Table 23 as background data for Chapter 9. All causes except' stomach and' duodenal ulcers show some increase in the mortality ratio for the heavier smokers. The rate of increase cannot be regarded as accurately determined in view of the small' numbers of deaths. CIGARS AND PIPES In view of the small numbers of deaths involved, the data for cigar and pipe smokers were combined in7ablb 24, which lists the totatexpected deaths,, total observed deaths and mortality ratios from five studies (British~ doctors, U.S. Veterans, Canadian Veterans, and men in~ 9 an& 25 States). Causes of death with relatively high mortality ratios are oraI cancer (13.4) , cancer of the esophagus (3'.2)1, cancer of the larynx (2.8)1„ cancer of the lung (L7),, cirrhosis of the liver (1.6),, and stomach and duodenal ulcers (1.6). It should be noted that all these ratios are based on modest numbers of deaths. TABLE 24.-Numbers of'expected and'observed deaths and mortality ratios for cigar and pipe smokers, in five studies " UnderlyinK cause of death Number of deaths Mortality Expected Observed ratio Cancer of oral cavity (140-8)L_______________________________________ 13.5 46'. 3.4 Cancer ofesophagus (150)_______________ _-_____________ 10:2 33 3.2' Canceroflarynx (1F1)----------------------------------------------- 3:2 9 2.8 Cancer oflunQ (162-3) ----------------------------------------------- 65.2 113 1.7 Cirrhosis of liver (581)______________________________________________ 47.5 77 1.6 Stomach and duodenal ulcers (540-1)________________________________ 35.2 56 1.6 Cancer of kidney (180)----------------------------- °--------------- 30!8 39 1.3 Cancer of intestines (152-3)_________________________________________ 174.6 219 1.3 Other circulatory diseases (451-168)_________________________________ 89.1 105. 1.2: Allothercancer_____ _________________ ___ 396. 7 456'. 1. 1 Cancer of prostate (177)---------------------------------- ___________ 127.2 144 1.1 Cancer of stomach (151)_____________________________________________ 116.8 ' 132 1.1 Cancer of rectum (154)----------------------------------- ___________ 78.2 ' 88 1. 1 Hypertensive heart disease(440-3)__________________________________ 194. 5 218 1.1 Other heart diseases (421-2;,430+4)_ ___________________ 272. 6 303 1.1 Bronchitis and emphysema (502; 527.1)______________________________ 33.7 37 1.1 Cerebral vascular lesions (330-4)____________________________________ 685. 3 720' 1.1 Coronary artery disease (420)__--_-_____°__________________________ 2,721.5 2,842 A1l other causes----------------------------------------------------- 612. 9 587 1.01 Influenaa andlpneumonla (480-493):_________________________________ 93.8 88 0.9 Accidents. suicides..violence (806-999)____________________________-_ 347.1 318 0.9 Cancer of bladder(181)---------------- _____________________________ 63.1 56'. 0.9 Oenerallarteriosclerosis (450)________________________________________ 124.1 109 0.9 Nephritls (592~)~------------ --------------------------------------- 63.6 55 0.9 Rheumatic heart disease (400-416)___________________________________ 100.5 69 0.7 A11 causes----------------------------------------------------------- 6,500.9 6,910 i 1.06 i Ineludes British doctors, men ini 9 States, U.S. veterans, Canadian veterans, and men in 25 States; includes ex-smokers for men in 9 States;,excdudes pipe smokers for Canadian veterans. Separate breakdowns by cause of death for cigar-only smokers and for pipe:only smokers are available in only three studies. The numbers of deaths are too few to throw any light on the question whether there are differences between cigar and pipe smokers in the causes of death for which~ mortality ratios are elevated. 107 As.% 11~. ,, l tl

TIIE CONTRIBUTION OF DIFFERENT CAUSES TO EXCESS MORTALITY Several of the reports previously published on these studies have included a table showing how the excess number of deaths of cigarette smokers over non-smokers is distributed among the principal causes ofi death. For each cause, the difference between the observed and the expected number of deaths f'or cigarette. smokers is divided by the total excess for all causes, and multipliedl by 100 to express the figures on a percentage basis. Table 25 presents these percentages for the sevem studies for 13 groups, of causes. A negative percentage, which occurs in a few places in the table, implies that for this cause the observed smoker deaths were smaller than the expected deaths. TABLE 25.-Percentage of total number of, excessdeatlts, of'cigarette smokers due to dijfereat causes1 Underlying cause British ~Mcndu dbctors. 9'States II.S. veterans California~California occupa- Legion i tiona3 i Canadianj veterans. MIetrin 25 States ~ Coronary arterv disease_ ------ 32.9 51.9J 38.6 ! 43.5 43. 5 44.2 51.7 Otherheartd.isease------------- 9.9 3A ' 6.8 ! 1.4 ' 4..5 5.9 5.5 Cerebral.vascularlesimu------- 6.11 4..5, 4.9. '5.3 6.,5: -1.8 3:3 Other circulatbrp,diseases------ 1.9 2J7 7.1 1.71 0.2 5.6 4.4 Cancer of lung_ _______________ 24.0 13.5 14.9 20.2 16.8 18.3 1ti:6 Cancer of oral cavity, esopha- gus,dhrynz__--------------- 3.3 2:9 2.7 0.2 3.0 2.2 2.2 Othercaneer----------------- _ Bronchitisand emphyscma___ -0.2 9.6 9:8 I 1.1 , 8.9 4.0 6.3 1i.3 -2.2 5.6 7.2 8.2 7.6 3.8 Influenza and' pneumoni:i _ _ 2.4 1. 6. j 0.4 2.4 I ! 1.5 1..5. 1.5 Stomach and duodenaliuleers _ 2.7 3.1i 1.4 -1:7 2.2 2'9 1.3 Cirrhosisotliver_ _____________ 2.9 1:6 2:5 6.9 2.2 0.8 0.9 Accidents, suicides, violence__ 0.2 1i 2 i 2.0 0 8.3 3.7 4.6 0.8 All.othercatLVes:---------------- 9.2 3.0 5.8 4.2 12:,5 0:4 3.4 All causes_____________________ I 100.0 100.0 100.0 I 100:0 100.0 100.0 100.0 I All cigarette smokers, (current and' es-) for the two California and men in 25 States studies;: current cigarette smokers only for the remainder. As previous writers have noted, all studies agree inshow~ing, coronaryartery disease as the prime contributor to excess mortality, with lung cancer in second place. Other rubricsthat show a substantial contribution in some studies, though not in all, are bronchitis and emphysema, cancers other than those ofe the mouth and lungs, and heart'disease other tham coronary. SUMMARY This report summarizes the results of the seven major prospective studies of the relative death rates of male smokers' and non-smokers. TOTAL MORTALITY Cigarette Smokers The d'eathi rate for smokers. of! cigzrettes only who were smoking at the time of entry is about 70 percent higher than that for non•smokers. 108

11 989S911c0 TABLE 26.-Numbers o f expected and observed deaths f or smokers o f cigarettes only, and mortality ratios, each prospective study and all studies Cause of death Cancer of lung-------------------------- (162-3) Bronchitis, emphysema_____________ (502, 527.1) Cancer of larynx-------------------------- (161) Cancer of oral cavity-------------------- (140-8) Cancer of esophagus----------------------- (h50) 9tomach-and duodrnal uic_ers_________(5_40,541) Other circulatory diseases--------------- (451-fi8) Cirrhosis ofliver-------------------------- (581) Cancer of bladder------------------------- (181) Coronary artery disease _______ _________(420) Other heart disea.ses-------------- (421-2, 430-4) Hypertensive heart diseaso ___ __ ___(440-3) General artericsclerosis ___ ____ ______(450) CanceCof kidney------------------------- (180) All other cancer----------------------------- ---- Cancwr ofstomach------------------------ (151)Influcnza, pneumonia------------------ (480-93) All other causes--------------------------------- Cerebral vascular lesions---------------- (330-4) Cancer of prostate________________________ (177) Accidents, suicides, violence_====______(800-999) Nephritis------------------------------- (592-4) Rheumatic heart disease--------------- (400-16) Cancer of rectum .-------------------------(154) Cancer of intestines--------------------- (152-3) All causes-------------------------- ---- British doctors Men in 9(3tates U.S. veterans California occupational Deaths Deaths Deaths Deaths Mortalit Mortality Mortality Mortality y ratio ratio ratio ratio Expected Observed Expected Observed Expected Observed Expected Observed 6.4 129 20.2 23.4 233 10.0 43.3 519 12.0 8.7 138 15.9 -- 4.2 --53 12.5 12.8 30 2.3 14.4 141 9.8 2.8 11 4:3 .0 7 --------- 1.3 17 13.1 2.4 14 5.8 .0 3 __________ .0 6 _ 7.8 22 2.8 8.1 54 6.0 7.2 7 1.0 3.3 7 2.1 2.7 18 6.6 5.2 33 6.4 5.5 4 .7 .0 14 __________ - 2.2 61 5.0 21:5 67 3.1 23.1 12 .5 17.2 27 - 1.6 - 19.7 53 2.7 66.4 228 3.4 11.5 18 1.6 .0 15 ---------- 23.5 49 2.1 31.2 11l 3.6 14.7 59 4.0 13.9 12 ----:9 17.2 41 2.4 31.4 55 1.8 2.2 13 6.0 366.9 535 1: 5 9 27: 7 1,734 1.9 1, f300. 3 3,037 1.7 273.9 551 2.0 78.8 115 1.5 _ 72: 5 108 1.5 122.2 244 2.0 23.8 24 1.0 21.0 32 1.5 89.7 107 1.2 138.7 223 1.6 27.2 28 1.0 21.2 21 1.0 9.1 18 2.0 97.0 1Fi.1 1.7 .0 5 __________ ,0 8 ---------- 14.0 21 1.5 23.1 34 1.5 .0 10 - - 81. 7 73 .9 132.9 230 1.7 315.8 457 1:4 72:1 105 1.5 2Fd:3 31 1. 1 33.7 76 2.3 f11.5 90 1.5 31:4 24 - .8 47.0 35 . 7 15.6 41 2.6 22.6 36 1. 6 10.3 25 2.4 144.0 182 1.3 209:5 263 1.3 354.8 530 1.5 69.9 101 1:5 161.1 192 1.2 208:8 279 1.3 309.1 467 1.5 42.2 76 1.8 29.0 15 . 5 32.4 51 1: 6 53. 7 106 2. 0 8.6 4 . 5 89. 2 90 1.0 174.1 192 1.1 241.5 306 1.3 108.4 161 1.5 8.1 17 2.1 43.3 34 .8 18.6 30 1.6 16.0 10 .6 10.2 13 1.3 48.4 43 .9 67.4 77 1.1 22.9 31 1.4 --4.2 15 3. 6 29.8 25 . 8 68. 7 62 . 9 13.6 14 1.0 26.1 28 1:1 65.6 35 .5 121.2 152 1.3 217 22 .9 1,161.8 1,672 1.44 2,227.7 3,781 1.70 4,043. 1 7,236 1.79 818.5 1,456 1.78

TABLE 26.-Numbers of expected and observed deaths for smokers of cigarettes only, and mortality ratios, each prospective study and all studies-Continued Cancer of IunK____ (162-3) Bronchitis, emphy sema_:(502,5?7.1) Cancerof7arynz__ (161) Cancer of oral cavi ty_________(140-8) Cancer of esopha8 us____________(150) Stomach and duodenal ulcers 541) Other circulatory diseases_ __(431 _!i8) Cirrhosis of liver__ ______________(581) Cancer of lladdeF= -------_---___(181) (540, as __(421-2, 430-4) Coronary artery di sease___:____(420) Other heart disens 7Iypertensive hear t disease___(440-;i) General arterioscle rosis_________(450) Cancer of kidney_ ______________(180) -------------- -- All other cancer_ _-------------------_ Cancer of stomach _ ------------ (151) Influenza, pneumo nia_______(480-93 ) All other causes___ ___________________ Cerebral vascular 1 esion8 _____(330~t) Cancer of prostate (177) Accidents, suicid~, vlolonce (800 999) i~lephritis _.______ (692 4) Rheumatic heart d isease_____(406-16) Cancer of rectuxn_ ______________(154) Cancer of intestin s___________(152~) e All causes--_------ Caus death e of California Legion Canadian veterans Men in 25 States Total, all studies Median Deaths Deaths Deaths Deaths mortality Mortality Mortality Mortality Mortality ratio ratio ratio ratio ratio Expected Observed Expected Observed Expected Observed Expected Observed 19.9 98 4.9 27.1 317 11.7 41.5 399 9.6 170.3 1,833 10.8 11.7 3:6 30 8:4 36:5 166 4:6 15:4 115 7.5 89:5 546 6.1 7.5 4.0 6 1.5 .0 5 ------ ____ 6.3 23 3.7 14.0 75 6.4 5.8 5.2 10 1.9 6.1 20 3.9 3.6 33 9.2 37.0 152 4.1 3.9 1.8 9 6.1 6.8 22 3.3 8.4 20 2.4 33.7 113 3.4 3.3 1.8 12 6.8 7.9 54 6.9 38.6 74 1.9 105.1 294 2.8 6.0 16.7 37 2.2 41.5 96 2.3 81.0 190 2: 5 2.54: 0 649 2: 6 2.3 13:1 73 1:8 37:6 50 1:3 49:1 72 1:5 169.2 379 2.2 2.1 7:8 -7 4:0 22:3 38 1.7 22.8 50 2.2 111.6 216 1.9 2.2 312.8 515 1.7 882.5 1,582 1.8 1,863.6 3,223 1.7 6,430.7 11,177 1.7 1.7 13.1 26 2.0 75.3 156 2.1 140.3 195 1.4 526.0 868 1.7 1. 6 24.9 29 1.2 36.2 bt3 1.6 71.5 154 2.2 409.2 6:31 1.5 1.5 39.1 20 .5 14.7 48 3.3 29.6 35 1.2 210.7 310 1.5 I:7 8.3 6 .7 9.5 13 1.4 24.1 28 1.2 79:0 120 1.5 1.4 75:4 84 1:1 104:1 149 1:4 279:4 426 1:5 1,061.4 1,524 1.4 1.4 20.5 25 1:2 41.2 76 1.9 68.6 01 1.3 285.2 413 1.4 1.3 14.7 22 1.5 135.0 159 1.2 58.0 97 1.7 303.2 415 1.4 1.6 39.1 94 2.4 361.5 360 1.0 330.9 416 1.3 1,508.7 1,946 1.3 1.3 57. 1 87 1.5 2~34. 1 266 . 9 389.4 477 1.2 1,461.8 1,844 1.3 1.3 22.1 19 .9 32.3 48 1.5 74.9 75 1.0 253.0 318 1.3 1.0 46.0 62 1.4 101.3 174 1.7 303.7 325 1.1 1,063.2 1,310 1.2 1.3 :0 3 _______:__ 11:6 17 1.5 58.8 62 1.1 156.4 173 1.1 1.5 14.2 18 1.3 48.1 39 .8 79.4 88 1.1 290.6 309 1.1 1.1 12.0 9 .8 41.3 24 .6 38.2 64 1.7 207.8 213 1.0 .9 33.2 13 .4 48.6 64 1.4 106,2 - 81 .8 422.6 395 -.9 :9 -- - 799. 4 1,264 1. 58 - 2,. 420. 1 4, 001 ---- 1.65 4,183. 8 - -- - 6, 813 1.63 15,653.9 26,223 1.68 1.65 ,o: 4 e9S9GE0

The death rates increase with the amount smoked. For groups of men smoking less than 10, 10-19,, 20-39, an& 40 cigarettes and over per day, respectively, the death rates are about 40 percent, 70 percent, 90 percent and 120 percent higher than for non-smokers. The ratio of the death rates of smokers to that of non-smokers is highest at the earlier ages (40-50) represented im 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 was substantially higher fbr men who started to smoke under age.20 than for men who starte& after age 25. In general~ the mortality ratio was increased as the number of years of smoking increased'y although the pattern of in- crease was irregular fromi study to study. In two studles which recorded the degree of inhalation; the mortality ratio for a given amount of smoking was greater for inhalers than for non-inhalers. Cigarette smokers who had stopped smoking prior to enrollment in the study had mortality ratios about 1.4 as against 1.7 for current cigarette smokers. Two studies reported the number of years since smoking, was stopped~ In these, the mortality ratio declined in general as the number of' y.ears ofl cessation increased. The mortalfityy ratio of ex-cigarette smokers increased with the number of years of smoking and was higher for those who stoppe& after age 55 than for those who stopped at an earlier age. (These results «•ere available in one study only..). Taken as a whole tlhe seven studies offer a substantial breadth of sampling, of the type of men and environmental exposures to be found in NortL America an& Britain, although none of the groups st'udie& was planned as a random, sample of the U.S. male populationL All the studies had death rates below those of the U.S. white male population in 1960. To some extent this is to be expected, since men in poor health were likely to beunder-recruitedl in these studies. Only a, minor part of these differences in death rates can be attributed to a failure to trace all deaths or to higher death rates among non-respondents in these studies. The data; on~ smoking status and' on amount smoked were subject to errors of measurement, particularly since smoking, status was measured only once and some: men, presumably changed their status after entry into thee study. For men designate& as current smokers of cigarettes only; our judgment is that the net effect of such errors of! measurement is to make the observed mortality ratios relative to non-smokers underestimates of the true mortalityy ratios. The studies suffered from a failure to obtain substantial portions of thee study populations selected for investigation. For a non-response rate of 32 percent in the prospective studies, calculations based on the available informatiom about the non-respondents indicate that reported mortality ratios lying between 1 and 2 might overestimate the corresponding figure for the complete study population by 0.2 or 0.31 In our judgment these biases can account for only a part of the elevation in mortality ratios found for cigarette smokers (see Appendix I). In three studies in which the data could be subdivide& by size of city, the mortality ratios differed little in the four sizes of communities studied. 714-422 0-64-9 111

In one study numerous other variables that might influence the death rate, such as longevity of parents and grandparents, use of alcohol, occupational exposure and educational level, were recorded. Adjustment for each of these variables individually produced little change in the mortality ratios. Although similar information from other studies would have been~ wel- come, it is our judgment that the mortality ratios are unlikely to be explaine& by such environmental, social class, or ethnic differences between cigarette smokers and non-smokers. Except for the analyses reported above by longevity of parents and grand- parents and by previous serious disease, no direct information is available on whether there are basic constitutional differences between cigarette smokers and non-smokers that would! affect their longevity. As described elsewheree in this reporty differences have been~ found between cigarette smokers and non-smokers on certain psychological'i andl behaviorall variables. However,, even for these variables the distributions for cigarette smokers and non- smokers show considerable overlap. It seems a reasonable opinion that the same situation would apply to the constitutional hardiness of cigarette smokers and non-smoker~s, if it were possible to measure such a variable. This implies that constitutional differences, if they exist, are likely to express themselves in only a moderate difference in death rates. Cigar Smokers Death rates 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 (i9 percent to 27 percent) than for non- smokers in, the four studies that gave this information, There is some indi- eation, that this higher death rate occurs primarily in men who have been smoking for more than 30 years and in men who stated they inhaled the smoke to some degree. Death rates for ex-cigar smokers were higher than those for current smokers in alll four studies in which this comparison coul& be made. Pipe Smokers 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-pipe smokers, on the other hand, showed higher death rates than both non-smokers and current smokers in four out of five studies. The epi- demiological studies on ex-cigar and ex-pipe smokers are inadequate to explain this puzzling phenomenon. According to Hammond and Horn (10) and Dorn (6), the explanation may be that a substantial number of cigar andlpipe smokers st'op smoking because of illhess: MORTALITY BY CAUSE OF' DEATH In the combined results from these seven studies, the mortality ratio of cigarette smokers was particularly high for a number of~ diseases: cancer of 112 i

the lung (10.8), bronchitis and emphysema (6.1)', cancer of the larynx (5.4), oral cancer (4:1), cancer of the esophagus (3.4), stomach, and duodenal ulcers (2.8), and the rubric, 451-468, "other circulatory diseases" (2.6). For coronary artery disease, the mortality ratio was 11.7. 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. The explanation of the moderate elevations in mor- tality ratios in this large group of causes is not clear. Pan may be due to the sources of bias previouslly mentioned or to some constitutional and genetic difference between cigarette smokers and non-smokers. There is the possibility that cigarette smoking has some general debilitating effect, although no medicali evidence that clearly supports this hypothesis can be citedl The substantiatnumber of possibly injiurious agents in tobacco and its smoke also may explain the wide diversity in diseases associated with smoking. In alli seven studies, coronary artery disease is the chiefl contributor to the excess number of deaths of cigarette smokers over non-smokers, with lung cancer uniformly in second place. For cigar and pipe smokers combined, the data suggest relatively high mortality ratios for cancers of the mouth, esophagus, larynx and lung, and for cirrhosis of the liver and stomach~ and duodenall ulcers. These ratios are, however, based on small'numbers of deaths. APPENDIX I APPRAISAL OF POSSIBLE BIASES DUE TO NO11I'-RESPONSE The non-response rates in the prospective studies were approximately as follows: 15 percent! for the California occupational study; 15 percent for the U.S: veterans' study during the 3-year period 195 7-1959 and 32 percent during the 3-year period 1i954-L956: 32 percent for the British doctors' study; and about 44 percent for the Calif'ornia Legion study and the Canadian veterans' study. Ini forming ai jud'gment about the size of the bias that may be due to non-response, we have concentrated! on a non-response rate of 32 percent, since this represents roughly an average figure for these five studies. The objective is to estimate by how much the mortality ratio for the whole populationi might differ from that found in the respondents. The only useful informationlin any detaiL about the non, respondents comes from the U.S. veterans' study. Table 27 shows data on d'eathi rates ini 1958 and 1959 (16)'. For the present purpose the 1957 respondents will be regarded as a; part of'~ the 32 percent': of non-respondents to the original questionnaire for wliom, we are fortunate to have some data. Table 27 indicates that, the non-respondents in 1954 have higher death rates than respondents for both non-smokers and smokers. For non-smokers the ratio: of the death rate of 1957 respondents to 1954 respondents was 1.35 in 113

TABLE 27.-Age-adjusted death rates (per 1,000 person,years)' for 1954 respondents, 1957 respondents, and non-respondents in U:S. veterans study (3roups. 1954 respondents--------------------------- J~ lnn$znokers; liAll smokers_---------- 1957 respondents_-------------------------- V on-smokers----_ ---- All smokers------- _ -- AFon-respondents--------------------------- A11----------------- 19.84 1958 and 1.27 in 1959. For smokers the corresponding figures are 1.18 in 1958' and 1.14 in 1959. If the adjusted death rates in Table 27 are weighted by the proportions of men in the population, it is found that the over-all 1958 death rate for 1954 respondents was 17.77 as compared with 19.05 for the complete study popula- tion. The ratio 19.05/17.77 is 1.07, so that in 1958' the deatL rate for the study population was 7 percent higher than for the 1954 respondents. In 1959 the corresponding death rates were 1!7.46 for 1954' respondents and 18.31 for the complete population, the ratio being 1.05. These ratios agree wit'h, Doll's judgment (4) ' that in the Brit'ish doctors' study the death rate in the complete population may exceed that in his 68 percent of respondents by from 5 percent to 10 percent. Comparison of the 1954 and 1957 respondents also suggests that the non- respondents in 1954 contain a higher proportion of smokers than the re- spondents. In the 1954 respondents, non-smokers contributed 183,094 person-years of experience dilring 1957-1959 as compared with 179,750 person-years for current smokers ofl cigarettes only, non-smokers represent- ing 506 percent of the total of the two groups. Among the 1957 respondents the corresponding figure was 46.8' percent. A further decline may have oc- curred in the non~respondents to the 1957, questionnaire. From these data the following assumptions were made in investigating the non-response bias as it affects the mortalit'y ratio of current smokers of ciga- rettes only. 1. The proportions of the relevant groups in the complete population are as follows: Groups Tw on- smokers Cigarette smokers . Total V on-res pondents------- _-_- _ ----- 0.14 0.18 0.32 Bes p onde nts------------------------ .34 .34 CompVete populat8on--------- .52 1.00 This assumes that in the 68' percent of respondents, non-smokers consti- tute 50 percent of non-smokers plus cigarette smokers, but in the non.res spond'ents this figure has dropped to 44 percent. Death rates

2. The death rate in the complete population is 10 percent higher than in the respondents. 3. One further numerical relationship is needed in order to obtain con- crete results. For this, the computations were made under two different sets of assumptions. The more extreme (3a) is that cigarette smokers have no higher death rates among non-respondents than among, respondents. The alternative (3b) is that the death rate of cigarette smokers was 10 percent higher among, non-respondents than among respondents. Both sets of assumptions seem more extreme than the indications from the U.S. vet- erans' study in which, as alteady noted, the smoker death rates were 18 percent and 14 percent higher among 1957 respondents than among 1954! respondents. For total mortality, the calculations of most interest are those for a mortality ratio of 1.7 among the respondents, since this is the average ratio found in, the prospective studies for smokers of cigarettes only. For indi- vidual causes of death, however, the mortality ratios among respondents range from 1 to 10, so that calculations were made for a series of different mortality ratios among respondents. Table 28 illustrates the caleulations made on assumptions (3a) and (3b) for a mortality ratio of 1.7 among respondents. f, TABLE 28. Illustration of calculation of non-response bias Assumption (3a) Assumption (3b) Mort6lity ratios Non-respon dents _-__- H e s po n ue n t s_..- --- --- ~ Non- 6Ismokers I+ (1i865) 11000 Cigarette smokers ll 700 11 700 Complete populatton- M. H'----- s (1:252)11° (ll700) , I (1i 36), ' (1.772) Non-respondents_.-_- 1 (}.350) Heeponde.nts____-_- Mortality ratios Non- smokers Cigarette smokers 4 (1'646) 1.000 1.870 1.700 2 (11485) Compl&Le.population_ diL188). ^ M.H----------------- 7 (1. 48) I e' (1.772) . 1 (1.350) 2 ' (1.4S5) ~ The figures without parentheses in the mortality ratio tables represent the start of the computations. The indexes (1 2 etc.) show the order in which other figures are computed. For assumption (3a); (1.350) '=[(0.34)(1.000),+(0.34)(1.700)U,(0.68) (1.485) 2 =(1.1) (1.350) ~ (1.772) e=[(1.485)-(0.6'8).(1.350)]/(0:32)', (1-865) 4=[(0:32)(1.772)-(0:18)(1.700) /(0.14) (1.252) a-[(0:14)(1.8tV5);+(0.34)(1A00)1l(0.48) (1.700) 5=[(0:18)(1.700)+(0.34)(1.700)1/(0.52) (ll36) 7=1.700/1.252 Thus, the mortality ratio drops from 1.7 to 1.36 in the complete population under assumption (13a ) and to 1.48 under assumption (3b). One conse- quence of assumption (3a) is that the mortality ratio of cigarette smokers among the non-respondents is less than 1. Table 29 shows the results obtained for a range of mortality ratios in the respondent population. For the high mortality ratios the assumptions may appear unduly extreme. For instance, under assumption (3a) with mortality ratio 10.0 in the respond- ents, the non,smoker death rate in the non-respondents has to be 3.6 times 115

that in the respondents, although the smoker death rates are assumed the same in~ respondents and non-respondents. It may be of interest to quote Berkson's (11), example in the same form (Table 301). TABLE 29.-Mortality ratios in respondents and computed values f or the complete population In complete.population~~ In respondents (68 percent) Assump- tion (3a) Assump- tion (3b) 1.2`---------------------------------------------- 1.00 1.06 1.4----------------------------------------------- 1.14 1,23 ---------------------------------------------- 1.28 1.40 1.8----------------------------------------------- 1.43 ' 1.56 2:0----------------------------------------------- 1.57 1.73 5:0----------------------------------------------- 3.43 4.07 10,0---------------------------------------------- 5.65 7.41 TASLe 30.-Proportions and death rates for Berkson's example Proportions D eath rates Group Non- Smokers Total Non• Smokers Total smokers smoke rs Blon-respondents.------------- 0. 0049t 0, 28360 0.28 854 60: 121 4.217 ' 5.174 Res po nclents--- --------------- .1951N'i. . 51f:k0 .71 140 1. 553 2.:332 2:1d8 Total!------------------ .20000. .80000 1 1.00 000 3. 000 3: 000 3.000 In their general direction, Berkson's assumptions are similar to those made in this Appendix, but the differences in death rates between respondents and non-respondents were more extreme in his example. The d'eatL rate in thee complete population (3.000)' was 42 percent higher than the respondent death rate. The non~smoker death rate was over 38 times as high among' non- respondents as among respondents (60.1211/1.553), whereas among' the smokers it was only 1.8 times as high. His calculations referred to the early years of a study, in which the effects of differential entry of ill persons among' smokers an& non-smokers are likely to be most marked. Further, as we in- terpret his writing, the example was intend'ed as a warning' against the type of subtle bias that can arise whenever a': study' has a high proportion of non- respondents, rather than a claim that this numerical estimate of the bias ac- tually applied to these studies. To summarize, the amounts of non-response in the prospective studies could have produced sizable biases in the estimated mortality ratios. Taking assumption 3b in Table 29;, as representing fairly extreme conditions, it appears that a reported mortality ratio between 1 and 2 might overestimate by 0.3, a ratio of 5.0 by 1.0 and a ratio of 10.0 by 3.0. 116

APPENDIX II STABILITY OF MORTALITY RATIOS In computing,the mortality ratio: of a group of smokers to a group of non- smokers, each group is subdivided into age-classes (usually 5-year). For the ith agp-class let yi denote the number of smoker deaths and' x, the num- ber of non-smoker deaths. The "expected" number of smoker deaths in the f ith class (expected on the assumption that srnokers have the same age-specific death rates as non-smokers)' is ~ (Person-years for smokers in class i) (Person-years for non-smokers in class i),x,=X~x, (sayl The estimated mortality ratio R is defined as Iy' 1 R=Y.?LJx (i ) summed over the age-classes. In, the interpretation of the values of R found in the seven studies, much ~ weight has been given to the consistency of the values from one study to another, on the grounds that if the values of R for a particular cause of death f are highi in, alli seven studies, this evidence is more impressive than R values t that are high in say, three studies but show no elevation in the remaining four studies. As a: consequence, the question whether the value of R in an individual study is significantly above unity, in the technical sense of this term; becomes less important. Nevertheless, an answer to this question is occasionally useful in the analysis. Moreover, for some causes of death the total numbers of deaths, even when all seven studies are combined, are small enough so that ai measure of the stability of the combined R is need'edl ~ Assumptions In attempting to get some idea of the stability of R without too much com- plexity, the following assumptions will be made. 1. The numbers of deaths yt and x, are distributed as Poisson variables. As Chiang (3) has shown, a more accurate assumption is to regard yt and x„ as binomial numbers of successes. But with causes of death for which the probability of dying in a 5•year age span is very small the Poissom assump- ;, tion, which is slightly conservative, is reasonable. 2. The qNantities A, can be regarded as known constants. This is not qµite correct. Initially, the Ai are the ratios of the numbers of smokers to non-smokers in the age-classes, which cani reasonably be regarded as given: In subsequent-years, however, the numbers are depleted by deaths, and the number of deaths is' a random variable. When death rates are small, how- ever, this assumption should introduce little error. 3. The variates y; and yi are uncorrelated. An error in the age assigned to a death, putting it ini the wrong age-class, induces a negative correlation between, yj and yj. The existence of such errors should have no effect on 117

the variance ascribed to Y,y,, on the assumption of independence. The same remarks apply to the assumption that xt and xi , are uncorrelated. variates, and numerator and denominator are independent of one another. The exact distribution of a ratio of'this type has not been worked out. Twoo approximate methods of obtaining confidence limits for the true mortality ratio R will be given. Confidence limits are presented rather than the standard error of R because the distribution of R is skew when the numbers of deaths are moderate or small, so that the standard! error is harder too interpret. xl and y,. Such errors should of course not be allowed to happen, since they vitiate the comparison of the death rates that is the main point! of the study, but occasional errors of this type may have_occurred. With these assumptions the numerator ly, of R follows a Poisson distri- bution. The denominat'or Y,,Clxi, is a linear function of independent Poisson 4. The variates xl and yl are uncorrelated. An error in assigning a death~ to the correct smoking,category would induce a negative correlation between~ The Binomial Approximation Ifl the, A;, can be regarde& as approximately constant ('=,1, say)' then R becomes of the form y/Xx, where y and x are independent Poisson variates. Since Xx then represent_s the expected number of deaths of the smokers, the quantity A is estimated as the ratio of the expected number of smoker d'eaths to the number of non-smoker deaths. By a well-known~ result it follows that' x/(y+x), the ratio: of non-smoker deaths to smoker plus non-smoker deaths, is distributed as a binomial proportion with n=number of'. trials=y+ x p=probability of success=l/(1-'~ XR)' where R' is the true mortality ratio. Confidence limits for R are found' from those for p. Example. For the study of men in 25 States; the figures for lung cancer for cigar and pipe smol.ersare as follows: Non- smokers Number otAe.nths- ----------------- Observed 16(%). Smokers Observed 15(y) Expected 9:71(xx) Hence, X=9.71/16=0.607 and the binomial ratio is 16/31=0.516. Hald's. (9) table of the 95 percent two-tailed confidence limits of the binomial distribution gives 0.331 and 0.698 as the confidence limits for p. Those for R are given by the relation R=(L-p)/,k'p This yields 0.7 and 3.3 as the 95 percent limits for R. Since the lower limit, 0.7, is less than unity, the estimated R, 1.5, is not significantly above unity. 1'18 1 Oak

U2lfortunatell- the assumption thatX] is constant is not true in these studies. For instance, in~ the study of inem in 25 States A] has the value 3.85 for cigarette smokers aged 45-49 and declines steadily with increasing age to a value of 0.96 for men aged 75-79. For cigar and pipe smokers the fluctuation in~ yj with age is less drastic but is still~ noticeable. The Narmal, ApproximertionThis approach avoids the assumption that the Ai are constant„ but makes other assumptions that are shaky with smalli numbers of, deaths. If Risthe true mortality ratio, the quantity y- Re where e=1a;xi is the expected' number of smoker deaths, will follow a; distribution that has mean zero. If µi, m; denote the true means of y; and xi, respectively, the variance of (y-Re) is Y.(µ„+R'h;my) The basis of this approximation is to regard the quantity ~ y- Re ( µ;+R2k;m,) (2) as normally distributed with zero mean, since y, and x; are regarded, ass previously, as independent Poisson variates. The 95 percent confidence: limits for R are then obtained, by a, standard device, by setting the absolutevahle of this quant2ty, equat to 1.96 and solving the resulting quadratic equationi for R. Since the µ, and the mi are unknown, a further approximation is to substitute y as an estimate of :~µi and ~~;xi as an estimate: of, t Example. For the example previously discusse& the data are as follows: i y=15: e=9.71: :~k2.1=6:059 On squaring, (2), the quadratic equationi becomes (15-9.71R)z=3.84(15+6:059R'). The roots are found to be 0!7 and 3.4, in goodi agreementl with, the: limits 0:7 and 3.3 given by the binomial approximation. This agreement is better than will usually be found withi small numbers of deaths. The following are 4 comparisons of the confidence limits for cigarette smokers in the same study. Number of deaths 95 percent limits Cause oGdeath, Non- smoker s Cigarette smok ers Mort'®l ratio ity Binomial N ormal observe d Observ ed! Exp ected Cancer of lung---------------- 16 399 41120 9.7 (5'.0, 14.:5) (5.0.21.4) . ~ EmphFsema ----------------- 7 115 15.31 7.5 ' (3. 5~, 18-.1) : (4! :0, 40: 0)'. Canoer of rectum---- -------- 16 641 38.42 1.7 (1.0.3.3'); (1.0;3;6) Influenza and pneumonia__- 29 97 58. 01 1.7 (1. 1, 2. 6) ~~ (1. 1, 2.9)~. 119

The lower confidence limits agree well; but the upper limit'1 runs higher for the normal approximation. For cigarette smokers the normal method is perhaps more accurate. The binomial method has some advantage in simplicity. _ REFERENCES 1'. Berkson, J. The statistical study of association between smoking and lung cancer. Proc Staff Meeting,, Mayo Clin 30: 319-48, 1955. 2. Best, E: W. R., Josie,, G. H.,, Walker, C. B. A Canadian study of mor- t'alfity in relation to smoking habits, a preliminary report. Canad J Pub Health 52 : 99-106. 1961. 3. Chiang, C: L. Standard error of the age-adjusted death rate. Vital statistics. U.S. Department of Health, Education and Welfare. SpeciallReports No 47, 275-85, 1961. 4. Doll, R. Personal'i communication to the Surgeon General's Advisory Committee on Smoking and Health. j 5. Dolh R., Hill, A. B. Lungcaneerandlothercauses of! death in relation to smoking. Brit Med J 2: 1071-81, 1956. 6. Dorn, H. F. The mortality of smokers and~ non-smokers. Proc Soc Stat Sect Amer Stat Assn~ 34-71, 1958. 7. Dunn; J. E., Jr., Linden, G., Breslow, L. Lung cancer mortality ex- perience of men in certain occupations in California. Amer J PubHealth50~: 1475-87, 1960; 8. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department ofi Public Health. Special report to the Surgeon General's Advisory Committee on Smoking and HealthL 9. Hald, A. Statistical tables and formulas: Wiley, New York, 1952. 10. Hammond, E. C., Horn, D, Smoking and' death rates-report on forty- four months offollbw-uponi 187,783 men. Part I. Total mortality. Part II. Death rates by cause. JAMA 166: 1159-72, 1294-1308, 1958. 11. Hammond, E. C. Special report to tihe Surgeon Generalrs Advisory Committee on Sinoking, and Health. 12. Hammond, E. C. Special report to the Surgeon~ General's Advisory Committee on Smokingand Health. 13. Hammond, E. C. The effects of' smoking. Sci Amer 207: 3-15, 1962. 14. Ipsen, J., Pfaelzer, A. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 115. Korteweg, R. The significance of selection in prospective investiga- tions into an association between smoking and lung cancer. Brit J Cancer 10: 282-91, 11956. 16. Krueger, D. Personal communication tothe S'urgeoni General's Advis- ory Committee on Smoking andl Health. 17. Yates, F: Sanipling methods for censuses and surveys. Griffin, Lon- don, (Section 9.4), 1'960. 120

Chapter 9 -.. Cancer I

Contents Page CANCER MORBIDITY AND MORTALITY ....... 127 Sources of Information . . . . . . . . . . . . . . . . 127 ~ Sex Ratio . . . . . . . . . . . . . . . . . . . . . . 133 I! Geographic Variation . . . . . . . . . . . . . . . . . r 133 , Urban-Rural Gradients . . . . . . . . . . . . . . . . . ]33 Income Class . . . . . . . . . . . . . . . . . . . . . 133 Occupation . . . . . . . . . . . . . . . . . . . . . . 134 Ethnic Group . . . . . . . . . . . . . . . . . . . . . 134 Trends . . . . . . . . . . . . . . . . . . . . . . . . 135 Age-Specific Mortality From Lung Cancer . . . . . . . . 136 Effects of Changes in Lung Cancer Diagnosis on Time Trend s . . . . . . . . . . . . . . . . . . . . . . . 139 CARCINOGENESIS . . . . . . . . . . . . . . . . . . . 141 Fundamental Problems in Carcinogenesis in Relation to Induction of Neoplastic Changes in Man by Tobacco Smoke ..................... 141 Threshold . . . . . . . . . . . . . . . . . . . . . 143 Carcinogenicity of Tobacco and Tobacco Smoke in Animala.. 143 Skin ........................ 143 Subcutaneous Tissue . . . . . . . . . . . . . . . . . 144 Mechanism of the Carcinogenicity of Tobacco Smoke Condensate . . . . . . . . . . . . . . . . . . . . 144 Other Materials of Possible Importance in Carcinogen- icity . . . . . . . . . . . . . . . . . . . . . . 145 Pesticides . . . . . . . . . . . . . . . . . . . . . 145 i Lactones . . . . . . . . . . . . . . . . . . . . 145 Radioactive Components 145 . . . . . . . . . . . ~ . . . ~. Summary . . . . . . . . . . . . . . . . . . . . . . 146 Carcinogenesis in Man . . . . . . . . . . . . . . . . . 146 Polycyclic Aromatic Hydrocarbons . . . . . . . . . . 146 Industrial Products . . . . . . . . . . . . . . . . . 147 Soot . . . . . . . . . . . . . . . . . . . . . . 147 Coal Tar and Pitch . . . . . . . . . . . . . . . . . 147 Mineral Oils . . . . . . . . . . . . . . . . . . . 147 Summary . . . . . . . . . . . . . . . . . . . . . 148 CANCER BY SITE . . . . . . . . . . . . . . . . . . . 148 Lung Cancer . . . . . . . . . . . . . . . . . . . . . 149 Historical . . . . . . . . . . . . . . . . . . 149 Retrospective Studies . . . . . . . . . . . . . . . 150 Methodologic Variables . . . . . . . . . . . . . . . 151 Form of Tobacco Use . . . . . . . . . . . . . . . . 155 122

k t t !i CANCER BY SITE-Continued Lung Cancer-Continued Retrospective Studies-Continued Page Amount Smoked . . . . . . . . . . . . . . . . . 155 Duration of Smoking . . . . . . . . . . . . . . . . 158 Age Started Smoking, . . . . . . . . . . . . . . . 158 Inhalation . . . . . . . . . . . . . . . . . . . . . 159 H istologic Type . . . . . . . . . . . . . . . . . . 159 Relative Risk Ratios from Retrospective Studies . . . . 160 Prospective Studic s . . . . . . . . . . . . . . . . . 161 Experimental Pulmonary Carcinogenesis . . . . . . . . 165 Attempts to Induce Lung Cancer with Tobacco and Tobacco Smoke . . . . . . . . . . . . . . . . 165 S ummary . . . . . . . . . . . . . . . . . . . . 165 Susceptibility of Lung of Laboratory Animals to Carcin- ogens . . . . . . . . . . . . . . . . . . . . 166 Polycyclic Aromatic Hydrocarbons . . . . . . . . 166 Viruses . . . . . . . . . . . . . . . . . . . . . 166 Possible Industrial Carcinogens . . . . . . . . . . 166 Summary . . . . . . . . . . . . . . . . . . . . 167 Role of Genetic Factors in Cancer of the Lung. . . .. 167 Summary . . . . . . . . . . . . . . . . . . . . 167 Pathology-Morphology. . . . . . . . . . . . . . . . . 167 Relationship of Smoking to Histopatliological Changes in the Tracheobronchial Tree . . . . . . . . . . . 167 Summary . . . . . . . . . . ... . . . . . . . . 172 Conclusion . . . . . . . . . . . . . . . . . . . 173 Typing of Lung Tumors . . . . . . . . . . . . . . 173 Conclusions . . . . . . . . . . . . . . . . . . . 174 Evaluation of the Association between Smoking and Lung C ancer . . . . . . . . . . . . . . . . . . . . . 175 Indirect Measure of the Association . . . . . . . . . 175 Direct Measure of the Association . . . . . . . . . 179 Establishment of Association . . . . . . . . . . . 179 Causal Significance of the Association ....... 182 The Consistency of the Association. . . . . . . . . 182 The Strength of the Association . . . . . . . . . . 183 The Specificity of' the Association . . . . . . I . . . 183 Temporal Relationship of Associated Variables ... 185 Coherence of Association . . . . . . . . . . . . . 185 (1.) Rise in Lung Cancer Mortality . . . . . . . 185 (2.) Sex Differential in Mortality . . . . . . . . 185 (3.)' Urban-Rural' Differences in Lung Cancer Mor- tality . . . . . . . . . . . . . . . . . . 186 (4.) Socio-Economic Differentials in Lung Cancer Mortality . . . . . . . . . . . . . . . 186 (5.)' The Dose-Response Relationship. . . . . . . 187 (6.) Localization of Cancer in Relation to Ty pe of Smoking . . . . . . . . . . . . . . . . 188 Histopathologie Evidence . . . . . . . . . . . . . . 189 123 W 0

CANCER BY SITE-Continued Lung Cancer-Continued Constitutional IIypothesis . . . . . . . . . . . . . . Genetic Considerations . . . . . . . . . . . . . . . E pidemiological Considerations . . . . . . . . . . . (1.) Lung Cancer Mortality . . . . . . . . . . . (2.)' Tobacco Tars . . . . . . . . . . . . . . . . (3.)' Pipe and Cigar Smoking . . . . . . . . . . . (4.) Ex-Cigarette Smokers . . . . . . . . . . . . Other Etiologic Factors and Confounding Variables ... (1.)' Occupational Hazards . . . . . . . . . . . . (2.) Urbanization, Industralization, and Air Pollution . (3.)' Previous Respiratory Infections . . . . . . . . (4.) Other Factors . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . Oral Cancer . . . . . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . Evaluation . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . Laryngeal Cancer . . . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . Evaluation of the Evidence . . . . . . . . . . . . . . Time Trends . . . . . . . . . . . . . . . . . . . Sex Differential in Mortality . . . . . . . . . . . . Localization of Lesions . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Esophageal Cancer . . . . . . . . . . . . . . . . . . E pidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Evaluation of Evidence . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Urinary Bladder Cancer . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . Carcinogenesis . . . . . . . . . . . . . . . . . . . Evaluation of the Evidence . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . Stomach Cancer . . . . . . . . . . . . . . . . . . . . Epidemiological Evid'ence . . . . . . . . . . . . . . . Retrospective Studies . . . . . . . . . . . . . . . Prospective Studies . . . . . . . . . . . . . . . . 124' Page 190 190. 192 192 192 192 192 193 193 194 195 196 196 196 196 202 203 203 204 205 205 205 209 210 210 210 210 211 211 212 212 212 212 217 217 217 218 218 218 218 222 223 223 225 225 225 225 228 ,

CANCER BY SITE-Continued Stomach Cancer-Continued Page Carcinogenesis . . . . . . . . . . . . . . . . . . . 228'. Evaluation of the Evidence . . . . . . . . . . . . . . 228. Conclusion . . . . . . . . . . . . . . . . . . . . . 229 SUMMARIES AND CONCLUSIONS'. . . . . . . . . . . . 229 Lung . . . . . . . . . . . . . . . . . . . . . . . . . 229. Oral Cancer . . . . . . . . . . . . . . . . . . . . . . 233 Larynx . . . . . . . . . . . . . . . . . . . . . . . . 233 Esophagus . . . . . . . . . . . . . . . . . . . . . . 234. Urinary Bladder . . . . . . . . . . . . . . . . . . . . 234 S tomach . . . . . . . . . . . . . . . . . . . . . . . 235 Figures f 1. Mortality from cancer (:all sites), U.S. Death Registration I I Area of 1900, 1900: -1960 . . . . . . . . . . . . . . . 128 2. Age-adjusted mortality rates for cancer-all sites, in 17 countries, 1958-1959 . . . . . . . . . . . . . . . . 129 3A. Age-adjusted mortality rates for cancer of six sites in~ six selected countries-males . . . . . . . . . . . . . . 130 ` 3B. Age-adjusted mortalityy rates for cancer of six sites in six selected countries-females . . . . . . . . . . . . . 1311 4: Comparison of age-adjusted mortality rates by sex, United States, 1959-1961, with incidence rates from State regis- tries of New York and Connecticut . . . . . . . . . . 132 5. Trends in age-adjusted mortality rates for cancer by sex- all sites and respiratory sy stem in the United States, 1930-1960 . . . . . . . . . . . . . . . . . . . . . 136 6. Trends in age-adjusted mortality rates for selected cancer sites by sex in the United States, 1930-1960 ...... 137 7. Age-adjusted mortality rates for cancer of the lung an& bronchus by birth cohort and age at death for males, United States, 1914, 1930-1932, 1939-1941, 1949-1950, ' 1959-1961 . . . . . . . . . . . . . . . . . . . . . 138 8. Age-adjusted mortality rates for cancer of the lung and bronchus by birth cohort and age at death for females, United States, 1914, 1930-1932, 1939-1941, 1949-1950, 1959-1961 . . . . . . . . . . . . . . . . . . . . . 139 i 9. Crude male death rate for lung cancer in 1950 and per capita consumption of cigarettes in 1930 in various countries .. 176 10. Percentage of persons who have never smoked, by sex and ; age, Uhited States, 1955 . . . . . . . . . . . . . . . 178' iV 125

Illustration Page 1. Examples of normal and abnormal bronchial epithelium . 168-9 List of Tables 1. Expected and observed deaths and mortality ratios of cur- rent smokers of cigarettes only, for selected! cancer sites, all sites, an& all causes of death; each prospective study and all studies . . . . . . . . . . . . . . . . . . . . . 149 2. Outline of! methods use& in retrospective studies of' smoking in relation to lung cancer . . . . . . . . . . . . . . 152 3. Group characteristics in retrospective studies on lung cancer and tobacco use . . . . . . . . . . . . . . . . . . 156 4. Relative risks of lung cancer for smokers from retrospective studies . . . . . . . . . . . . . . . . . . . . . . 161 5. Mortality ratios for lung cancer by smoking status, type of smoking, and amount smoked, from seven prospective stud ies . . . . . . . . . . . . . . . . . . . . . . 161 6. Percent of slides with selected lesions, by smoking status and presence of lung cancer . . . . . . . . . . . . . . . 168 7. Changes in bronchial epithelium in matched triads of male non-smokers and smokers of different types of tobacco .. 171 8. Relation between W'HO and Kreyberg classifications of lung tumors . . . . . . . . . . . . . . . . . . . . . . 174 9. Mortality ratios for cancer of the lung by smoking class and by ty pe of tumor, U.S. Veterans Study ...... .. 175 10. Outline of retrospective studies of tobacco use and! cancer of the oral cavity . . . . . . . . . . . . . . . . . . 198 10A. Summary of results of retrospective studies of smoking and detailed sites of the oral cavit'y by type of smoking ... 201 11. Oiutline of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . . . 206 12. Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus ..... ... 13. Summary of results of retrospective studies of tobacco use 214 and cancer of the esophagus . . . . . . . . . . . . . 216 14. Summary of methods used in retrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . . . 220 15. Summary of results of retrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . . . . . 221 15A. Summary of results of retrospective studies of cigarette smoking and cancer of the bladder in males ...... 222 16. Summary of methods used! in retrospective studies of smoking and cancer of the stomach . . . . . . . . . . 226 17. Summary of results of retrospective studies of smoking and cancer of'the stomach . . . . . . . . . . . . . . 227 126

a Chapter 9 CANCER MORBIDITY AND MORTALITY Cancer has been the second ranking cause of'~ death in the United States since 1937. Reviewing the mortality statistics of'~ those parts of the United States which began relatively accurate reporting in 1900, (District of Colum- bia and 10 states-the so-called Death Registration Area of 1900) it can~ be seen that the number of cancer deaths per year has increased markedly (Figure 1). After subtracting the part of the increase due to growtL of the population and the part due to increase in life expectancy or aging of the population, there is still a residual increase of sigpificant proportions. While a part of this is undoubtedly due to improvement in~ diagnosis, most observers agree that a true increase in the cancer death rate has occurred during this time. As general background inf'ormation, it is useful to review the pattern of cancer risks found in the population of the United States as compared with, the patterns in other countries. Segi has prepared systematic international compilations of cancer mortality (317). These show that the United States occupies an intermediate position in comparisons of death rates for all sites combined: the age-adjusted rates for U.S. males and females are lower than those in Austria and higher than in Norway and Japan (Figure 2). The point to be stressed, however, is not the rank order of countries according to over-all, cancer mortality, but the differences in, ranking for individual sites (Figures 3A and 3B)s Mortality statistics, cancer register data, and collected series of pathological specimens are in general agreement in identi- fying individual countries as having, their own characteristic site patterns of risk (146). Some of the more striking features in the United States are very low risks for esophagus and stomach and moderately high rates for urinary bladder; lung cancer mortality for males, while below the rates in England and Finland, is well above those in Canada, Norway and Japan. SOURCES OF' INFORMATION Information on morbidity and mortality from cancer in the Uhited States comes from three principal' sources: mortality statistics prepared by the National Vital Statistics Division of the U.S'. Public Health Service, the large central registries receiving reports omdiagnosed cases in Connecticut (136)~ upstate New York (112) and California (37), and the morbidity surveys conducted in ten metropolitan areas in 1937-39 and 1947-48 (91) and in Iowa in 1950 (148). Each body of material has its virtues and weaknesses. Mortality statistics report on the national experience and cover longer time spans than the specialized sources, but the diagnostic information in the death certifications is less reliable and complete. Recent studies of medical certifications have demonstrated that the quality of information for most 714-422 0-64-10 127

MORTALITY FROM CANCER (All sites), U.S. DEATH REGISTRATION AREA 111 OF 1900, 1900-1960 sa 70 60 50 40 30 20 RESIDUAL INCREASE INCREASE DUE TO AGING INCREASE DUE TO GROWTH OF POPULATION CANCER', DEATHSIN 1900 1900 1910 1920 1930 1940 1950 1960 i FIGURE1. Includes Maine, New Hampshire, Vermonts Massachusetts, Rhode Island, Connecticut, New York„New Jersey, Michigan, Indiana, District of'Columbia. Sources: a. United States Census of Population: 1940, 1950, 1960. 1 b. Vital Statistics of the United States, Part 1, 1940; Voll 111, 1950;, Vol. II, Part B, 1960. i c. Cover, Mary. Cancer Mortality in the United States, Part I, Public Health Bulletin 248, 1939: cancer sites can be regarde& as good (91, 247), so that the problems in~ interpretation are less formidable than those arising in studies of cardio- vascular disease. Completeness of reporting to the major registries is satisfactory and the accuracy of diagnostic information is excellent, but the registers cover only a limited number of: areas. Fortunately, the registers in Connecticut 128

AGE-ADJUSTED MORTALITY RATES FOR CANCER - ALL SITES, IN 17 COUNTRIES 1958-1959.111' RATE PER 100,000 / AUSTRIA I} FIINLAND ~ EN'GLAN'D & WALES SWITZERLAND FRANCE GERMANY FR DENMARK NETiNERLANDS UNIITED STATES AUSTRALIA CANADA JAPAN ITiALY IRELAND NORWAY SWEDEN ISRAEL DENMARK AUSTRIA GERMANY FR NETHERLANDS SWITZERLAND ISRAEL ENGLAND 8. WAL ES CANADA FINLAND IRELAND SWEDENI UNITED STATES FRANCE NORWAY, AUSTRALIA ITALY, JAPAN 5 0 10 0 15 0 200 I MA LE I FiGURE 2. ILS: data age-adjusted to total population o/ the continental United States, 1950. Source: Calculated from Segi„M, and Kurihara, M. (317). and New York have been in operation long enough to provide reliable data on incidence trends over the past two decades. The morbidity surveys for 1947-48 produced a comprehensive report on cancer incidence in large cities with very good medical care facilflties; but this information has not been updated by resurveys. 129 , 250 . FEMALE V- - ____

AGE-ADJUSTED MORTALITY RATES FOR CANCER OF 6 SITES IN 6 SELECTED COUNTRIES - MALES (4 RATE PER 100,000 POPULATION! ! ENGLAND FINLAND UNITED STATES CANADA NORWAY JAPAN JAPAN FINLAND NORWAY ENGLAND CANADA UNITEDSTATES UNITED STATES ENGLAND CANADA FINLAND NORWAY, JAPAN' 20 40 60 80 100 I I FINLAND JAPAN ENGLAND UNITEDSTAT~ES CANADA NORWAY I STOMACH I ESOPHAGUS IE ENGLAND I II UNITEDSTAT!ES M M M M MMEENNNEI CANADA FINLAND BLADDER & URINARY NORWAY JAPAN FINLAND ENGLAND UNITED STiATES CANADA. JAPANI NORWAY EF TRACTI (excludiing Kidnely) LARYNX FicLee, 3A. U.S: data age-adjusted to the total' population of, the continental Uhited States, 1950. Source: Calbulatod from Segii M.,,and Kurihara, M. (317). The deficiencies in, any single set of data; should not be overstressed. Com- parisons of the various sources indicate good internal consistency among them and they usually lead to the same inferences on, patterns of risk for 130

AGE-ADJUSTED MORTALITY RATES FOR CANCER OF 6 SITES IN 6 SELECTED COUNTRIES - FEMALES IN RATE PER 100;000 POPULATION ENLLAND UNITEDSTAT~ESFINLAND CANADA' JAPANI NORWAY JAPAN FINLAND NORWAY ENGLAND CANADA, UNITED STATES FINLAND ENGLAND NORWAY UNITED STATES CANADA JAPAN FINLAND JAPAN ENGLAND CANADA UNI TED STATiES NDRWAY ENGLAND UNI TED STATESCANADA NORWAY FINLAND JAPAN ENGLAND, JAPAN FINLAND CANADA UNITEDSTATESNORWAY MM r BUCCAL CAVITY & PHARYNX ~I II ESOPHAGUS I I I BLADDER & URINARY TRACT (excluding Kidney) I I I LARYNX I FiGUxE 3B. U.S. data age-adjusted to the total population of the continental United States 1950. Source: Calculated' from Segi, M., and Kurihara, M, (3ll7)_ individual sites„ particularly those for which~ the five-year survival rates are very low. Figure 4, which contrasts recent mortality and incidence rates, demonstrates that these rates differ markedly only for sites with more favor- able progtlosis-oral cavity, prostate, and urinary bladder. These differ• ences are compatible wit'h~ existing, information on the survival experience of cancer patients. 131 I

COMPARISON OF AGE-ADJUSTED MORTALITY RATES BY SEX IN THE UNITED STATES 1959-1961 WITH INCIDENCE RATES FROM STATE REGISTRIES - UPPER NEW YORK STATE 1958-1960 AND CONNECTICUT 1959. MALES FEMALES i G4'-~,.i :.;,~~~ ~: .; 0 20 - 40 60 0 20 _ MORTAIIITY, UNiTED ST'~ATES WHITE POPULATION„1959-1961 ~ INCIDENCE, UPPER NEWYORK STATE, 1958-1960 ~ INCIDENCE, CONNECTICUT, 1959 Lung and bronchus Esophagus Stomach Buccal cavity and pharynx Bladder and other urinary organs, excluding kidney Larynx Fccvta 4. Sources: Vital Statistics of the United States, annual volumes; Ferber, B. eUal (112). Eisenberg, H.,, personal communication to the Surgeon General's Advisory Committee oniSmoking and Health. The next sections describe some aspects of incidence or mortality for eight sites-lung and bronchus, larynx, oral cavity, esophagus, urinary bladder, kidney, stomach and prostate. Of these, six were selected for spe- 132

cial consideration because they are the ones most often reported by the prospective studies to have the highest mortality ratios of tobacco-users to non-users, and stomach was included because the trend in cancer of this organ in recent years has been in such marked contrast to that for cancer of the lung and bronchus. SEX RATIO The male-female ratios of age-adjusted death rates (US., 1959-61) (252) from cancer for the six sites common to both sexes are given belbw: Male/Female Ratio Whites Male/Female Ratio Nonwhites. Larynx ------------------------- 10.8 7.6 Lung and bronchus--------------- 6.7 6.2 Oral cavity---------------------- 3.8' 3.3 Esophagus----------------------- 4.1 4.2 Stomach ------------------------ 2.0 2.3 Urinary bladder------------------ 1.3 1.6 The ratios of male/female death rates vary with site: ranging from about 10 to 1 for larynx to much less than 2 to 1 for urinary bladder, the findings for white and nonwhite populations being in substantial accord. The male- female ratios for five of the six sites have remained quite stable over the past 30 years, lung cancer providing the important exception. The lung cancer sex ratio was 1.5 to 1 in 1930 and! has steadily, increased during the inter- vening period to the current value of over 6 to 1. Mortality, register and survey data yield consistent information on~ sex ratios, and material from the latter sources need not be reproduced here. GEOGRAPHIC VARIATION Cancers of the oral cavity, larynx, lung and bronchus, prostate, and urinary bladder do not exhibit any consistent marked regional departures from the over-all U.S, incidence and mortality experience (91, 130). Cancer of the esophagus is higher in the Northeast and North Central regions, an& gastrie cancer is encountered less frequently in the South thani ini other parts of the country. Within regions, some cities are known to display exceptionali incidence of certain types of cancer (91). URBAN-RURAL GRADIENTS I I The excess risk for residents of urban areas is most pronounced for cancer of the lung and bronchus, oral cavity, and esophagus. This urban excess is not characteristic of the data for stomach,, prostate, or bladder (208). INCOME CLASS Information on income class gradients in cancer risks by site was secured in the morbidity surveys of ten U.S. metropolitani areas in 1947-48 (91). 133 8

According to this source, incidence was inversely related to income class for five sites under review-oral cavity, esophagus, stomach, larynx,, lung. The rates for males in the lowest income class for esophagus and ltrng were about double those for high income males;, the range for the remaining sites was not quite so pronounced, the excess in low income risks being, on the order of 60-80 percent, For one site within the oral cavity, salivary glands, no: relationship was found between incid'ence and income class. The inverse gradient by income class, while present,, was much weaker among females for esophagus, stomach, and lung. The female risks for cancer of the oral cavity and the larynx were too small to permit meaningful state- ments on this t'opic. Incidence of bladder cancer was not relate& to income class for either males or females. OCCUPATION From unpublished'tabulations of deaths for 1950 according to occupation and indYrst'ry prepared by the National Vital Statistics Division of the Public Health Service (252), it is possible to select cert'ain occupations with un- usually high mortality for specific sites. One of the more striking results is the liability of bartenders, waiters, and others engaged in the alcoholic beverage trade to oral and esophageal cancers, the: mortality ratios beingg about double those for all males of comparable age. Similar findings have been reported by the Registr~ar-Generall of England and Wales (135)'. Review of the distribution of~ lung cancer risks by occupation indicates a large variety of occupational groups in metal working trades, such as mold- ers, boilermakers, plumbers, coppersmiths, sheet metal workers, etc., who are subject to a 70-90 percent excess risk for this site. One feature which does not come through clearly in the rather crude occu- pational mortality data is the high risk of bladder cancer among, workers exposed to aromatic amines, as established by observations on workers in individual plants ('179, 336)~. The 50 percent excess of bladder cancer mor- tality of workers in chemical and allied industries, reported in vital statistics, must represent a dilution of' higher risks in specific occupations in which the hazards are mu& greater. This dilution occurs because data from a number of industries and occupations, including many in which no partfie- ular bladder cancer hazard's are present, are pooled in~broad categories. ETHNIC GROUP Foreign.born migrants to the United States as a group have age-adjusted death rates for cancer of the esophagus and stomach about twice those re- corded for native-born white males and females. Lung, cancer mortality is about one-third higher among the foreign-born, again for both sexes. No important differential between native- and! foreign~born has been~ observed for oraP cancers (both sexes)' or for bladder (males) ; the rates for bladder cancer are about 30 percent lower for women born abroad than for women born in the Uhited States. Laryngeal cancer has not been systematically studied from this point of view (144). 134

The several ethnic groups in the United States display their own charac- teristic patterns of excesses and deficits in risk by site. Men and women born in~ Ireland have high death rates for oraI and esophageal cancers. The Polish-born Americans have pronounced excess mortality for esophageall and gastric cancers for both sexes, and Polish males rank first in lung cancer. The Russian-born, a large proportion of whom are Jews, show high death, rates for stomach (both sexes) an& a striking excess risk for esophageal cancer among women. The English-born American men and women, have above-average lung cancer risks. TftENDS Figure 5 describes the divergent behavior in mortality trends for cancer,, all sites, among men and women since 1930. The age.adjpsted death rate has been declining slightly in females, but increasing in males; most of the rise for males is obviously attributable to the sustained upturn in lung cancer certifications. The succeeding logarithmic graph (Figure 6)' portrays trends in mortality among whites for individual sites; nonwhites have been excluded because the comparability of data over time for this group would be affected more seriously by recent improvements in quality of death certifications. Lung cancer mortality among males has risen at a fairly constant rate since 1930; . for females the trend has also been consistently upward, but at a much slower pace. This form of cancer was responsible for the deaths of approxi- mately 5,700 women and 33,200 men in the United States in 1961. As recently as 1955, the corresponding, totals were 4,100 women~ and 22,700 men (252). The register and survey data: also have reported a marked rise in lung cancer incidence. No other cancer site has exhibited in recent history a rate of increase, absolute or relative, approaching that recorded! for lung cancer in males. Inspection of age-adjusted mortality rates for oral cavity, esophagus, larynx, prostate, and urinary bladder cancers pinpoints no dramatic shdflt in risk. The rates for stomach cancer, however, have been declining steadily. This has led some observers to conjecture that the rise in lung cancer and the decline in stomach cancer may represent two aspects of the same phenomenon, a progressive transfer of deaths to lung, cancer which might formerly have been certified as stomach cancer. Detailed examination of the data on possible compensatory effects by country, sex, age and other variables con- clusively rules out diagnostic artifacts of this type as a possible explanation. The Connectieut, and New York State registers (112, 136) an& t'he ten-city surveys (91) confirm the decline in gastric cancer and the absence of impor- tant changes over time for oral cavity, esophagus, urinary bladder, and kidney, and show a small increase for larynx. The registers also indicate a small rise in incidence of prostatic carcinoma; the age-adjusted rate in upstate New York increased from 21'.4 in 1941-43 to 24.9 in~ 1958-60, and the Connecticut experience revealed a similar displacement. A possible reason for this increase in case reports of prostatic cancer to registers may be found in more careful examination by pathologists of prostates removed 135 L

TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR CANCER BY SEX - ALL SITES AND RESPIRATORY SYSTEM IN THE UNITED STATES, 1930-1960. (l) 150 0 . .~, .. MALE 19601930 1940 FEMAL ® 1930 1940 1950 1950 1960 ••••-• CANCER, ALL SITES - CANCER, EXCLUDING RESPIRATORY SYSTEM --- CANCER, RESPIRATORY SYSTEM ONLY F9GURE 5. Age-adjusted to the total population o/'the continental United States, 1950. Source: Vital Statistics of the United States,,annual volumes: surgically, which would result in discovery and' reporting of more asympto- matic prostatic carcinomas. The mortality data relate to clinically active prostatic carcinomas and in this instance probably give a more accurate assessment of changes over time than the registry data: AGE-SPECIFIC MORTALITY FROM LUNG CANCER The schedules of age-specific lung cancer mortality rates for males studied in five successive time periods from 1914 to 1960 are shown in Figure 7 (dotted lines). It can be seen that the rate rises to a maximum at age 70 and then declines gradiially thereafter. Incidence data from~cancer registers provide a close parallel (112). 136 ~ ~ Ca

TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR SELECTED CANCER SITES BY SEX IN THE UNITED STATES, 1930-1960. ('Y l ~ - F EMAL ES 0 -- _ 0-- i ~ I . 5- ~ . . .. ~ E _- - 4.; . . I , Z ~ • i tt 1 I 5 I MALE S ~ • 0 0 0 0 0 0 • 0 0 LUNG AND BRONCHUS STOMACH BLADDER AND OTiHER URINARY ORGANS (EXCLUDING KIDNEY) PROSTATE ESOPHAGUS BUCCAL CAVITY'AND PHARYNX. LARYNX KIDNEY FtGVttE 6. Data are for the white,population,,age-adjusted to the total population o/, the continental United States, 1950: Sources: Gordon T., et al. (130) ; and unpublished calculations of the Biometry Branch, National Cancer Institute, UIS. Puhlic Health Service. However, when any separate cohort (a group of persons born dtrring the same ten-year period) is scrutinized over successive decades, the seeming downturn of mortality rates after age 70 can be seen to bean artifact due. I 137

AGE-ADJUSTED MORTALITY RATES FOR CANCER OF THE LUNG AND BRONCHUS BY BIRTH COHORT AND AGE AT DEATH FOR MALES, UNITED STATES 1914, 1930-32 , 1939-41, 1949-50, 1959-61. f 200 100 50 o. a LU a. a ; q0 I a~- 9 , ~--- _ -- ~- -- - - ~~ - - - . r / ~ I I i / / /' \ , . -~ -- --- --__..- -- - ---- ~.~~~- - --- _._ --.~-.---- ~ / __ 0 0 0 00 0 . 0 i : 0 9 30 20 3 .3 AGE FIGUAE'7: Data are for the white population. Sources: Dorn, H. F., and Cutler, S. J. (91). Unpubli'shed calEulations of the Biometry Btanch, National Cancer Institute, U.S. Public Health Service. to the admixture of cohorts with differing mortality experiences. When the points representing mortality rates among members of the same cohort group are connected, from each~ dotted'•line curve to the next, the new curve (each of the bold lines) represents the mortality rates over time for the members of a cohort. Thus, to cite the cohort born around 1880 as an example, the bolde llne curve shows the mortality, rates of the cohort in 1911 when its members were about 34 years old, in 1930-32 when they were about 51 years old, in 1939-41 when they were about 60 years old, im 1949-50 when they were about 70years old, and in 1959-61 when they were about 80 years old. The new, series of curves,, representing, the mortality' experience of the individuall cohorts, reveall two important facts :(a ) Within each cohort, lung cancer mortality increases unabated to the end of the life span;, and (b)) successively younger cohorts of males are at higher risks throughout life 138 ~939-41 1930-32 1914 0

AGE-ADJUSTED MORTALITY RATES FOR CANCER OF THE LUNG AND BRONCHUS BY BIRTH COHORT AND AGE AT DEATH FOR FEMALES, UNITED STATES 1914, 1930-32, 1939-41, 1949-50, 1959-61. 0), 0 m 20 F" 40 AGE m 60 m tE 90 FIGURE 8. Sources: Dorn, H. F., and Cutler,, S. J. (9L)_ Unpublished calculations of the Biometry Branch, National Cancer Institute;, UiS. Public Health Service. than their predecessors. The increasing steepness of the slope of the cohort mortality curves, beginning with the 1850~ cohort, and~ examining the cohort curves from right to left, shows that the rise in lung cancer mortality is much more rapid in the recent cohorts. The pattern would suggest that the effects noted may be attributable to differences in exposure to one or more factors or to a progressive change in populhtion composition among the several cohorts. For women, incidence and mortality increase up to the older ages, when the rates fluctuate irregularly (Figure 8). A cohort approach to the female experience reveals only small displacements in rates between successive cohorts, the effects being smaller than those noted for males. EFFECTS OF' CIIANGES IN! LUNG CANCER DIAGNOSIS ON TIME TRENDS The cause of death is at times difficult to establish accurately from~ clin- ica1 findings alone, and the incidence and mortality rates recorded fbr lung 139 J

cancer vary with the diagnostic criteria adopted (147, 148). A pathologic anatomic diagnosis provides the most reliable evidence for the classification of lung cancer deaths. Shifts in diagnostic standards or in diagnostic errors must be considered in evaluating the trends in lung cancer mortality shown in tabulations pre- pared! by the offices of vital statistics. In recent years, about two-thirds of the certifications of lunn cancer deaths have been based on microscopic examination of tissue from the primary site and the percentage is even higher for deaths under 75 years (146, 247)1, The proportion of lung cancer certifications in the 1920's and 1930's based on comparable diagnostic evi- dence is unknown, but the figure was certainly much lower. Gilliam (128) has attempted to evaluate the possible effects of diagnostic changes onn the published lung cancer mortality statistics: He caleulated that if two percent of the deaths certified to tuberculosis in 1914 were really due to lung cancer, the observed increase in bronchogenic carcinoma between 1914 and' 1950 could be scaled downi from 26- to 8-fold for males and from 7-fold to L3-fold fbr females. If 1930 or a later year had been used as the point of departure to estimate the effects of continued misdiagnoses of tuberculosis on this scale, the downward revision in the slope of the lung-cancer rates would' have been much smaller. The improved accuracy of lung cancer diagnoses must be concededy so that the issue remains a quantitative one: what part of the recorded increase can be accounted for by control of diagnostic variation? Retrospective adjustment of vital statis- tics from past years can yield only rough qualitative judgments (267), and we must re1W on the: composite evidence from several sources. The f'ollowing points have been advanced to support the thesis of a real increase in lung cancer (62) : (a) The rising ratio of male to female deaths (b), The increasing mortality among successively younger cohorts (e)The magnitudeof the increase in mortality in recent years To this we would add that the question can be resolved by referrence to the contemporary experience of large,, population-based cancer registers for which, a high percentage of the cases reported have microscopic confirma- tion. Sufficient time has now elapsed to permit the tumor registries in Connecticut (136). and New York (112) to supply convincing, evidence for a true increase in lung, cancer. Diagnostic comparability is a far less im- portant consideration in the review of data collected by cancer registries. Between~ 1947 and 1960 there were no significant advances in diagnostic methods (exfoliative cytology studies of the sputum have been used for diagnostic purposes since 1945)'. In upstate New York the age-adjusted incidence of lung cancer per 100,000 males rose from 17.8 in 1947 to 41.0 in 1960 and for females from 3.2 to 4.9. These figures imply an average annuall rate of increase of about 7 percent! for males and' 3-3.5 percent for females during this interval. For earlier years the relative frequency data from necropsy series con- tribute valuable information:. The records of large general' hospitals where diagnostic accuracy of lung cancer has been uniform and excellent~ for many years also support the thesis of a reall increase in lung cancer. Institutions such as the Universit'y of Minnesota Hospitals (Minneapolis) (350), Presby- 140.

terian HospitaP (New York City) (323)~, and the Massachusetts General Hospital (Boston) (54), now find many more lung cancers than in the past. In the Massachusetts General Hospital, for example, only 17 cases of brorn- chogenic carcinoma, 11 males and 6 females, were diagnosed in 5,3000 autopsies from 1892 to 1929 (autopsy rate of 33 percent), compared to 172 cases, 140 males and 32 females, in 5,000 autopsies from 1956 tb, 1961 (autopsy rate of 68 percent)1. This American experience is consistent with that reported abroad, where virtually all patients dying in certain hospital services have been subjected to autopsy for many years. Steiner (328)i summarized several such series and' Cornfield et, al. (62) returned to the original sources and found' the collective evidence to affirm a rise, in the percent of lung, cancers found at necropsy fromi 1900 om The Copenhagen Tuberculosis Station data, reviewed by Clemmeseni et al. (56), present an unusual opportunity for evalnating the effect of improve- ment in diagnosis on the time trend. In the Copenhagen tuberculosis referral service, used extensively by local physicians, where diagnostic standards and procedures including,systematic bronchoscopy remained virtually unchanged between 1941 and 1950, the lung cancer prevalence rate among male examinees increased at a rate comparable to that recorded by, the Danish cancer registry for the total male population. The rising trend for lung cancer during the past 15 years thus is welll documented. The increasing frequency of lung cancer found at necropsy from 1930 onwards while of itself not decisive, when considere& in the light of recent events reported' by cancer registers, would support the conclusion that the rise in lung cancer did not begin in the 1940 decade, but was a continuation of a trend begun earlier. CARCINOGENESIS Tobacco and tobacco smoke contaim a complex mixture of hundreds of different chemical components among which are (a) numerous polycyclic aromatic hydrocarbons and (b) inorganic compounds. Many of these:com- pounds have been shown to be carcinogenic in animals. For information on other components of' tobacco and tobacco smoke see Chapter 6. Before considering the biological evidence available for the carcinogenic eflect of these components of tobacco and tobacco: smoke, it may be helpful to review briefly some basic principles of carcinogenesis. FUNDAMENTAL PROBLEMS IN CARCINOGENESIS IN RELATION TO INDUCTION OF NEOPLA'STIC CHANGES IN MAN BY' TOBACCO SMOKE Carcinogenesis is a complex process. Many factors are involved. Some are related to the host, others to the agents. The host factors include genetic,, strain, and organ differences in sensitivity to: given agents; hormonal and other factors which modify sensitiivity, of cells; and nutritional state (123). The character of the agents involved in carcinogenesis varies greatly. Some agents by themselves cause irreversible alterations in cells which may 141

lead to the production of cancer; others promote the carcinogenic process. (21, 33). The former are called initiators, the latter promoters. Some subst'ances,such as urethan, can be both. Several classes of chemicals are known to be capable of inducing cancers (143). The chemical properties, the physical state of a substance, and the vehicle in which the substance is introdueedl into the body can influence the carcinogenic potency of environmental agents, e.g., insertion of! a plastic membrane into tissues can cause a cancer (2, 261, 347), but a fine powder of the same plastic has not done so (257). Carcinogens vary with respect to organ affinity and mechanism of inducing a neoplastic change. There is mounting evidence that viruses may also play an important role in the induction of tumors (137, 140; 345). It follows from these considerations that failure to produce cancer in a given test, by a given mat'erial, does not rule out the carcinogenic capacity of the same material in another species or in the: same species when applied under different circumstances. Conversely, induction of cancer by a com- pound in one species does not prove that the test compound would be carcinogenic in another species under simil'ar~ circumstances. Therefbre, tests for carcinogenicity in animals can provide only supporting, evidence for the carcinogenicity of a given compound or material in man. Neverthe- less; any agent that can produce cancer in an~ animal is suspected of being carcinogenic in man also. The types of cancers produced by the polycyclic aromatic hydrocarbons and other carcinogens depend on the tissues with which they make contact. Carcinogenesis can be initiated by a rapid single event, best exemplified by the carcinogenic effect of a split-second exposure to ionizing radiations (e.g., from atomic detonation) (40, 351)~. More often, however, it appears to be characterized by a slow multi-stage process, preceded by non-specific: tissue changes, as exemplified by cancers arising in burns. Evidence is pre- sented in~ another section ofl this Report that cancer of the lung in cigarette smokers, as well' as experimental cancer induced by presumed carcinogens in smoke, is preceded by distinct histologic alterations whic6 can progress to the development of "cancer in situ." These need not proceed to the formation of invasive cancer, and may regress following, removal of the stimulus: The character of "precancerous" change varies in~ different organs; e.g., in the bladder it is manifested by the formation of "benign" papillomas; in the oral cavity, by theJbrmation of white patches of thickened squamous epithelium-leukoplakia-al non-neoplastic reversible change. The evolved cancer is also subject to further changes. Often, rapidly growing variants develop, a process termed progression (119). Almost every species that has been adequately tested has proved to be susceptible to the effect of! certain~ polycyclic aromatic hydrocarbons identi- fied in cigarette smoke and designated as carcinogenic on the basis of tests in rodents. Therefore, one can reasonably postulate that the same poly- cyclic hydrocarbons may also be carcinogenic in one or more tissues of man with which they come in contact. Experimental studies have d'emonstrated! the presence of substances in tobacco and smoke which themselves are not carcinogenic, but can promote 142 ~s..;,..

carcinogenesis or lower the threshold to a known carcinogen. There is also some evidence for the presence of anticarcinogenic substances in~ tobacco and tobacco smoke (107). Threshold In any assessment of carcinogenicity, dosage requires special considera- tion. The smallest concentration of benzo (a) 'pyrene known to induce carci- noma when dissolved in acetone and applied to the skin of mice three times weekly is 0.001 percent (380). Subcutaneous cancer follows injection of only 0.00195 mg. of benzo(a)pyrene in 0.25 ml. tricaprylin. Whether there is a threshold for effective dosage of a carcinogenic agent is cont'ro• versial at the present time. The evidence.for the existence of a.threshold has been summarized by Brues (43):. When pulmonary tumors were in- duced in mice with dibenzanthraceneand'~urethan byH'eston et'1 al. (172, 232')1, a linear response was demonstrated at higher doses but a curvilinear re- sponse appeared at lower doses. At extremely low d'osage, the possible effect of the agent became obscured! by the incidence of spontaneous pulmonarytumors. In the case of induction of cancer by ionizing radiation, it has been claimed that there is no threshoU (210')1. It is conceivable that thersisno threshold for certain neoplasms, whereas there: may be one for others. Neither the available epidemiolbgic nor the experimental data are adequate to fix a safe dosage of chemical carcinogens belbw which there will be no response in man (43, 172, 210, 232). CARCINOGENICITY OF' TOBACCO AND TOBACCO SMOKE IN ANIMALS There is evidence from numerous~ laboratories (31, 42,92; 93, 1105, 1:32, 139, 263, 296. 297. 338, 3712, 373. 382, 383)~ that tobacco smoke cond'ensates and extracts of tobacco are carcinogenic for several animal species. Several laboratories obtained negative results (154, 262, 267, 268). The nature of the test system is critical in studies on carcinogenic activity ofl such complex mixtures. The relatively high suscept7bilityof mouse skin to carcinogenic hydrocarbons has made it a favorite test object (6, 278). A second test system also used is the induction of pulmonary adenomas in mice. This will be detailed in the section on Experimental Pultnonarv Car- cinogenesis. A third system which has been used less frequently is the induction of subcutaneous sarcomas in the rat whose connective tissues have been found to be susceptible to the carcinogenic action of many different chemicals as well as of complex materials. Another test, which has been used in some studies and can be read within five days after painting the skin of mice with a carcinogen, consists of determining t'he number of sebaceous glands and the thickness of the epidermis (342a). However, the reliability of this procedure as a bio-assay for. carcinogenesis is open to question. Skin. Many investigators have shown that the application of tobacco tar to the skin of mice and rabbits induces papillomas and'carcinomas (31, 42, 92, 93, 714-422 0-64-111 143

105, 132, 139, 263, 296, 297, 338, 372, 373, 382, 383)1. Wynder et al. (382) applied a 50 percent solution of cigarette smoke condensate in acetone three times weekly to the shaved backs of mice so that each received about 10 gm. yearly. The animals were usually painted for 15 months: More than 5 gm: annually was required for the induction of epidermoid carcinoma and more than 3 gm. for the induction of papillomas (372, 373). Since the carcinogenic potency of! a smoke condensate can be altered by varying condi- tions of pyrolysis, the manner of preparation of the tar is of importance (392). This may be one reason for the negative reports (154, 262, 267, 268) encountered in the literature. Extracts of tobacco usually have weaker carcinogenic activity than do the condensates of cigarette smoke (93, 390). Gellhorn (126) and Roe et al. (290, 293) have reported'that condensates of cigarette smoke have cocarcinogenic or promoting properties. It was found that the application of a mixture of! benzo(a)pyrene plus condensate of' cigarette smoke to the skin~ of mice resulted in~ the production of many neoplasms, whereas the same concentration of benzo (a) pyrene alone failed to elicit tumors. Gellhorn (126) found that the tobacco smoke condensate ap- peared to accelerate the transformation of papillomas to carcinomas. Anti- carcinogens have also been reported in condensates of cigarette smoke (107). Nicotine is not' usuallyy considered' a carcinogen on the basis of animal experiments (346, 3911). Removal of nicotine or other alkaloids did not diminish the carcinogenicity of condensates of! smoke for the skin of mice. The induction of pulmonary adenomas in mice by urethan~ (120)~ and! of skin tumors in mice by ultraviolet radiation (121) are not altered by the administration of nicotine or some of its oxidation prodlicts. Subcutaneous T issue Druckrey (92) found! that cigarette smoke condensates or alcoholic ex- tracts of eigarette tobacco regularly induced sarcomas in rats at the site of subcutaneous injections. The material was injected once weekly for 58 weeks, the totall dose administered being 3,2 gm. The animals were followed, thereafter, until death. Approximately 20 percent of the animals in each experiment developed the neoplasms. Druckrey also carried out similar ex- periments with benzo (,a) pyrene and found that the amount of this polycyclic aromatic hydrocarbon in smoke eond'ensates or tobacco extracts cannot account for more than a few percent of the activity of the tobacco products. This same discrepancy between the quantity of benzo(a) pyrene in smoke con- densates and the carcinogenic potency of the condensates has been reported by several investigators using the mouse skin test (192, 93, 126, 372; 390). Mechanism o f the Carcinogenicity o f Tobacco Smoke Condensate Tobacco smoke contains many carcinogenic polycyclic aromatic hydro- carbons (Table 2, Chapter 6). Benzo ( a) pyrene is present in much larger concentrations than is any other carcinogenic polycyclic hydrocarbon. The inability to account for the carcinogenicity of the tobacco products, except to a very minor degree, by the amount of benzo(a):pyrene present was unanticipated. Both Druckrey (92) and Wynder (372) emphasized that 144. O W ~ Q: C!' ~ ~ N

the benzo(a)pyrene concentration of various t'obacco and smoke prepara- tions is only sufficient to account for a very small part of the carcinogenicity of these: materials. One hypothesis suggests that promoting agents present in tobacco and tobacco smoke, such as various phenols, enhance the potency of the carcinogenic hydrocarbons so as to account for t'he biologieal activity of the tobacco products. Further, possible synergism between low levels of the severall known carcinogens in the tobaccol condensates and extracts may also enhance the carcinogenic potency. Other Materials of Possible Importancein, Carcinogenicity PESTICIDES Pesticides currently used in the husbandry of tobacco in the United States include DDT, TDE, aldrin, dieldriny endrin„chlordhne, heptachlor, malathioni and occasionally parathioni (see Chapter 6)1. The: first two are used more commonly than the others nearer the time for harvesting. TDE has been detected in tobacco and its smoke (242), an& endrin has been extracted from tobacco on the market (34, 35). Aldrin and dieldrin have been found to increase the incidence of hepatomas in mice: of the C3HeBiFe strain (68). Aldrin is metabolized to dieldrin, and the effect may be due only to the latter or some subsequent metabolite. DDT has been shown to induce hepatomas in trout (153) andl rats (253)~. The possible role of these compounds in contributing to the potential carcinogenicity of' tobacco smoke is not known (see also Chapter 6, section oniPesticid'es). LACTONES The lactones have been suggested as contributors to the carcinogenic effects of tobacco. Attention, was focused oni these compounds by the dis- covery (74, 74A, 291, 292, 362) thati,td-propiolactone, used as a sterilant and preservative, is carcinogenic,for mice. Coumarin„a 8-lactone, has been used as a common flavoring in t'obacco: Hydroxy- and methoxy-coumarins are constituents of the leaf itself and are carried over in the smoke. Also the y-laetone, ,(3.levantenolide, is present in both tobacco and smoke (354). The follbwing,lactones (not suggested to be present in tobacco) have been found to~ be carcinogenic for animals: y-lactones (patulin, penicillic acid, methyl protoanemonin)~ and S-lactones (parasorbic acid lactone and aflatoxins). RADIOACTIVE COMPONENTS Potassium 40, a/3-emitter; has been reported to be a source of radioactivity in cigarette smoke. The amounts of this activity taken into the lung, even by the heavy smoker, are minute when compared with the daily uptake of K 40 from the diet. Furthermore this material is highly, soluble and it is rapidly eliminated from the lung tissue thereby prevent'ing any local build~up (300a). The .-particle activity due to the radium~ and thorium content of tobaccoo smoke, even for the heavy smoker, is less than one:percent of the atmospheric radon an& thoron inhaled daily by any individual 047a) . A recent but still unpublfshed'report holds that Po 210 is the major source of radioactivityin~ cigarette smoke. The amounts calculsted! to be absorbed are higL enough to merit further study as a possible factor in carcinogenesis (282a)!.. No data 145

appear to have been~ published on the uptake by the tobacco plant of radio- active constituents from fall-out (e.g., Strontium 90 and Cesium 137). over a long period of time is not understood. but the biological action of mixtures of the:known carcinogens and promoters genic activity. Promoting agents have also been found in tobacco smoke and by painting the bronchial epithelium of dogs. The amount of known carcinogens in cigarette smoke is too small to account for their carcino- tion to the skin of mice and of rabbits, by subcutaneous injection in rats, Condensates of tobacco smoke are carcinogenic when tested by applica- Summary CARCINOGENESIS IN MAN ii Despite the many uncertainties in the application to man of'~ research results in animals, the animal data: serve a purpose in indicating potential careinogenicitiy. The greatest consistency is observed in respect to those groups of chemical compounds which are carcinogenic in~ many species. Several, of the polycyclic aromatic hydrocarbons present in tobaeco smoke f'all int'o this category in that they are carcinogenic for most animal~ species tested. Since the response of most human tissues to exogenous factors iss similar qualitatively to that observed in experimental animals, it, is highly probable that the tissues of man are also susceptible to the carcinogenic action of some, of the same polycyclic aromatic hydrocarbons. The results of exposing humans to pure polycyclic aromatic hydrocarbons or to natural products containing such compounds have been reviewed by Falk et; al. (108). Polycycl'ic Aromatic Hydrocarbons Cancer induction in man by the application of "pure" polycyclic aro- matic hydrocarbons has not been reported. Klar (1188) reported an epi- theliall tumor on, his left forearm that appeared three months after termination of an exper,iment in which mice were painted with 0.25 percent benzo (a) pyrene in benzene. Cottini and R'Iazzone (63) applied 1.0' percent benzo(a)pyrene in benzene to the skin of 26 volunteers in daily doses and observed& the sequentiall development of erythema, pigmentation, desquama- tion, and verrucae. The changes were more pronounced in older than in younger volunteers. After 120 applications, the experiment was terminated and the lesions regressed within, three months. Rhoads et al. (286) de- scribedl similar changes in human skin painted with the same carcinogen. These reversible changes were similar to the initial changes in the skin of men, who ultimately developed invasive cancers following industrial ex- posure to carcinogens: Cancer of the skin of the fingers has not been re- ported' in cigarette smokers, despite the intense discoloration so often seen at this site (212). Howeverr, spont'aneous cancer of the skin of the fingers is very rare. 146 1

SOOT Cancer of the scrotum in~ chimney sweeps subjected to prolonged massive exposure to soot was a common finding in the eighteenth century (279)~. As many as one in every ten men engaged' in this occupation developed can- cers (204). Sporadic cases of cancer of the skin~ at other sites, such as the face (60), the ear,, and the penis (264), were also: described. The neo- plasms usually oecurred~ in men between 18' and 47 years of age (213), possibly reflecting the early age at which boys entered this occupation. Whether there is an increase in cancer in persons now working in industries involving exposure to "carbon black" is being debated (108). The chemi- cal and physical properties of "carbon black" vary widely (109, 110). As early as 1922, Passey (266) found that cancer of the skin, could be produced experimentally by extracts of soots. More recently, Falk et a]. (111), showed that polycyclic hydrocarbons in the "carbon black" were present in processed rubber, and rubber extracts were found to be carcino- genic for the skin of mice. Also Falk and Steiner (I109, 110) found, furnace• type black rich in pyrene, fluoranthene, benzo(a)'pyrene, benzo(e)pyrene, anthanthrene,, benzo(g,, h, i)iperylene, and coronene in particles having an average diameter of 80 mµ or larger. These compounds were not present in channel blacks which have smaller particle size: The amount of benzo- (a) pyrene extracted from different soots varies from none to 2 mg. per gm. (307). COAL TAR AND PITCH Butlin ('50)in 1892 described cancer of the skin as an occupational hazard in the coal tar industry. The distillation of coal tar yields many different organic compounds wit6 a residue of pitch containing polycyclic aromatic hydrocarbons (300). Henry (166) reported that up to 1945; 2,229 of 3,753 cases of industrial skin, cancer-studied were attribute& to exposure to tar and pitch, the remainder to mineral oils. The latent period for in- duction of this type of cancer is estimated to be 15 to 25 years. Most reports about this type of cancer have come from England (166), but they have also appeared from other countries (44, 73, 231, 310)1. Bonnet (32) reporrted'an interesting case of pulmonary cancer in a workman exposed to hot tar containing three percent.benzo(a)pyrene. He estimated that 320 µg, of the carcinogenic hydrocarboni could have been inhaled' hourly. Car- cinogenicity of botih, creosote oil and anthracene oil for the skin of workmen has beenidocumented (18„39, 259). MINERAL OILS So-called paraffin cancer is not caused! by parafHn but by exposure to impurities in oils used in the process of purification (165; 203). Recent work (321) has confirmed the view that refined paraffin wax does not contain polycyclic aromatic hydrocarbons and that it is not, carcinogenic. The danger incidental to exposure to mineral oils has been decreased by extraction of carcinogenic hydrocarbons with sulfuric acid' (164). Bioassay of mineral oils indicates that their content of carcinogens varies with their 147

geographic origin (348)~. Animal tests show that the carcinogenicity of mineral oil' increases as the temperature of distillation increases or when, cracking is instituted for the formation of new compounds. A variety of carcinogenic compounds has been isolated from~ different fractions. Some fractions presumably free from benzo(a)pyrene have nevertheless been .found to be carcinogenic. Coal tar contains 0.3 to 0.8 percent benzo(a)i- pyrene, soot 0.03 percent, an& American shale oil 0.003 to 0.004 percent (51). SUMMARY There is abundant evidence that cancer of the skin can be induced in man by industrial exposure to soots, coal tar and pitch, and mineral oils. All of these 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. CANCER BY SITE The seveni prospective: studies described and summarized in Chapter 8' provide a natUral point of departure for considering the relative risks, for smokers and' non.smokers, of cancer at specific sites. The consolidated findings (Table 1) identify eight sites as displaying higher risks of cancer among cigarette smokers, who in recent decades have been the predominant consumers of tobacco. These sites are lung, larynx, oral cavity, esophagus, urinary bladder, kidney, stomach~ and prostate. The mortality ratios for cigarette smokers vis-a-vis non-smokers range in descending order from nearly 11 to 1 for cancer of the lung and bronchus to 1.3 to 1 for prostatic cancer. For five of these sites-lung, larynx, oral cavity, esophagus, and urinary bladder-cigarette smokers have a substantially higher cancer risk than non-smokers. The smaller excess risks among, cigarette smokers for cancer of the stomach, prostate, and kidney deserve comment. The prospective studies are. not in complete accord as to an association with smoking history, for cancer of! the prostate and kidney, and in some of the studies which were conducted with other objectives in mind, the relationships of prostatic and renal cancer with smoking history represent incidental findings. No other evidence can be adduced in evaluating and interpreting,the prostatic and renal' mortality ratios, since the effects were not large enough to draw the attention of investi- gators. For these reasons, cancer of the prostate and kidney will not be dis- cussed further at this time. This decision does not imply a conclusion that the findings must be artifacts, but rather that jiudgment on these sites should he suspended until more data become available. The case for considering cancer of the stomach in more detail is not much stronger than for prostate and kidney, but the consistency among the pros- pective studies is better. In addition,,the st'udies report a stronger association of~ smoking history with stomach ulcer. Clinical impressions of this relation- 148' -1.::....,. ..... ..'«~t..:,:...x„ ..".d:,...a. . .. , . -- .- ,.,~,......

TAsLE 1. Ezpected and observed' deaths and mortality ratios of current smokers o f cigarettes only, f or selected cancer sites, all other sites, and all causes of death; each prospective study and all studies United Cali- Calii Cana= Site of cancer British Men in States ! fornia fornia dian Men in Total' doctors 9 States veterans occupa- Legion ~ vrtcans 25 I ti0nal I States I Ltmg and Observed 129 233, 51 19 138' 98 317 399 1,933 bronchus, Expected 6.4 23;4 43;3 8.7 19.9 27,1 41.5 170:3 162-3a Ratio 20.2 , 10.0 I 12:0 - 15.9 4.9 11.7 9.6 10.8 Larynx, 161 Observed 7 17 r ' 14 3. 6 5 23 75 Expected 0.0 1.3 2.4 0.0 4.0 0.0 6.3 14;0 Ratio --------- 13.1 5.8 --------- 1.5 --------- 3.7 5.4' Oral Cavity, Observed 6 22 54 7 10 20 33 152 140-8. Expected Ratio 0;0. --------- 7.8 2:8 8.1 6.6 7:2 1.0 5.2 1.9 5.1 3.9 3.6 9.2 37:0 4:1 ESophagus,150 Observed ' 7 18 33' 4 9 22 20 113' Expected 3:3 2,7 5.2 5:5 1.8 6.8 8.4 33:7 Ratim I 2: 1 1 6.6 6. 4' 0.7 5.11 3.3 2.4 3!4'. Bladder„181 Observed 12 41 55 13 7 38 50 216' Expected 13.9 ' 17.2 31.4' 2.2 1.8 22.3 22.8 111.6 Ratio 0.9 I 2:4: 1.8 6.0 4.0 L7 , 2.2 1.9 Kidney, 180 Observed 8' 21 34. 10 6 13 28 120'. Expected 0.0 14.0 23:1 0.0 8.3 9.:5 24.1 79:0. Ratio ________ 1.5 1.5 _________ 0.7, li4 1.2 1.5 Stomaclii.151 Observed 31 76. 9ii. 24' 25 76 91 413'. Expected . 28:3 33:7 61.5 31.4 20-5 41i2 68.6 285.:2 Ratio L 1.1 2.3 1.5 0.8 1.2 119 1.3 1.4' Prostate, 17Z Observed 15. 51 106 4' 19 48 75 318'. Expected 29.0 32:4'. 53:7 8.6 22,.1', 32:3 74.9 2531.0. Ratio 0.5 1.6 2.0 0.5 0.9 115 1.0 1.3' All Other Sites. Observed , 116' 290. 671 141 106. 237 571' 2; 13T Expected 112.0 228.3 505.7 109.4 120.6 192:.1 473.8 1,692:.0. Ratio 1.0 1.3 1.3 1.3 0.9 L 2 1.3 1.3 ' All Causes of~ Observed ~- 6l 72 3; 781 7, 236 1,456 1, 264: 4,001 6,813 26; 223 Death. Expected 1, 161.8 2,:227:7 4,043, 1 818. 5 799.4 2;420..1i 4, 183.3 15;65319' Ratio 1.44 1.70~ 1.79' 1.78 1.58' 1:65~ 1163: 1.68 I Includes all cigarette smokers (durrent' and ex-smokers). 2 International StatisticaliClassification number. ship undoubtedly stimulated some of the case-control studies of smoking and stomach cancer which have been reported. Stomach cancer incidence and mortality have been declining, rapidly in the United States im recent years, simultaneously with the rise inJung cancer. This and the presence of addi- tional evidence from retrospective studies justify reviewing stomach cancer in more d'etail in this chapter. Thus the six cancer sites to be reviewed here are lung, larynx, oral cavity, esophagus, urinary bladder, and stomach. LUNG CANCER Historical The earliest suspicions of an association between smoking and lung cancer were undoubtedly evoked by the provocative clinical observations that lung cancer patients were predominantly heavy smokers of tobacco. Early investi- gators, including Miiiler (250) in 1939 and Schairer and Schoeniger (309)' 149 ~. . .._1..~ ... ~. , ......~_. .a.r-.H..

in 1943, were impressed not only with the clinical observations of a high proportion of tobacco smokers among lung cancer patients but also with the rise in the percentage of lung cancers in autopsy series in Cologne and Jena. Among the early observations in the United States were those of Ochsner and DeBakey (258) who were impressed by the probable relationship be- tween cigarette smoking, and luna cancer. The initial observations prior to Muller's work were not, however, corroborated by surveys including controls without lung cancer. As early as 1928, Lombard and Doering (221) in a studyof'~ cancer patients' habits in Massachusetts, wrote that "any study of the habits of individuals with cancer is of little value without a similar study of individ- uals without cancer." Their analysis of 217 cases of cancer and 217 controls identified, among other things, an association between heavy smok- ing (all types combined ) and cancer in~ general, and between pipe smoking, and oral cancer in~ particular. The pipe smokers then~ constituted the bulk (73.1 percent)i of the heavy smokers. This is of historical interest in rela- tion to the present-day percentage of heavy cigarette smokers. Further- more, since there were but five lung cancers in Lombard°s test group in an era before much of the rise in hing cancer incidence had occurred, the data were not adequate to demonstrate an, association between lung cancer and cigarette smoking. Probably the first study designed to explore this association system- aticallk- was by Miiller in 1939 (250) who had noted the increase in~ per- centage of primary carcinomas of the lung, being diagnosed at autopsy be- tween the years 1918 and 1937 in Cologne, an~ increase almost entirely in males. Although consid'ering other variables as possibly, related to the rise in lung, cancer mortality, such as increases in street dusts, automobilee exhaust! gases, war gas exposure in World War I, increased use of X-rays, influenza, trauma, tubercul'bsis, and industrial growth (air pollution?), he took special cognizance of the preponderant increase: of~ lung, cancer among, males and the parallel rise in tobacco consumption f'rom~ shortly before and since World War I and selec.tedl this variable for study. In what appears to be a caref'ully conducted inquiry of smoking habits in a series of 86 lung cancer patients and 86 apparently~~ healthy controls; matched by age,, a significant excess of heavy smokers was observed among the lung cancer patients. In the next ten years, three more case-control studies or comparisons withh cancers of other sites reached the literature (280, 309, 363) and from 1950 to the present time 25 additional retrospective (38, 82, 138, 147, 150, 152, 192, 199, 207, 211, 222, 236, 238, 277, 283, 301, 311, 314, 316, 335, 337, 365, 375, 379, 381) and 7 prospective studies (25, 83i 84, 87, 88; 96, 97, 157, 162, 163) were undertaken. Retrospective Studies The 29 retrospective studies of the association between~ tobacco smoking and lung cancer are sumarized in Tables 2 and 3. As these tables suggest, the studies varied considerablly in design and method. Methodologic varia- tions have occurred in the omission, inclusion, or;treatment of the f'ollowing: 150

METHODOLOGIC VARIABLES Subject SelectionL 1. Males and/or females. 2. Occupational groups 3. Hospitalized cases 4. Autopsy series 5. Total lung cancer deaths in an area 6. Samplings of nationwide lung cancer deaths Control Selection- 1. Age matching vs. age groups 2. Healthy individhals 3. Patients hospitalized for other cancers 4. Patients hospitalized! for causes other than cancer S. Deaths fromicancers of other sites 6. Deaths fromiother causes than cancer 7. Samplings of the general population Method' of Interviewing- 1. Mailed questionnaires 2. Personall interviewing of subjects (or relatives) and controls a): By professional personnel b) By non-professional personnel Tobacco-use Histories- 1. By type of smoking (separately and combined ). 2. By amount and type 3. By amount, type, and duration 4. By inhalation~ practices Other Variables Concurrently Studied- 1. Geographic distribution a) Regional bY Urban-rural 2. Occupation 3. Marital status 4. Coffee and alcohol consumption 5 Other nutritional factors 6. Parity 7. War gas exposures 8. Other pathologic conditions 9. Hereditary factors 10. Air pollution 11. Previous respiratory conditions This listing of methodologic variations is by no means complete, nor does it imply that't'he individual retrospective studies should be criticized for their choice of study methods and factors for observation. The individual points of criticism have usually applied to one or two studies but not t'oall. It is indeed striking that every one of the retrospective studies ofl male lung cancer cases showed an association betweem smoking and lung, cancer. All1 have shown that proportionately more heavy smokers, are found among the lung cancer patients than in the control populations and proportionately fewer non-smokers among the cases than among the con- trols. Furthermore, the disparities in proportions of heavy smokers between "test" groups and controls are statistically significant in all the studies. The differences in proportions of non•smokers among the two groups are also~statisticallly significant in all studies but one (236)I; in the latter study, although there were fewer non-smokers among lung cancer patients, the difference was very small. In the studies which dealt wi'th female cases of lung cancer~, similar find- ings are noted in all of them with one exception (238). In this latter study, although significantly more heavy smokers were found among, the lung cancer cases than among the controls, the proportion of non-smokers among the cases was distinctly higher than among the controls. This is the only inconsistent finding among, all the retrospective studies. Its meaning is not clear but the aut'hors have indicated that non-response among their female cases was 50 percent. The weight to be attached to the consistency of the findings in the retro- spective studies is enhanced when one considers that these studies exhibit considerable diversity in method'olbgic approach. 151

N ;.r:rAfia'Ls's TABLE 2.-Outline of methods used in retrospective studies of smoking in relation to lung cancer Number of persons and method of selection Investigator year and Country Sex of Collection of data , , reference cases Cases - - Controls MUller 1930 (250) Germany M 86 Lung cancer decedents, BOrger 86 Healthy men of the sanre age Cases: Questionnaire sent to relatives of Ilospital, Cologne. deceased. Controls: Not stated. Sehaircr and Schoenfger Germany M 93 Cancer decede.nts autopsied at Jena --- 270 Men of the, city of Jena aged 53 and Cases: Questionnaire sent to next of kin 1943 (309). Pathological Institute, 1930-1941: - 54(average age of lung cancer victuns= (195 for hmg canrer). Controls: Ques- - a3.9). - tionnaire sent to 700. Potter and'fully 1945 (280) U.S.A. M 43 Male patients aged over 40 in Mas- 1,847 Patients of same group with - Cases and controls interviewed in clinlc9 ---- - sachusetts cancer clinics with cancer diagnoses he rt ha n ncer. o t cx - ---- of respiratory tract. _ _ _ _ _ _ _ _ - - -- Wessink 1948 (363) Netherlands M 134 Male clinic patients with lung can- 100 Normal men of same age groups as Cases: Interviewed In cllnic. Controls: cer. cases. Not stated. Schrek et al., 19,50 (311) U.B.A. M 82 Male lung cancer niLses among 5,003 - 522 Miscellaneous tumors other than Smoking habits recorded during routine - -- - -- -- - - - - patients recorded, 1941-4!}. - Iung, larynx and pliarynz. - hospital interview. - . Mills and I'orter 1950 (237) U.$.A. M 444 Respiratory cancer decedents in 4;30 Samplo of residents matched by age Ca.ses: Relatives queried by mail ques- - in Detroit, Cincinnati, 1940-45 and in Cobunbus, Ohio, from census tracts tionnaire or personalvisit. Controls: _ 1942--16. " stratificd by degrec of air pollution. House-to-house interviews. Levin et al., 19.50 (207) U.8.A. M 236 Cancer hospital patients diagnosed 481 Patients in same hospital with non- Cases and controls: Routine clinical lung caneer. cancer diagnoses, history taken before diagnosis. " VJ der & Graham 1950 U.S.A. M-F 605 Hospital and private lung cancer --- 780 Patients of several hospitals with Nearly all data by personal interview; a - 381). patients in many cities. diagnoses other than lung cancer. few cases by questionnaire; a fow from intimate acquaintane,es. Some Inter- views with knowledge or presumption -- of diagnosis, some with none. - McConnellet a1.,1952 (236) England M-F 100 Lung cancer patients, unselected, 200 Inpatients of same hospitals, Personal interviews by the authors of - in 3 hospitals in Liverpool area, matcheil by age and sei, without c[m• both cases and controls, with few ex- 1940-19. - --- ---- cer, 1944-50. ceptions:__ Doll and Hill 1952 (82) Great M-F ,465 Patients with lung cancer in hos- 1 1,465 Patients in same hospitals, Personal interviews of cases and controls Britain. _ _ pitals of several cities. matched by sex and age group; some by almoners. with cancer of other sites, sofne with- out cancer. Sadowsky et al., 1953 (301) U.B.A. M 477 Patients with lung cancer I_n_ hos- 615 Patients in same hospitals with il1- Personal questioning by trained intsr- pitals in 4 states. nesses other than cancer. viewers. ~ 6z~`.4S94f:0 ,, _

wynuer and Cornneld U.d.A. M 63 Physicians reported in A.M.A. 133 Physicians of same group dying of Mailquestionnairetoestateso-deoedonts 1953 (379). Journal as dying of cancer of the cancer of certain other sites. lung. Koulumies 1953 (192) Finland M-F 812 Lung cancer patients diagnosed at 300 Outpatients of same hospital aged Cases and controls questioned about one hospital in 16 years. over 40, living in similar circum- - smoking habits -wh en- taking case stances, and without cancer, February histories. and March-1952: Lickin t 1953 (211) Germany M-F 246 Lung cancer patients in a number 2.002 Sample of persons without cancer Personal interviews by staff members of of hospitals and clinics. living in the same area and of same sex cooperating hospitals and clinics, and age range as cases. corresponding in time to Interviews of . . . . ... ..... . ... . . ea5es. Breslow et al., 1954 (38) U.S.A. _- M-F - 818 Lung cancer patients in il Califor- 518 Patients admitted to same hospitals Cases and controls questioned by trained n ia hospitals, 1949-52 about the same time, for conditions interviewers, each matched pair by the other than cancer or chest disease, same person. matched for race, sex, and age group. Watson and Conte 1954 U.S.A. M-F 301 All patients of Thoracic Clinic at 468 All patients of same clinic during The 769 consecutive patients of case and (365). Memorial Hospital who were diag- same period with diagnoses other than control Qroupswere questioned by the nosed lung cancer, 1950-52. lung cancer, Caine trained interviewer. Osell 19.M (138) -- - -- Switzerland -- M 135 Men with diagnosis of bronchial 135 Similar hospital patients with diag- Personal interviews, all by the same carcimmma. noses other than lung cancer, and of person. - the same age. Randig 1954 (283) Germany M-F 448 Lung cancer patients in a number 512 Patients with other diagnoses, Controls were interviewed at about the of West Berlin hospitals, 1952-.1951. - matched for a¢e: same time as the cases, each case- cqntrol pair by the same physician. 8tocks and Campbell 1955 (Preliminary; see 19.57 report below.) - (337). Wynder et al., 1959 (375) U.S.A. F 105 Patients with lunq cancer in sev- 1,304 Patients at Memorial Center with Cases: Personal Interview or question- eral New York City hospitals, 1953- tumors of sites other than respiratory nairemailedtocloserelatlves or friends - 5. or upper alimentary, 1953-1955. Controls: Personal lutervlew. Segi et al., 1957 (316) Japan M-F 207 Patients with lung cancer in 33 5,636 Patients free of cancer In 420 local Cases and controls by personal interview hospitals in all parts of the country, health centers, selected to approxi- using long questionnaire on occupa- 1053-55. mate the sex and age distributions of tional and medical history and living cas~s. habits. Mills and Porter 1957 (238) U.B. A. M-F 578 Residents of defined areas dying of 3,310 Population sample approximately Cases: From death certiflcates, hospital respiratory cancer; I947-55. proportional to oases as regards areas records, and close relatives or friends. of residence, and 10 years or more in Controls: Personal home visits or tele- the area. phone calls, usually interviewing housewife: -- Stocks 1957 (335) England M-F - 2,356 Patients suffering from or dying 9,362 Unselected patients of the same Cases: Histories taken at the hospital or with lung cancer within certain area admitted for conditions other from relativesby health visitors. areas. than cancer. Controls: Personai lnterview in hospital.

TABLE 2.-Outline of methods used in retrospective stu dies o f smoking in relation to lung cancer-Continued Number of persons and method of selection Investigator, year, and Country Sex of Collection of data reference cws_e_s_ Cases Controls Schwartz and Denoix 1957 France M 602 Patients with bronchopulmonary 1,204; 3 groups: patients ]n same hospi- Personal interviews in the hospital; cases (313). cancer in hospitals in Paris and a tals with -other cancer, with non- and controls at about the same time by few other cities. cancer illness, and accident cases, the same interviewer. matched by age group. - - ------ Haenszel et al., 1958 (150) U.S.A. F 158 Lung cancer patients available for 339 Patients in same hospital a nd service Personal interviews by resident, medical interview in 29 hospitals, 1955-57. _ at same time, next older and next social worker, or clinic secretary. younger than-each-case.--- Lombard and Snegireff U.S.A. M 500 Men dying or lung cancer, micro- 4,238 Controls in 7 groups including Personal interviews by trained workers. _ 1959 (222). scopically confirmed, 1952-5.9. volunteers, hospital and clinic pa- tients, random population sample, and house-to-house survey samples. Pernu 1960 (277) Finland M-F 1,606 Respiratory cancer patients in 4 1,773 Cancer-free persons recruited by Cases: From ease histories or mailed hospitals and from cancer registry Parish Sisters of 2 institutes in all questionnaires. between 1944 and 1958. parts of the country. Controls: Questionnaires distributed by Parish Sisters. - Haenszel et al., 1962 (147) U.S.A. M 2,19( Sample of 10 percent of white 31,516 Random sample from Current Cases: By mail from certifying physi- male lung cancer deaths in the U.S. Population Survey used to estimato cians and family informants. in 1959. population base. - Populatlon: Personal interview by Census enumerators. Lancaster 1962 (199) Australia M 238 Hospital patients with lung cancer 476 Twogr oups, one with other cancer, Personal interviews of both cases and one with some other disease, matched - eontrois in hospitals. by sex and age. Haenszel and Taeuber U.S.A. F 749 Sample of 10 percent of white 34,339 Random sample from Current Cases: By mail from certifying physi- 1963 1 (152). female lung cancer deaths in the Population Survey used to estimate cians and family informants. U.S. in 1858and 1959. - population base. Population: Personal interview by Census enumerators. I To be published. I-4 S911f;0 -a.

Germane to this concordance is a recent study (386) of Seventh Day Adventists, a religious group in which smoking, and alcohol consumption are uncommon. On the basis of expectancy ofi male lung, cancer incidence derived from the control population~ only 101percent of the cases expected were actually found among Seventh Day Adventists. FORM OF TOBACCO USE In considering the details of the individual retrospective studies listed in Tables 2 and 3, 13' of'~ the studies, combining, all forms of tobacco consump- tion, found a significant association between smoking of any type and lung cancer (138, 1199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381) ; 16 studies yielded an even stronger association with cigarettes albne as com- pared! to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236;, 237, 238, 277, 283, 301, 311, 314, 335, 379) when these forms -)f smoking were considered separately and in combinations for males. The females, in the studies investigating the relationship of smoking and lung cancer among them, were almost invariably cigarette smokers so that comparisons with other forms of tobacco use were not indicated. AMOUNT SMOKED Twenty-six of the studies quantitated the amount of smoking, per day either by combining weights of tobacco consumed in any form, or, more often, by quantities of the specific forms of tobacco. In each of the studies investigating male lung cancer, the degree of association increased as the amount of smoking, increased (38, 82, 138, 147, 150, 192, 199, 211, 222, 236, 250, 277, 280, 283, 301, 309, 311, 314, 316, 335, 363, 365, 379, 381). One retrospective study (82) by Doll and Hill found a sharper difference in amount smoked between cases and controls among recent smokers (10 years preceding onset of the disease) than in a: comparison of the maximum amount ever smoked. The authors cautione& against accepting this finding as being against their hypothesis of a gradient of risk (which would more properly be tested by the whole life history of! "exposure to risk") by citing the inaccuracies resulting from "requiring the patient to remember habits of many years past." Of the 11 retrospective studies with data on females and tobacco use by amount smoked daily, six (211, 236, 277, 283, 365, 381) showed trends of increasing, association with amount smoked daily, but had too few cases for reliability of the trend. However, five studies (82, 150, 152, 335, 375) did have large numbers of female lung cancer cases for analysis by smoking class; three of these (150; 152, 375) were directed towards female cases only. In each of these latter five studies, the degree of association increased with the amount of cigarettes smoked daily. Four of the retrospective studies dealt~ with ex-srnokers as well (147, 152, 211, 314)~; in one of these (31i4.), where relative risks were derived indirectly by the Cornfield method (61), and in another by conventional use of' stand- ardized mortality ratios (147), male ex-smokers showed a lower risk than 155 -A

TABLE 3.--Croup characteristics in retrospective studies on lung cancer and tobacco use Authors $efer-. enCe Year MOller _____ (250) 1939 Schairer & Schoeniger=== (309) 1943 Potter &'Fully -_ _ (280) 1945 Wassink____ ____ (363) 1918 Schrek et al_____________ '311) 1950 Mills & Porter__________ (237) 1950 Levin et al______________ (207) 1950 Wynder & Flraham_____ (381) 1950 McConnell et al_-.______ (236) 1952 Doll & II111_____________ (82) 1952 Sadowsky et al.._____-__. (301) 1953 Wynder & CornOeld___. (379) 1953 #oulumles__________ ____ _ (192) 1953 Lickint_________________ (211) 1953 Breslow et al____________ (38) 1954 Watson & Conte________ (365) 1954 Osell-------------------- (138) 1954 RandlB--------------•--- (283) 1954 Stocks & Campbell__.__ (337) 1955 Wynder et al_=_____-____ (375) 1956 Segtet al________________ (316) 1957 Mills & Porter__________ (238) 1957 Stocks------------------ (335) 1957 Schwartz & DenolY._ (313) 1957 Haenszelet al_:______(150) 1958 Males Females Cases Controls Cases Controls Remarks Num- Percent Percent Num- Percent Percent Num- Percent Percent Num- Percent Percent ber non- heavy ber non- heavy her non- heavy her non= heavy smokers smokers ~ smokers smokers I smokers smokers r smokers smokers I 88 3.5 85.1 80 18.3 36.0 93 3.2 31.2 270 15.9 9.3 (•) (•) 181emale cases not 43 7. 0 30.2 1,847 26.0 23 0 ? S ( (q 134 4.8 54.8 100 19.2 19.2 (') extlm Percentages chart. 82 14.6 18.3 522 23.9 9.2 (t) 444 7.2 S •? 430 30.5 (•') (•) 236 15.3 (") 481 21.7 (") (') Quantity smoked sldered . 605 1.3 51.2 780 14.8 19.1 40 57.5 25. 0 552 79.6 1.2 93 5.4 38.5 186 6.5 23.2 7 67.1 (") 14 78.6 (") 1.357 0.5 25.1 1.357 4.5 13.4 108 37.0 11.1 108 54.6 0.9 Percentage "heavy understated. 477 3.8 (") 615 13.2 ('•) (') (7redient with smoked. 63 4.1 87.8 133 20.8 29.3 f') (') (') ( ) (~) (') 812 0.8 58.9 300 18:0 25:0 f••) (•') ('•) (•) (') (') 224 1: 8 35.8 1.000 16. 0 4.8 22 64.0 4.5 1, 002 90.4 0. 1 b18 3.7 74.1 518 10.8 42.7 (•') O (•') (") (") ('•) Data include 493 females. 265 1.9 71.7 287 9.7 51.8 36 58.3 2.8 181 82.0 1.1 135 0.7 68.1 135 16.0 14.0 (•) (') (') (•) (*) (') 415 1.2 34.2 381 5.4 17:9 33 51.5 3.0 131 70.3 0 (See reference ( 335) helow ) ('3 (') (') 105 56.2 16.2 1,304 66.0 3. 4 166 (••) (•') 2,124 (") Quantities smoked averages only. D are statistically s 484 8.4 26.0 1,588 27.6 5.3 94 83.0 4.3 1,722 73.3 0.8 Percent "heasy" understated. O survey respons female cases. 2,101 1.0 28. 2 5,960 8.7 22.3 255 67.6 17.2 3,402 88_ 8 10.7 602 1 58. 2 1,204 9.6 36.2 (') (') (') (') (') (') (*) (0) (') (') (•) (') 158 51. 9 14.6 A.~9 6n 6 A 2 analyzed. ated from not oon- " smokers amount males, 25 stated as iffereneee ignificant. smokers nly 50% e among C`'LS94f:U

} ombard & L Snegirott____ (222) 1959 500 1.6 ('•) 4,238 11.0 (••) Authors' calculations fo heavy smoking o based lifetime number of pack of cigarettes. emu___________________ (277) 1960 1,477 6.6 34.5 713 37.2 20.8 129 85.3 26.4 1,060 91.6 0.7 Quantitl es given only I Haenazel et al___________ (147) 1962 2.191 3.4 41.9 f') 16.2 12.0 - grams per day. Population sample of 31,61 used as base. Not a case controi study. . ancaster--------------- (199) 1962 238 2.5 86.1 476 20.1 71.2 Haenszel & Taeuber_••_ (152) r19fi3 (•) (•) 749 60.9 11.5 (1) 67.3 2.5 Population sample of 34,33 used as base. Not a cese control study. I For this table heavy smokers are deflned as those smoking 20 or more cigarettes per day. I To be published. - •Does not apply. '•Data not given. r n a n 6 = 9 •

current smokers but greater than non-smokers. In a third study (152) of lung cancer in women, the ex-smoker risk was lower than the current-smoker risk but approximately equal to that for the non-smoker. i 0 DURATION OF SMOKING Duration of smoking was considered im 12 of the retrospective studies (82, 150, 207; 222, 236, 283, 301, 311, 316, 335, 375, 381). In only six of them, however, were : the data treated im such a way as to permit evaltiation of the relationship between duratiom of smoking and lung cancer-two studies in males (207,, 301) ; two in males and! females (82, 236)~; and two in females only (150, 375). Among the studies of male lung cancer, Levin (207), correcting his data for age, found a relationship between the number of years of cigarette smoking and lung cancer. McConnell (236) found a significant difference in duration of smoking, between cases and controls, but was reluctant to draw any definite conclusions. On the other hand, Dolli and Hill (82), in their age: and sex-matched study, showed a distinct and statistically significant association between the duration of smoking among males. In a well-conceived analytic study, Sadowsky et al. (301), recognizing that' duration of smoking is a function of age„ controlled the age variable, and found an increasing prevalence rate of lung cancer with an increase in duration of smoking among all age groups (age at diagnosis). Among the studies including data on female lung cancer, McConnell had too few female cases to resolve the question ofl dbration of smoking (236) and Doll and Hill, though finding differences between cases and controls, could not establish statisticall significance (82). In the two investigations in which only female lung cancer cases were studied (150, 375), neither showed an independent association between, duration of smoking and lung cancer. Haenszel states, however, that "among women, the association of' starting age and duration of tobacco use with current rate is so strong that it may be unrealistic to expect' to find a separate duration effect in retro- spective studies of limited size" (150). AGE STARTED SMOKING Closely related' to duration of smoking, and thus pertinent to the length of time that subjects have been, exposed to tobacco smoke is the variable of age when smoking was startedl Relatively few of the retrospective studies have dealt with this variable. Koulumies (192) found that males with lung, cancer had started smoking significantly earlier in life. In fact, 143 of his 845 cases or 17 percent began to smoke below 10 years of age as compared to 6.5 percent among his matched controls. The study of male cases and controls by Breslow et al. (38) found a definite trend in the same direction. Pernu (277) found a statistically significant difference in age at start of smoking, with a higher proportion of the male lung cancer group starting at under 15 years of age. Lancaster (199) indicated that the male lung cancer patients began to smoke at a significantly younger age. One other study (283) showed no difference. Of the three investigations of female lung cancer which explored this variable, there were too few smokers in one study for a test of significance (277), and in the remaining two (150, 283), no differences were found. 158

INHALATION If the association between smoking, particularly cigarette smoking, and lung cancer is a causal' relationship, then inhalation, should provide more exposure than non-inhalation and should thus contribute significantly to the lung cancer loadl Four retrospective investigations were addressed to this question. In the earlier Doll and Hill study (82), no difference in the proportioni of smokers inhaling was found among male and female cases and controls. However, four subsequent studies of men (38, 211, 222, 313')) found' inhalation of cigarettes significantly associated with lung cancer. Although in Breslow's study (38) of age-, sex- and race-matched case and control patients, the variable ` quantity-smoked" was not held' constant in the comparison when type of smoking though not quantity was controlled, an association was found! between inhalation and lung cancer. In the studyy by Schwartz and Denoix ('3'13) who held constant both type of smoking and' amount of cigarettes smoked, the relationship of inhalation was significant for those smoking cigarettes alone but not for the smokers of both cigarettes and pipes. Furthermore, although inhalers among lung cancer patients averaged a significantly higher number of cigarettes per day than dld the controls, the relative risk differences between inhalers and non-inhalers, calculated' by the Cornfield method (61), become smaller and almost equal each other at the highest cigarette consumption levels. Lombard and Snegireff (222) demonstrated similar relative risk ratios. HISTOLOGIC TYPE The earliest retrospective study which considered histologic type of lung cancer was by Wynder and Graham (381) in 1950: These authors presented data on smoking habits of male and female adenocarcinomatous patients and for female patients with epidermoid cancers which were but 25 in number. With this partial analysis only a hint of' a higher proportion of smokers among female epidermoid cases could be derived. Of the 1,465 lung cancers in the Dolll and Hiill retrospective study(;82) , 995 werehistologically, con- firmed (916 males and 79 females). Of the confirmed cases, 85 percent of thee males and 71 percent of the females were of the epidermoid or anaplastic types. Although no statistically significant difference in smoking habits was elicited for the several types, a relatively higher proportion of non-smokers and light smokers were found among patients of both sexes wit'h ad'enocarcinoma. Following the presentation by Kreyberg, of a Typing Classification of the epid'ermoid and oat cell or anaplastic types as Group I and the adenocar- cinoma and bronchiolar or alveolar cell types as Group II', and the suggestion of' a relationship between Group I and smoking (196), several ensuing retrospective studies dealt with this question. Breslow's study revealed a higher percentage of non-smokers among the patients with: adenocarcinoma than among those with epidermoid types (38). In rapid succession six additional retrospective studies analyzed the rela- tionship between histologic type of lung cancer and smoking. The 1956 study of female lung cancers by Wynder et al. (375) indicated that adeno- carcinomata apparently had little or no relationship to smoking but that a relationship did exist between smoking and the epidermoid and anaplastic: types. Schwartz et al. (313), similarly, in 1957, found a highly significant 714-422 0-64-12 159

association between, smoking of cigarettes, amount of smoking as well as inhaling, and the epidermoid and anaplastic types of tumors. No such association with "type cylindrique" was noted. In that same year Doll and' Hill furnished Kreyberg with lung cancer slides from 933 British patients. Kreyberg, without knowledge of the patients' smoking history or clinical data, separated these into two groups. A strong correlation was found between smoking history and histologic type; smoking and amount were highly associated with~ the epidermoid and anaplastic types, and non-smokers were predominantly among the adenocarcinomatous types (86). In this study of lung cancer in women, Haenszel, et al. (150) found statis- tically significant relative risk gradients for amount of cigarette smoking among Group I cancer patients. No increased risk was established for Group II cancers: In his later study of a current mortality sample of white males for 11958, Haenszel found relative risk gradients f'or the several smok- ing classes for both adenocarcinomas and epid'ermoid' cancers (147). A parallell study of white females for the current mortality sample of 1958 and 1959 showed essentially the same findings, except possibly for a lower effect on adenocarcinomas among smokers of less than one pack daily (152). Haenszel points out that: in both these studies a "true differential in risks" for the two histologic types could well have been dilYrted seriously by report- ing and classification errors whi& were definitely known to exist from re- inquiry of a sub-sample of deaths (152)1. (iFor current evaluation, see section on Typing of Lung Tumors. ) RELATIVE RISK RATIOS FROM, RETROSPECTIVE STUDIES Retrospective studies are usually designed to establish the probability of association of an attribute A with disease X; or, given disease X, what is the probability that A will be found in association (P [AJX] )~? Pro- cedurally, one compares a supposedly representative group of patients with disease X, witL another group as controls, in regard' to the percentages of individuals with and without the attribute A. This procedure may reveal significant differences leading to judgments of association but it does not yield' an estimate of the magnitude of the relative risk of disease X among those with attribute A and those without. A method which estimates this relative risk, developed by Cornfield (61):, has been referred to several times earlier and can be applied to data derived from retrospective studies if two assumptions, inherent in the first procedure of judging the association, are made: (a) that patients with disease X interviewed or otherwise studied are a representative sample of all cases with disease X, and (b) that thee controls without disease X or who have escaped disease X are a representativee sample of all persons without disease X. An estimate of the prevalence of disease X in the population is a requisite. Such an approach was utilized by a number of investigators in retro- spective studies on lung cancer. Dolll and' Hill (82) made similar calcula- tions and found a linear gradient of deaths f'rom~ lung cancer for men~ and women increasing with amount of tobacco smoked daily. Sadowsky et al. (301) found similar increases in risk for amount smoked' daily in virtually all but the oldest age groups and calculated an age-standardized risk ratio of 4.6:1 for all smokers compared to non-smokers. These authors also 160 I

utilized the data of Wynder and Graham (381) an& Doll and Hill (82) for calculating similar risk ratios, deriving ratios of 13.6:1 and 13.8:1, respec- tively. Their calculations of estimated prevalences by quantity smoked daily for age groupings similar to their own also showed linear increases of risk. Breslow et al. (38) treated their retrospective data similarly and developed relative risk ratios of 7.7:1 for males aged 50-59 years and 4.6:1 for those aged 60-69. In considering heavy smokers (40 or more cigarettes per day), they showed relative risk ratios of 17:1 and 25.5:1, respectively. Randig (283)' also demonstrated a linear progression of risk with increasing amounts of daily tobacco consumption and an over-all ratio of 5.1:1 for all smokers to non-smokers among males and 2.2:1 for females. Schwartz and Denoix (313)' reported' similar findings in amount smoked daily and a risk ratio of smokers to non.smokers of approximately 8:1. Lombard and Snegireff (222) approached their data in a different way, utilizing,"life- time number of packs of cigarettes consumed" as a measure of exposure. Their estimated' prevalence rates also increase linearly' with amount smoked. The risk ratio which can be calculated from their tabulated data ranges from 2.4:1 for light smokers to 34,1:1 for heaviest smokers. Haenszel, in his two studies on male and female lung cancer mortalitv as related to residence and smoking histories, calculated relative risk ratios of 4.1:1 for one pack or less daily and 16.6:11 for more than one pack a day among males (147), and 2.5:1 and 10.8:1, respectively, among females (152). Table 4 summarizes the relative risk findings of the nine studies. TABLE 4'.-Rel'ative risks of lung cancer for smokers from retrospective studies Author and~ Reference Year Sex Relative risk-Smokes:': non-smokers Sadowsky et~ al. (301) 1953 M 4.6 Doll and Hill (82) 1952 M 113.8 K'qnder and Graham (381) 1950 1 M i 13:~ Rreslow et al. (38) 1954 M 7.7 aee 50-59 4.6 " 60--fi9: ' 17.0 " 50-59 ' „ }veryheavysmokers ~.5 ~9 Randig. (283) 1954 M-F 5. 1 M. 2.2 F Schwartz and Denoix (313) 1957 M 8.0 Lombard and Snegireff (222). 1959 M 2.4 ]ight'smokers 34.1 heavy smokers Haensul (147). 1962 M 4.1<1~pack/day. 16.6>i pack/day. Haenszel (152)' Unpnblishedl F 2.5<1 pack/day 10.H>1 pack/day 1 Calculated by Sadowsky et a11 (301)' from other autliors' data. Prospective Studies It lias 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

i J, a 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 studfes may not truly assess the existent risks with reasonable accuracy. However, when all the cases of a disease in an~ area and a representative sample of the population without the disease are 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 om an Evaluation of the Association Between Smoking and Lung Cancer. Suffice it to say at this point that certain shortcomings of the retrospective survey approach, some real and some exaggerated, led severall 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, 84)'. There then followed im rather rapid suc- cession, five additional independent studies in the United States and Canada (25, 87, 88, 96, 97; 157,,162, 163), all' but one of which continue to be active. The earlier study, by Hammon& and Horn, among,187;783 white males aged 50-69 years, initiated between January and May 1952, was terminated after 44 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 1.085,000 persons (in25 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- sociatiom between cigarette smoking and total death rates has increased as the studies have progressed. This has particularly beem true for lung can- cer. The presently calculated total mortality ratios have been presented im 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 am 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't 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 observe& and expecte& values of most recent' data. 162

Several of the studies have fortunately provided data for a measure of the "dose of exposure" relationship (84, 88, 96, 157, 163). It can readily he 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 ratioss lower than any of the cigarette smoking classes, including combinations of cigarettes with pipes and%or cigars (25, 84, 88, 157,,163 ). 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 upom the length of the interval since smoking was stopped. In the Doll and Hill study (83), 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 H'orn study (163). 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 (87, 88), currently brought up,t'o date (89')~, provides a measure of relative risk by amounts of smoking prior to st'opping. 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 smokedl daily, but of thee degree of inhalation, with smokers starting at earlier ages very distinctly tending to smoke more and inhale more deeply than those starting,to smokee at older ages (157). According to Hammond, men who smoke more per day also tended to inhale more deeply thani 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 clhsses are calculated! Referring again to Table 5, in at least two of the studies (83, 96), caleulationi of the expected deaths among smoker classes had to be based on extremely small numbers of non-smokers. However, 163

i ~14,ss44Co ,~--,.--,--- TABLE 5.-Mortality ratios f or lung cancer by smoking status, type o f smoking, and amount smoked, f rom seven prospective studies Dunn, Dunn, Best, Study Doll and Hammond Dorn Linden and Buell and Josie and Hammond H111 and Elotn Breslow- Breslow- Walker Occupational Legion - Lung cancer deathsin Study--------------------------------------------- 129 -- 448 536 - 139 98 221 --- - 414 Lung cancer deaths Non-smokers---------------------------------------- 13 t25 }68 }3 f12 18 t18 - - (Reference number) (83) -- (163) (88) ---- (96) (97) (25) - (1b7) MORTALITY RATIOS: - All Smokers---------------------------------------------------.----- 12.8 - 10.7 6.0 - -. '2b.2 t8.1 1-14 gm. tobacco-------------------------------------------------- 8.7 - =- - - - - 15-24 gm:tobacco------------------------------------------------- 12.3 - - - - - - -- 25 gm:tobacco---------------------------------------------------- 23.7 - - - - - - - • Current: " Cigarettes only--------------------------------------------------- t2d• 2 }10.0 t12.0 }15.9 t4.9 }11. 7 t9.8 <10---------------------------------------------------------- ------ - - 4.4 t5. 8 r5. 2 5)- 8.3 }8: 4 10-20 . ... 10:8 }7.3 Y9. 4 ~10)- 9.0 - ... Y13:5 - 21-39 __ __---- --- ___ ---- -- `-~ -------------------------------------------- ----- - -- --------- -------------- - 1 y 43.7 / f15.9 121.7 t18:1 t23:3 (20)-19.4 (30)-25.1 - 1 . . f t16.1 _ (40) 28. 7 ;5 1 pack ?------------------------------------------------------------ 8.1 8.9 8.1 13.6 4.2 11.8 >1 pack t------------------------------------------------------------- 43.8 16.9 18.0 24.1 7.4 I5:1 Pipes only- , b. 4l 2 8 1. 3j _ --- Cigars only ------------ - } } t4. 8 1.0~ }1. 3 1. 5 } L1. 8 - };1.1 } 11. b Pipes and clgars-------------------------- f JJJ _ - - I - - JJJ 111 Cigarettes, pipes and clgars------------------------- _ _______________ 9.7 10.7 8.2 - - t24.4 - Occasional------------------------------------------------------------ - 1.3 - - - - - Ex-Smokers: - >10 yrs0 since stopped-------------------------------------------- 5.0 - - - - - - <20 cigarettes------------------------------------------------ - 2.4 - >20 cigarettes-------------------- ---------------------------- - 17.8 - - - <10 yrs. sincestopped-------------------------------------------- 8.4 _ - - - - <20 cigarettes--------------------------------- --------------- - 10.4 - - - - - >2D clgarettes---------------------------°------------------- - 22.8 - - - - - <20 cigarettes (lrrespective of when stopped)______________ ______ - - t1.3 - - - - >20 cigarettes (irrespective of when stopped)_______________ - - t1.8 - - - - 'Current and ex-smokers combined. tMost recent information. -Data not avallable ar not available for designated clasaes. ••Two California studies and current Hammond study include all cigarette smokers (cigarettes and other and current and ez-cigarette smokers). ,

the other studies have now yielde& 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 ATTEMPTS 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 (331). Mice rarely develop spontaneous bronchogenic, oral, esophageal. gastric, prostatic, lhryngeal, or vesical carcinomas, but cerrt'ain~ inbred strains have a high incidence of spontaneous pulmonary adenomas (6). 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 regarde& as beni¢n,,and probably arise from the alveolar epithelium (4, 5, 6, 13!1i, 330) rather than the bronchial walll They have no resemblance to most humani bronchogenic carcinomas. Essenberg (106) and Miihlbock (248)' exposed mice to cigarette smoke, but their reported results are equivocalL 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 alL (205a.): described a sequence ofi microscopic changes in htngs 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 proliferationi of the epithelium. Some areas of hyperplasia showed atypicall 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 (1273, 274, 275). Blacklock (29): found one car- cinoma when tar from cigarette filters was placed in olive oil together with killed tuberele 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: SoM MA.xY.-Bronchogenic carcinoma has not been produced by the application of tobacco extracts, smoke, or condensates to the lung or the tr~acheobronehial tree of experimental animals witL the possible exception of dogs. 165

i' SUSCEPTIBILITY OF LUNG OF LABORATORY ANIMALS TO CARCINOGENS POLYCYCLIC AROMATIC HYDROCARBONS.-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) induce& epiderrnoid carcinomas in the lungs of rats by the local application of polycyclic aromatic hydrocarbons, either by thread transfixation or pellet implantatiom Distant metastases occurred from some of! the carcinomas. The changesin the bronchial tree at different 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 inAhe 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 benzo(a)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. VIRidsEs.-Bronchogenie 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 CARCINOGENS.-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- genic 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 incllided 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 gpinea 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), Sunderrnan and Sunderman (342) in- duced bronchogenic carcinoma in rats by exposure to this compound. This 166

i group also found 1.59 to 3.07 µg, 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 chromiumi 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 cani be produced without difficulty in experimental animals by inhalation of asbestos fibers (359)', but efforts to produce bronchogenicc carcinoma have been unsuccessful (129, 181, 227, 358)'. SLJ:KMAxY: The lungs of, mice, rats, hamsters, and primates have been found to be susceptible to the inductyoni of bronchogenic carcinoma by thee 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 indwcedl tumors. Link- age betweeni multiplL genes for susceptibility to spontaneous and induced tumors in, mice and specific chromosomes has also been established (47, 168) an& transplantation experiments (171, 173) indicate that the genetic susceptibility resides within the pulmonary parenchyma. A number of in- vestigators (136, 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 been investigated only superficially. SuMm[ARY.-Genetic susceptibility plays a significant role in the develop• ment of pulmonary adenomas in mice. Pathology-Morphology RELATIONSHIP OF SMOKING TO HISTOPATHOLOGICAL CHANGES INI 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 ~A

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, (b) 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 illustrations below). Hyperplastic changes were also seen in the bronchialiglands. TABLE 6.-Percent of slides with selected lesions,' by smoking status and presence of lung cancer Group Percent of slides with cilia absent and averaging 4 or more cell rows in depth Number cases , Number , slides No :cells atypical sOme oells latypical All I cells atypical 3 Total Cases without lung cancer Never smoked regular]y-------------- 65 3,324 110 0.03 - 1. 1 Es-cigarette smokers-_--------------- 72 3,436 3.5 0. 4 Q 2 4.1 Cigarettes-S~ pk. a day-------------- 36 1,824 0.2 4. 2 0.3 4.7 Cigarettes-Sti-1 pk. a day------------ 59 3,016 h--------- 7:1i 0.8 7. 9 Cigarettes-1~2 pks: a day----__----- 14.3 7,062 12: 6 4.3 16. 9 Cigarettes-2+ pks: a day_----------- 36' 1,787 26.2 11.4 37:5 Lung,cancer cases °---------------- ------- 63 2, 784 12.5 14.3 28.8 I ]n some sections, two or more lesions were found. In such instances, all of the lesions were counted and are inc]uded in both individual columns and in the total colhnin of the table. Lesions found at the edge of an ulcer were excluded. r These lesions may he called careinoma-in-situ. J Orthe 63 who died of lung cancer, 55 regularlysmoked'cigarettes up to thee time of diagnosis, 5 regularly smokedicigarettes but stopped before diagnosis, i smoked cigars„1 smoked pipe and'eigars; 1 was an occa- sionalicigar 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 epithelium with a thick layer of cells resembling stratified squamous epithelium. 3. Extensive basal-cell hyperplasia with numerous atypical cells. Source: Auerbach, Oscar. Special communicationi 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 atypicali 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. The most severe lesion, aside from invasive carcinoma, consisted of! loss of cilia,, and hyperplasia up to five or more cell rows 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). Nb 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 meniwith respect to additional variables~- sex, age, pneumonia, and amount smoked. One or more epithelial lesions were found ini 68.2 percent of sections from men smokers and 68.6 percent from womeni smokers when matched groups were examined. However, on further study, hyperplastic lesions composed entireHy 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' 7fi 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 moree 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 bronchial 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 epithelialilesions 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 stud'y was the finding of "cells with disintegrating nuclei"' in~ the 170

TABLE 7.-Changes in bronchial epithelium in matched triads o f male non-smokers and smokers o f di ff erent types o f tobacco." Group Number of sub- jects Total sections with epi- thelium Sections with 1 or more epithelial lesions 3+cell rows with cilia present Cilia absent Atypical cells present Atypical cells present with cilia absent Entirely atypical cells with cilia absent + Number Percent Number Percent Number Percent Number Percent Number Percent Number Percent 7th set (none vs, pipe vs. cigarette)a - - - - - - Non-smokers ----------------------- 20 985 214 21.7 110 11.2 101 10.3 26 2.6 3 0.3 0 __-___-__ Plpe sinokerv__===___:_____::::_::__= 20 924 605 65.5 352 38.1 117 12.7 342 37.0 29 3.1 0 _________ Ciearette smoker__s------------------ 20 914 885 96.8 810 88:6 116 12:7 870 95:2 111 12.1 35 ------3:8 8th set (none vs. pipe vs. cigarette) Non-smokers------------------------ 25 1,246 285 22.9 167 13.4 132 10.6 9 0.7 1 0.1 0 _________ Pipe smokers________________________ 25 1,164 800 68.7 451 38.7 172 14.8 445 38.2 38 3.3 0 _--_----- Cigarettesmokers-------------------- 25 1,126 1,084 96.3 999 88.7 238 21.1 1,008 89.5 205 18.2 70 6. 2 9th set (none vs. cigar vs. cigarette) Non-smokers ________:_____:_______ 35 1,706 467 27.4 216 12.7 281 16.5 14 0.8 3 0.2 0 ______.-- Pipe smokers------------------------ 35 1,733 1,573 90.8 694 40.0 247 14.3 1,275 73.6 173 10.0 5 0.3 Cigarette smokers____________________ 35 1,526 1,511 99.0 1.414 92.7 428 28.0 1,493 97:8 417 27:3 196 12:8 ~ Modified table from Auerbach et a]. (15a). a Carcinoma In situ. a'f`riads were matched for age, occupation, residency and (for smokers) by amount of tobacco used. g}7t.4ss4eo

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 observed by Auerbach et al. in the bronchial' epithelium of smokers have been confirmed by other investigators (64, 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 advance& atypical changes and loss of! cilia (the so-calle& 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 traeheobronchial' tree and carcinoma in-situ in other sites, such as the cervix, skin, and larynx. Lung cancer was induced in animals by radioactive substances (1198,,217), chemical carcinogens (198, 340), andl air pollutants plus influenza virus (191). These studies have demonstrated the occurrence of extensive atyp- 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 f'ound in the tracheobronchial tree in cigarette smokers are capable of de- veloping intb lung cancer. Thus, these: lesions may be a link in the patho- genesis of lung cancer in smokers. SuNtmnRY: 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 (if the epithelial changes in general increases with the number of cigarettes ,moked: Extensive atypical changes have been seen most frequently in men who smoked two or more packs of cigarettes a day. Hyperplasia without ahypical 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 ,Io menismofcers. However, at given levels of cigarette use, women appear !') show fewer atypical cells than do men. Older men smokers have many nu>re atypical cells thani do younger men smokers. Men who smoke pipes 'Ir cigars have more epitheliall changes than do non-smokers, but, have fewer , 6ungestihan d'o cigarette smokers consuming approximately the same amount -i' tobacco. Male ex-cigarette smokers have less hyperplasia and fewer 3tyIpical!cells than d'o current cigarette smokers. CoNcLUS[oN:-It may be concluded on the basis of human and experimental idence that some of the advanced epithelial hyperplastic lesions with many.it\"pical cells, seen in the bronchi of some cigarette smokers, are probably I, remalignantim fl'PI\'G OF LUNG TUMORS Historical aspects of the typing of lung tumors in relation to possible otiological agents are reviewed in the section on Retrospective Studies, His- t-dogic Types, Krevberg 1196, 196) noted that the increase of lung cancer in recent dec- lirs seemed to occur for only certain types of lung cancers (his Group I), ~rrl that other typesdid not increase (his Group II)~. Kreyberg''sclassifica- ~:l)n is compared with~ the World Health Organization classification in TAIile 8. His Group I includes epidermoid carcinomas and! small-cell' ana- i lhstic carcinomas. His Group II includes adenocarcinomas and a few rare tvpes. He postulated that a determination of the ratio between Groups I nd II is a good index of the occurrence and magnitude of an increase im lung cancer in a: given locality and his epidcmiologic studies linked the increase almost entirely to the use of cigarettes. His thesis has been aa cepted by many whilc 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's observed a marked increase im the number ofl 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 ofl the United States were typed "blind" by Dr. Kreyberg an& pathoingist's from the cooperat'ing institutions.' There was good agreement a; to: typing. The low ratio of Group I to Group II cancers at'. LACGH was confirmed. When typing of the reviewed cases was compared witL smoking ' Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963. 173

TABLE 8.-Relation between WHO and Kreyberg classi fccations of lung tumors WHO classiBCation I A. F,piUhetial Tumors 1. Epidermoid carcinomas---------------------------------------------------------- a. highly differentiated b. moderately differentiated c. slightly differentiated 2, Smallaeell anaplastic carcinomas------------------------------------- ------------ a. with ovalcell structure ("oat:cel]" carcinoma) 8. Adenocarcinomas ---------------------------------------------------------------- a. acinar (with or without formation of mucus), b. papillary (with or without.formation ofimucus) e. tumors with a predominance of "large cells"'some of which show forma- tion ofiglands andJor productioniof mucus. 4. Large-.rll undifferentiated carcinomas_-----_----------------------------------- 5. Combined eqidermoid and adenocarcinomas-_----_------------___--___---_ Fi. Bronchiolo-alteolar cell carcinomss.--------_----------------------------------- 7. Carcinoid tumors (solidi trabecular, alveolar)-----------------_---_---______ 8. 'Pumors of mucous ghlnds-------------------------------------------------------- a. cylindroma b. mucor,pidermoid tumors ~ 9. Papillomas of the surface epittielium__--------_-------------------_------_-- a. epidermoid b. epidermoid with goblet cells. P..,Sarcomas- ---------------------------------------------- ------------------------------ C., Combined Tumors of EpitheliaLand Mesenchymal Qella------------------ _.------------- D: hfesotheliomas ofthe Pleura------------------------------------------------------------- li Localized 2. Diffuse E., Tumors L'nclassifted~ ffreyberg classiflea- tion r Group I Group I Group II Other i' Othcr Group II Group II Group SI Other Other Other Other I Committee on Cancer of the Lung, World Health Organization. i'Kreyherg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor- wegian Universities Press, 1862,, 3 Types marked "other" are not includediin either of Kreyberg groups. histories, moreover, it became evident that both Group I an& 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, an& 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 Dorn, Herrold and Haens- zel (Table 9) (89) showed high mortality ratios for both Group I and Group II cancers in current heavy smokers (~over 20! cigarettes/day), al- though Group I had a higher mortality ratio (31.2) than Group' 11 (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 University (260), indicated that adenocarcinoma is also contributing to the increment of lung cancer in women. CoNCLUSIONS-(a) The histologicall typing of lung, cancer is reliable. However, the use of the ratio of Group I and~ Group lI 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 o f' tumor, U.S. veterans study All Deaths (]roup I Group II Nonsmokers I ------------------------------------------------------- 1.01 1.0 I 1.01 Pipe and7or ciear smokers _ ______________________ ______________ 1.5~ 2,2 0.61 CiRarette smokers, totai =_ _______________ --------------------------- 8.2 15.4 5.1 Current Total ------------------------------------------------------- 10. 0 18.9 5.A, <= 2t)'CiearettPSlda}"__________________________________________ 7.1 12.9 5.1 >20~ciearettes/day------------------------------------------ 1&01 31.2 7.2 Discontinued (By Maximum Amt. Ever Smoked) Total_ ---------------------------------------------------- 4.7 8.4 3.7 <= 20 ~ciearettes!day------------------------------------------ 3.5 6.6 27 >21)'Clgarettesiaay_°____ -------------------------- 7.4 12,1 5.6 Includes occasional Ismokers. ~ Includes men who werevsing pipe and/or cigars in addition to cigarettes: Source: Dorn, H. F., Haenszel, W. and Herrold, K. (89) (see Chapter 8 also): (b) Squamous and oval-cell carcinomas (Group I) comprise the pre- dominant types. associated with the increase.of lung, cancer in both males andi females. In several studies, adenocarcinomas(Group II) have also increased in both sexes although to a lesser degree. Evaluation of the flssociation between' Smoking, and Lung Cancer It is not practical to attempt an experiment ini man to test whether a causal relationship exists betweeni 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 rand'om 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 f'or many years. Because of the relatiively low incidence of lung cancer in the human population, both~ the test and the control groupss would have to be very large. As such an experiment in man is not feasible, the judgment of' causality must be made on other grounds. The epidemiologic method, when, coupled with cltinieal' or laboratory observations, can provide the basis from which j udgments of causality may be derived. INDIRECT' MEASURE' OF THE ASSOCIATION The crudest indieators of an association between lung cancer andl smoking are. cert'ain, 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 in 11 countries in~ 1950'with the per capita consumption of cigarettes in these countries in 1930, as presented by Dolt (76). Assuming a 20-year induction period for the appearance of lung,cancer, Doll found a significant correlation (0.73+0.30) between the death rates. and cigarette consumption. Since virtually all the tobacco consumption in 1930 was among men in the countries 7 14-422 0-64-13 175

CRUDE MALE DEATH RATE FOR LUNG CANCER IN 1950 AND PER CAPITA CONSUMPTION OF CIGARETTES IN 1930 IN VARIOUS COUNTRIES. i GREAT BRITAIN ~ RINLAND ~ SWITZERLAND r _ 0•73'*- 030 HOLLAND ~ U.S.A. DENMA'RK~ ~ AUSTRALIA ~ CANADA *SWEDEN ~NORWAY' ~ ICELAND 25 0 5 00 7 50 10 00 12 50 150 CIGARETTE CONSUMPTION FicuxE 9: Source: Do11~ 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 0

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, additionall 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 agee 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 ass well as a similar disparity between~ Holland and Great Britain. In Holland (156) the length of the cigarette butts was almost the same as in~ Great! Britain (1I9.7mm), but the crude male lung cancer death rate in Hollan& 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 accountL 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) found 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 25-34 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 SMOKED, BY SEX AND AGE, UNITED STATES, 1955 Age (in years) 18 and under 18-24 25-34 35-44 45-54 55-64 65 and over ~"r,.. . .?1.:.. . . r rr ~" j t Y, ~~S ~~J23 Lf \L P s j ` I ~'~ t~~`JS + ! ~ 1 ~ N y ir Ts~ ~~»~.1 PERCEN'rNEVER',SMOKED _ MALES M FEMALES FICURE 10: Source: I$aenszel„ W'. M. et; all (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 diramatically from 39.9 years for the age group 65 and over to 20.0 years for age 25-34. 6. Males in alli age groups smoked considerably more cigarettes per day than did'femalas. In ages 55 and over, 6.9 percent of the 178 20 40 60 80 1oa

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 im female lung cancer mortality. British: studies (344) also: revealed that females, especially before World War II, consumed much~ less tobacco than did males. A correction for the marked disparity im smoking habits of males and females reduced the ob- sem~ed 5-fold excess of male lung cancer deaths to: a 1.4•fold excess as of 1953 (149). Supporting, this finding are the data f'rom two retrospective studies (147, 152 ): in which the age-adjusted'lung cancer death rates ini 1958- 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: portioni of the sex differential in mortality. DIRECT MEASURE OF THE ASSOCIATION 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) andinon-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 signipicance: im 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 #hee basis of a possible genetic underlay which might determine bot'h, 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 populatiom In the latter explhnation they ignore the fact that aging of the population does not affect age-specific mortality rates which, f'or 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 skini 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 he spurious or that it has not been proved (22, 23, 24, 228, 229, 230). A number of these objections have been assessed in earlier discussions in this sectfion;, others willl 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. spective and prospective studies, diagnostic accuracy was not a critical factor im the establishment of an association between smoking and lung cancer. The qpestion of selection bias is,, of course, a more complicated problem. Several criticisms have been leveled at both the retrospective and prospective method's: 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 (24) that the selection of hospitalized cases may lead to bias if smokers with lung cancer in the general population. It would thus appear that in the data from retro- studies yield' relative risks of lung cancer by various smoking categories whi& approximate those found in the Doll and Hill: study (83)) where, obviously, diagnostic evidence would be more readily available than for those with less well-established diagnoses. Most of the prospective underestimated has been presented by Hammond and Horn~ (162, 163), who f'ound higher relative risk ratios among smokers for confirmed cases than smoking demonstrated' in all of the studies. Evidence that the specific estimates of'~ risk f'or lung cancer among smokers actually might have been rates higher than those for non-smokers and with a gradient by amount of from any cause were involved in the calculations, with the cigarette smoker 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 spective studies, this factor is less of a problem. history would thus appear to be markedly above the critical level for the firm establishment of an association by the retrospective method. In pro- carcinoma (86, 150;,163, 3113, 375). The reliability of response to smoking 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 r after interview, were found not to have the disease, reported smoking, his- tories similar to the controll groups and not the lung cancer groups (84). 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, of smoking habits (158, 229). In at least one retrospective study, both 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 suggeste& that knowledge of the illiiess might' have introduced bias in relation to histories results highly consistent with data on tobacco production and taxation (151) ; that classification errors in terms of amount of smoking were rela- It should be noted that the Current Population Survey of 1955 yielded 180

t i were more often hospitalized than~ non-smokers with the disease. However, nearly all lung, cancer cases are hospitalizeds 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 (379). 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 1254)'. There is no evidence for this basic assumption. Furthermore, it is inapplicable because almost all the retrospective studies were actually based on newly diagnosed cases collected serially over an interval of time long enough to remove this bias. Control groups pose a problem in retrospective studies. In 27 of the 29' retrospective studies (exceptions are references 147 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)', only to find that the association utilizing sick controls, significant though 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 problemi 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 operat'or 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 residuali 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 Dorn 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 studiy. 1 181

This also weakens the criticism by Mainland and Herrera (230) of the use 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 SIGNIFICANCE OF THE 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 ofjudgment which goes beyond any statement of statistieal' probability: To judge or evaluate the causal significance of the association between cigarette smoking and htng 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: (a) The consistencyy 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 ASSOCIATION.-This cIiterioni implies that di- verse methods of approach in the stud'y of an association will provide similar conclusions. It~ is noteworthyy 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 differencess in shortcomings which have been discussed in~ detail above. It is indeed remarkable that no reasonably we111 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, 1411) 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'y but no comparison of observed-to-expected rates was made om 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 ASSOCIATIO:V.-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 apply ing the non-smoker rate to: the population of smokers. This provides us with a measure ofl relative risk which camyield a judgment on the size of the e fject of a factor on a disease and which, even in the presence of another~ agent without causal effect, but correlated with the causal agent'6 will not be obscured by the presence of the non-causal agent. Cornfield! et al. (62) have not only provided us with a detailed analysis of the applications of both absolute and relative measures of risk, but have also: demonstrated the useful• ness of the relative risk measure in judging 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 (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 effective for appraising the non~causal nature of agents having apparent effects, the importance of one agent with respect to ot}ier agents, or the effect's of' refine- ment of disease classification. This, Cornfield and his co-authors (62) have demonstrated. In essence, then, a relative risk ratio measuring the strength of ani asso- 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 cancer among smokers and non-smokers were calculated, the ratios were not only high in all of the studies but showed a remarkable similaritv in magnitude. More importanty in the seven 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. Furthermore, the retrospective an& 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)i or of. cigarettes (25, 88, 96, 97, 163)) smoked per day increased (Table 5). Even the retrospective studies for which relative risks were calculated by amount smoked' (38, 147, 152, 222) showed similar increases ini risks with amount smoked (Table 4). It may be estimated from the data in! the prospective studies that, in com- parison withi non-smokers, average smokers of' cigarettes have a 9- to 10-fold risk of developing lung cancer, and heavy smokers, at least a 20-fold risk. Thus it would appear that the: strengihi of the association between cigarette: smoking and lhng cancer must be judged to be high. THE SPECIFICITY oF' THE ASSOCLATION.-This concept cannot be: entirely dissociated fromithe con,cept inherent inithe 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 frequent!ly the presence of one variable (e.g., lung, cancer) will predict,, ini the same indi- vidual„the presence:of another (e:g., cigarette smoking). In a discussion of the specificity of the relationship between any factor possibDy causall in character and a disease it may produce, it must be rec-

l ognized 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 difl'iculty 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 causali 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 thoughithe predictive value of any one of themi 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 Mycobacterium 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. This 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 way 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 residuall 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 (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 have yet been demonstrated. Another aspect of specificity requires some insight. Several critics of the causal hypothesis haved questioned the significance of the association on the grounds that the existence of an association witL such a wide varietyy 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 184

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 actioni 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 explbred. It would 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 na 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'ASSOCIATED VARIABLES.-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: dls- ease which it is purported to prodtrce. 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 patients 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 farr 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 ASSOCIATION.-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, 255) and the age-cohort patterns of smoking among males and females (151i) are highly compatible with a real increase in lung cancer mortality. (12.) Sex Differential in Mortality.-The current sex differences in tobacco use (151, 160), the pronuonced differences in age-cohort patterns between males and females, particularly in the older age groups-over 55 (151) 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

"were 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. (3J' Urban-Rural Differences in Lung Cancer Mortality.-A number of sources in this country (90, 136, 1A$; 1I75„238, 252) and overseas (82, 199, 335) have firmly established the existence of an urban excess in lung cancer mortality. Because of the possible implication of an air pollution effect, this urbanilung cancer mortality excess has been cited as either being incom• patible with the smoking,lung, cancer hypothesis (1784 229)i or minimizing its significanee (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, 152). Mills and Porter (238) demonstrated a much greater effect of smoking, on lung, cancer mortality thani 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 unity among heavy smokers. The first prospective study of Hammond and Horn (162) 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, cancen A perusal of his data; however, shows that by controlling on smoking, the lung cancer mortality rates are doubled by the factor of country of ori- gin; whereas, with 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-Econornic 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, also 186

i i i s 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 mayy 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 (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) were found in the group classifiedl as "some high school education (but not high school graduates)," whereas the lowest': proportion was found'among college graduates. The highest proportion of ex-cigarette smokers (as of' 1i961-62) was among college graduates. Although the relation of smoking and educational level 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. None 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. 1`o definitive study has been reported in which lung cancer has been correlated with occupation and smoking class; thecurrent! Hammond (157) and Dorn ('88)~ 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. (151). Keeping in mind that type of occupation is not a critical index of income, it will nevertheless be noted that the professional an& farmer an& 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 inilung 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 he 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 4W ~ ~ i C!t ~ A .4L

an& which was directed to amount~ of' smoking, duration of smoking, and age when smoking was begun, the associations or calculated~ relative risks (direa or indirect) revealed gradients im 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 discon- 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 tlhe lack of association between inhalation and lung cancer as noted by Doll and Hill (82) alluded to earlier. These authors have begun ~ collecting data (in 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 considere& and led to the provocative finding that'~ with increase in daily amounts of cigarettes smoked the differences in risks between inhalers and noninhalers 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.e., cigarettes in combination wit.h pipes and/ or cigars)' inhale in proportions intermediate totliese. These findings become compatible with the hypothesis that' the degree of inhalation accounts f'or a gradient of lung cancer risks, high to low, f'or smokers of cigarettes only, combination smokers, and pipe or cigar smokers (Table 5)i. Am explana- tion of the diminishing differences in risks between "inhalers" and "non- inhalers" with increase in amount smoked might be obtained if a more obj ective measure of inhalation were available. (b.) 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 lbwer 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 elicited (1207). Levin noted that statistical sig- nificance was achieved for cigarette smoking and' lung cancer and for pipe smoking and lip cancer and stated'y "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 cancer. Sadowsky (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 I J , point to no phenomenal rise of laryngeal cancer (only a slight rise for whites between 1930 and 1955) in the face of increased cigarette consumption. Although among cigarette smokers, the relative risk of mortality from lung cancer is presently greater than the relative risk for laryngeal cancer, the reverse seems to be true among cigar andl pipe smokers (Chapter 8, Tables 19 and 24)~. Furthermore, the per capita rise in cigarette consumption has been accompanied by a concomitant' decline in consumption of pipe and eigar tobacco, the smoke of which was not deeply inhaled. It is thus con- !1&' ceivable that the increase in cigarette consumption (and decline in cigar and pipe smoking)' couldl affect an increase in lung cancer more significantly than in lar n eal c er y g anc . ~~ f t Finally, there is no reason to assume that the susceptibility of the larynx to cancer equals that of the bronchus. Thus, a: reasonable explanation for I ~~ i 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 associate& with such inhalation (;chromates), laryngeal and tracheal cancer is rare. It is, on the other hand, easier to visualize a mode ofi action for pipe and cigar tobacco in production of lip and tongue and other oral cavity cancers. Thus, none of these considerations de- tract~ from~ the coherence of' the association between, cigarette smoking and lung cancer. HISTOPATHOLOGIC EVIDENCE In earlier sections of this Chapter it has been noted that the application of tobacco extracts, smoke or condensates to the lung, or tracheobronehiall tree of experimental animals has failed to produce bronchogenic carcinoma, except possibly in dogs (289). In 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 ear- cinogens, particularly polycyclic aromatic hydrocarbons isolated from to- A A' bacco~ smoke, has been demonstrated by a number of workers (5,,197; 302):. Of immediate import to, the smoking-lung cancer relationship is the observa- tion that the histopathologic characteristics off the cancers thus produced are similar to those observed in man and: are predominantly squamous 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 im frequency and intensity with thee number of cigarettes smoked daily by individuals without lung cancer and were most frequent and intense in patients dying of lung cancer (Table 6 of this Chapt'er). Ex-cigarette smokers and pipe an& 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 support the cigarette smoking-lung cancer hypothesis. 189

CONSTITUTIONAL HYPOTHESIS GENETIC CONSIDERATIONS.-Thus far in the evaluation, the Committee has considered whether the available 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 have a common cause which determines both that an individual shall become a smoker and also that he shall be predisposed to lung cancer. This has often beenicalledithe 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 (phenotype) that are due to an interaction of hereditary susceptibility and! the environment. The characteristics of individuals studied'i in relation to smoking,have been numerous and varied. Some of them have been physical attributes such as physique or somatotype, height an& weight and their ratios, masculinity, anthropometric variables,, physiologic variables (heart rate, pu1Ge pressure, blood pressure, cholesterol levels), and physical activity; others have been psychosocial ( ineluding, personality) 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 likely to have at least one parent with hypertension or coronary disease (115U, 214, 235). Many studies have been poorly designed and controlled, others have yielded contradictory findings, and still others, by admission of their authors, have includ'ed characteristics that could either have been acquired or have been produced by smoking. None of these constitutional attributes have been included im a prospective stud'y of mor- tality from lung cancer fulfilling satisfactory epidemiological criteria; except for a breakdowni by longevity of parents and grandparents in one study (159)~. The genetics of the characteristics themselves has not been deter- mined, and adequate analysis of common genetic determinants in relation to the habit of smoking has not been attempted. No environmental deter- minants that would universally induce smoking and also produce the char- acteristics are evident (62) or have been proposed. Fisher (118) has been foremost 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 which pulmonary cancer would appear on the basis of genetic suscepti- bilitv. Studies on the concordance of smoking,in twins (122, 127„281, 356) were used to support the hypothesis, since more monozygotic pairs have similar smoking habits than~ do dizygotic pairs. Although the d'ata on the smoking habit's of identical and fraternal twins raised apart are compatible with this hypothesis, the history of cancer in twins whose smoking,habits are known has never been documented sufficiently to be useful in helping to resolve the question of whether the concept of the constitutional hypothesis is valid. Also information about the habits and medicall history of other siblings, offspring, and parents is singularly scanty, and efforts to: separate genetic factors from influences of the environment ini such studies have been only rudimentary. 190 . .,..._ . _. 9:k~;i:+e.c..:..w_....:

s 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 explaining,the reduced incidence of cancer of the lung,in this group, it would be necessary Yo postulate another common genotype for those who smoke and subsequently terminate the habit. The argument becomes even more laboredl when multiple examples of identical genotypes for susceptibility t'o~ smoking and respective specific types of cancer are re- quired by the hypothesis to explain the multiple types of cancer associated with smoking, Since cancer of the lung occurs in both men and women who do not smoke, susceptibility genes acting alone or in combination witll~ extrinsicc or additional intrinsic factors can be effective without exposure to tobacco ,smoke. The occurrence of the disease, therefore, is not invariably linked to hypothetieall genes responsible for the habit of smoking. Since susceptibility to cancer may be due to multiple genes with variable penetrance, and sincee the expression of these genes may change wiYhi environmental conditions, a minor portion of the cases of pulmonary cancer cani be explained as the expression of genetic susceptibility in an environment exeluding, the habit of smoking. Smoking, then may 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- d'ence in both men and women~ has occurred in recent decades. This points either to a: change in the genic 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 thee assumption that the genome of man could have changed gradually, simul- taneously and identically in many countries during this century is almost inconceivable. 714-422 0-64-14 191

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 the contribution of the smoking habit in the etiology of lung cancer today. EPIDEMIOLOGICAL CONSIDERATIONs.-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) : (L) Lung Cancer Mortality.-Lung cancer mortality has been increasing in the last' 50 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 constitutional makeup 'are not genetic but the result of differential exposure to some new factor that predisposes to lhng 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 f ar exceeds any observed. (2.) Tobacco Tars.-Tobacco tars have been found to be carcinogenic for experimental animals. Although 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 withl laryngeal and oral cancer than with lung cancer. The constitutional hypothesis would require that there shall be two consti- tutionall makeups, one predisposing to cigarette smoking but not to pipe and cigar smoking andi 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 speciaU constitutional 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

I tween~ smoking and lung cancer, but recognizes differences,, define& or ill defined, between smokers and non-smokers may be stated as follows: There are factors in the individual acquired early (ior genetic) 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 AND CONFOUNDING VARIABLES Throughout this evaluation, it has been recoguized that a causal hypothesis for the cigarette smoking-lung cancer relationship dbes 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'), has provided 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 causali 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.) Occupationat Hazards.-In an extensive review of the literature on lung cancer in chromium and nickel workers and in uranium miners, Seltser (318) found the evidence for an,excess off 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, urani= miners an excess risk is apparent ('360), 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 ini 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 (81)~ and asbestos workers (77). In another revieww 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 Buechley ('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 arsenic as an insecticide and the consequent exposure of workers in insecti- cide manufacture, agricultural 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:cont'aminated beverages: It is noteworthy that for the nickel and chromate material the lung cancer niortality 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 hazardl 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 smalli and that these agents cannot account for the increasing lung cancer risk in the general population. (2.) Urbanization, Industrialization, and Air Pollution.-The urban.rural differences im 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 etiolbgic factors in an urbam 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) 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- formatiom 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) reveale& no differences in risk among,men and women and in residents of areas of different popula- tioni 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 Hi'stories 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 an1ypothesis 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 applications may be useful inAetermin- 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 lung 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 indilstrializa- 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 11920 to proliferative changes in cases of post-infliienzal 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 bronchitiss and pneumonia among lung, cancer patients even when smoking class was controlled. However, because a collaterall comparison with another controll 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 influenzall pneumonia and primary pneumonia but there did appear a highly suggestive association between mustard gas exposure and lung cancer. Nb 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 9- to 10-fold'risk in average cigarette smokers and the 20+ fold risk in~heavy smokers. sociatPd with lung, cancer via the smoking component)' as compared to the does more than double the risk (and' sometimes these are noted to be as- aleohol consumption, nutritional status, and beer drinking,,have been studied and some associations with lung cancer have been found, but' none of them (4.) Other Factors.-Numerous other factors, such as coffee drinking, 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 by Case and Lea and by Denoix et al. remain interesting. found a history of exposure to war gas and chronic bronchitis to predispose strongly associated with lung cancer than smoking of cigarettes, they et al. (72) studied 1160 characteristics. Among other factors, much less In an epidemiologic approach to other factors in lung cancer risks, Denoix chronic bronchitis is not a necessary intermediate pathogenetic process. The failure of the Beebe 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. relationship is stronger than the chronic bronchitis-lung cancer relationship, Conclusions and the number of cigarettes smoke& 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. 1. Cigarette smoking is causalliy 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 ORAL CANCER Epidemiological Evidence been recorded. The investigators noted the proportions of users of' the same observation. In the present era, additional clinical observations have of the lip among users of tobacco. In 1795, Soemmering, (322) made the The suspicion of an association between use of tobacco and orall cancer dates back to the early 18th Century when Holland (176)i first noted cancer 196

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 an& Tully (280) which indicated an increase in risk of oral cancer with increase in smoking. From the first two studies mentioned (li, 142),, it is immediately apparent that any reasonably meaningful'1 study of the relationship between tobacco and oral cancer must take into account not only the specific sites (lip, cheek, gingiva, tongue, oropharynx, etc.)! but, also the precise form of tobacco use (pipes, cigars, cigarettes, chewing tobacco, snuff, etc. ) . Of additional interest is the specialized use of tobacco as a component, of betel 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 quids without tobacco (104, 234, 367) in certain other areas of the world show no association of betel nut witL 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). These studies are described in Table 10 which includes general smoking data, for the most part, on com• binations of; specific sites of oral 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 smokin~,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 10A), in this sum- mary table, a statistically significant positive association is designated by a plus sign, whereas the lack of such an association is d'esignate& by a minus sigm A plus-minus sign indicates that there was some evidence of an asso- ciation which was not, however, statistically significant. It wilt 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, 3264 , 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 smoking 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 10.-Outline of retrospective studies of tobacco use and cancer of the oral cavity Cases Controls Investigator and year Ref- Country Sex Collection of data erence - Number Method of selection Number Method of selection Broders 1920 (41) U.S.A. M 526 Series ot clinic patients with epi- 500 Series of clinic patients without Apparently by Inter-vlew in the F 71 thelioma of the lip. epithelioma of the lip. clinic. 80.5% tobacco users 78.6% tolfacco users 75.1% smokers 75.2% sinokcrs 0.9% cigarettes 44.4% ciRarEttes 24.0% chew -- 13.4% chew 59.0% pipes 28.fi% pipes 38.5% cigars 44.0% cigars Lombard and Doer- - (221) U.S.A. M-F 217 Clinic patients with cancer of 217 Clinic patients without cancer, Personalintervlewbyinvestlgators ing 1928. various sites. Site breakdown matahed by sex and age. Smok- in clinics. and smoking data not clear. inR_ data not clear. Bigelow and (26) U.S.A. M-F (") Clinic and hospital patients, a p- (7) Paticnts without cancer, In com- Personal interview in hospitals and Lombard, 1933. parently several hundred. parable numbers. -" clinics. - 14 a`J~-non-users 26.5% non-users 36.4% excessive users (Table 111). 24.0°, excessive users (Table 111). Ebenius 1943 (103) Sweden M 439 Clinic patients with cancer of the Not defined. F 33 lip. -- 68.7% tobacco users, M - 79.7% tobacco users, M I-to 2%' tobacco users, F 57.6% tobacco user4, F (all pipes) 22.9% liipes, M 61•8%pi[fes. M 47.4% chew or use snuff, M fi0.7,%,q chew ar use snuff, M 32.5~o cigars and cigarettes,-M 12.9% cigars and cigarettes, M - - ----- Levin et al. 1950 (207) U.S.A. M 143 Cancer institute patients with 51 Cancer institute patients with Routine cllnic interview. cancer of the lip. - non-cancerdiseasesofs_amesite• - 84.5% smokers - 74A%srnokers - 45.3% cigarettes 43.0% cigarettes 48.1% pipes .. .. 30.7% pipes 26:5% cigars 34.9% cigars Mills and Porter 195_0 (297 ) U.S.A. M 124 24 1)eaths from cancer oi oral cavity 183 Sample of populatlon of Colum- From next of kin of deceased by iu Cincinnati and Detroit,1941t- bus, Ohio, and in same proportion mail questionnaire or by personal 46 and 1942-46, Pespectively. of color, sex, and age as in cases. interview. Controls by house- 35.5`7 ciprettes only 54.8% pipes, cigacs. or combina- 32.4%cigarett€s only 29.7% pipes, eigars, or combina- to-house interview. tions. tions. - 549`.,~;9LE0

C ~ ~ Moore et al. 1953 (245) U.S.A. M 112 rarlencs over 50 yrs. old since 1951 38 Patients of same age groups with Personal interview of controls; for with cancer of oral cavity, benign oral Iesions or benign cases, nextof-kin were visited or 58.0% chew surgical conditionS- contacted by letter. 42:01,1,, pil5es 31.6% chew - -- - - 38.4% cigars and cigarettes 47.4% pipes 52.6% cigars and cigarettes Sadowsky et al., 1953 (301) U.S.A. M 1,136 liospital patients with oral and 615 Patients with illness other than By trained lay Interviewers. pharynqeal cancer, 1938_43. cancer. - . 42.3% cigarettes only 53.3% cigarettes only 4.0% cigars only 3.4°a-cigars only 17.8% IirEies anly 7.0% pipes only 28.2% mixed 23.1% mixed Sanghvi et al., 1955 (306) India M 657 Ilospital patients with cancer of M 288 Hospital patients with diseases Personal history interview in hos- F 81 orsl cavity and pharynx. F 112 other than cancer. pital. 38.8°o srnoke and chew, M; 3.7% F -- 24.0% smoke and chew, M; 0% F 46.7% smoke only; M; 6.2%F 50.0% smoke only, M; 6.3% F- 11:7io chew only, M; 64.2% F 8.7%-chew on1y,M; 23.2%-F 2.7% neither, M; 25.9% F 17.3% neither, M; 70.5% F (Smoking is of bidis among both cases and controls.) Ledermann 1955 (202) France M 240 Patients with cancer of oral cavity 62 Patients with cancer of skin, bone, 4, pharynx. muscle. 4.601, non-smokers 17.2% non-smokers 23.4%>20 cigarettes per day 18.6%>20 cigarettes per day Wynder et al., 1957 (378) U.S.A. M 543 Patients with cancer of oral cavity M 207 Patients with cancer of other sites Personal interviews in hospital or F 116 F 232 iiiid benign diseuses. clinic. 3% non-users, M; 47% F 10% non-users, M; 70% F 20%ciFars; M--- -- 13% cigars, M 11% pipes, M 6% pipes, M 8% mixed, M 8% mixed, M 17% chew, M 8% chew, M 57% cigarettes, M; 53% F 63% cigarettes, M; 30% F 29%>35 cigarettes per day, M 17;%0>35 ciga[ettes per day, M 34%>16 cigarettes per day, F 11 %>16 cigarettes per day, F Wilkins and Vogler (369) - U.S.A. M 37 Clinic and hospital patients with None. Clinic and hospital histories. 1957. F 44 cancer of gingiva. 32% chew or chew and smoke, M 20% smokers, M 52% use snutT, F 9%srnokers,. F. Schwartz et al. (314) Franee M 332 lIospital patients with cancer of 608 Hospital patients with non-cancer Questioned about the same time oral cavity and pharynx. illness and accident cases, by the same interviewer. matched by age. 16.4% non-smokers 23.4So non-smokers 62.7% cigarettes only 5821Se cigarettes only 3.3% pipes only - 3.0% pi/Ses oiily

IS r 9 LL44S944E0 TABLE 10.-Outtifie of retrospective studies o f tobacco use and cancer of the oral cavity-Continued Cases Controls Investigator and year Ref- Country Sex -- Collection of data erence Number Method of selection Number Method of selection Wynder at al. 1957 - (388) -- Cuba M 178 - Hospital clinic patients with M 220 - Patients In same clinics with Personal questioning in clinic, all F 34 eancer of oral cavity and F 214 non-malignant conditions, by2intervlewers. pharynx. - - matched by sex and age. - 4% non-smokers, M; 24% F 16% non=smokers, M; 66% F 45% cigarettes predom., M; 62% F 45% cigarettes predom., M; 27% F 33 a cigars predom., M; 12% F 22% cigars predom., M; 6% F Wynder et al. 1957 (385) Sweden M 115 Hospital patients with cancer of M 115 Patients in seme hospital with Personal interview in hospital; and F 140 oral cavity and pharynx. F 156 cancer of sites other than oral, medical histories. -- pharynx iarynx, lung, esopha- gus and irreast. - --- 36.5%a cigarettes, M 36~-cigarettes, M 13:0%a cigars, M 9% cigars, M 12.2% pipes, M 16% pipes, M 15.7% mixed, M 13% mixed, M Peacock et al. 1960 (272) U.B.A. M 25 IIospital patients with oral cancer M 74 Patlents in same hospital without Personal interviews. F 20 F 72 oral cancer and 117 male and 100 female randomly selected outpatients. - - 55.6%a chewed or used snuff over 32.6% of first group, 20 years. 43.3% of second group chewed or - used snuff over 20 years. 8taszewski 1960 (327) Poland M 383 Male patients with oral cancer 912 Male patients with other cancer Personal lnterviews. and non-cancerous conditions. -- 5.7% non-smokers 17.3% non-smokers 72.8% "heavy" smoking index ----- - 49.0% "heavy^ smoking index 72.3% cigarettes-only 60.5% cigarettes only - 12.8% pipes and/or cigars 11.1% pipes arrd/or cigars - Vogler et al. 1962 - (355) U.S.A. M - 188 - Clinic patients with cancer of lip - - M 521 -- Patients of same clinic with other - Personal intervlews in clinic. - - - - F 92 and oral cavity. --- F 1,064 cancer or-non-malignant condi- - - -- - tions. 32.9% chewers, M y 6.1% snuff dippers, F y 22.9% excessive chewers, M 5_6 % tobacco users, M + F 72:0% snuff dippers, F 41.3% excessive snufi dippers, F 90% tobacco users, M + F- r Estimate of prevalence o use. 2 Due to varying tabular treatment of the data, the percentages of tobaoeo users are not all based on the same numbers of caees. - - 1 ~If:'9:Ci

V. P 1 I 94CaS944E0 TABLE 10A. Summary o f results o retrospective studies o f smoking by type and oral cancer of detailed sites ; Investigator and reference Cigarettes Pipes Cigars Chewing Miscellaneous Broders(41)--------------- - (Lip)----------------------- (Lip) - ---------------------- - -- (Llp)----------------------- (Lip)+• - Lombard and Doering ---------------------- (Oral)+ (221).- - Bigelow and Lombard (26) - - _____________ ___ -- _- .- ------------------------------ -... - ------------------------ (Allformscombined-oral){- Ebenlus(103) -------------- (Lip).. r-------------------- - Llp)+ ------------ --- - (Lip)-- Levin et al. (207)-------- - (Lip) -------------- (Lip)-I . ....... . (Lip)f Mills and Porter (237) ---- (Oial)t--------------------- -------- --------- ------- -------------------- ----- ----------------------- (Plpesand cigarscombined- Moore et al. (245)---------- (Lip, mouth)- 2 ------------ (Lip, mouth)-____---------- -_-__ _ ------------'-- -- --- (Lip, mouth)-F---------- ocal)+ . (Snu(i-lip, mouth)+. Sadowsky et al. (301)------ (Lip, tongue, other oral, (Lip, tongue, other oral)+___ . (Tongue, other oral)+. pharynx)-. Sanghvi et al. (300)-------- (Oropharynx){-3 ------------ ------------------------------ ------------------------------ (Oral){----------------- (If smoke and chew-base 01 Ledermann (202)----- ------ (Oral) }. tongue, hyp_op_harynz){. WyYideketal.(378)-------- fM,-fF(Floorofmouth)-- (Esshsiteexcepttongue)-},__ (Eachsite)+------------ ---- (Oingiva,iip)t. Schwartze6al.(314)------- (Pharynx)+I --------------- (Oral)-. Wynder et al. (388)-------- M-, F+ (Oral and phar- (Lip)+---------------------- M+, F+ (oral and phar_ Wynder et al. (385) -------- . ynx). (P,harynx)+, (Other - -- yn=) gingiva, phar - -------------------------- (Pipes, and cigars com- sites)- ynx)i-. .. - . bined-tongue)+. Peacock et al. (272) -------- ------- ------ --- ---- ------ ------- - -- ---------- _ (Oral)+ --------------- ° . (6nuft-oral)+.3 Staszewski (328)----------- (Lip, oral cavity)+--------- ------------------------------ - - ---------- ----------- --- - ---------- ------- (Pipes and cigats combined- Vogler et al. (355) ---------- ----- -- ---------------- lip, oral cavity)t. (All forms combined)+, I F+ (snuff-lip and buccal cavity In both cases). '+=8igniflcant association. -=Assoeiation absent or not significant. f=.Association of doubtful significance. 2 Cigarettes and cigars. I Bidis. 4 Includes cigarettes and other. 5 Only in individuals of low economic statua 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 oflthese (385) with pipe and cigar smoking combine& In two studies an association of gingival cancer with cigar smoking was demonstrated (378, 385) ; in one of thesee (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, 3784 385). An associationi with cigarette smoking was noted! in two out of three (306, 385)i; 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's cigars combined, and for other oral cavity cancers by number of pipefuls. Nb 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 ani 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 durationiof smoking and'bydiscontinuanee are notlyet 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 reqµire 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) 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, 24A., 245, 24.6, 271, 272, 303, 303a). Leukoplakia was re• ported to have been induce&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, 296, 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'~ carcinogenicc agents on the tissues of the oral cavity and the pharynx. The only positive results with carcinogens have been obtaine&with benzo(a)pyrene; 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 pachyderma oralis) and "true" leukoplakia, 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 histopathologicc 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 thee subsequent development of cancer. An association between~ leukoplakia an& oral cancer has been noted by other investigators in studies on individuals with, the habit of: dipping snuff (179, 200). Although these results do not warrant any conelusion~ 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

j udgment of consistency of the association except for cancer of the lip and 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 cavitycaneer such as mouth1ygiene, 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 an& 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 benzo(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 causali relationship of the smoking, of pipes to the development of cancer of the lip appears to be established. I 204 O W ~ ~ C!t ~ ~ N

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 presenf be stated.- LARYNGEAL CANCER Epidemiologic Evidence 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 (1)~. The Kennaways calculated standardized' mortality ratios for various occupational groups (against thee age-specific mortality rates for the general population of England and Wales for 1921-32) 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 an& 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 im the United' States (301, 376) and one each in Czechoslovakia (353),, Germany (30), France (314), Sweden (385), Cuba (388), India (100), and Polan& (327) (Table 11)1. 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, 388) 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 witL 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

9 TABI,E 11.-Outline of retrospective studies of tobacco use and cancer of the larynx Ret- Qases Controls Investigator and year er- Country Sex Collection of data ence Num- Method of selection Num- Method of selection tier ber Schrek et al. 1950 (311) U.S.A. M 73 Referrals from V.A. hospitals in 522 From same set of referrals, patients Random sample of 50o3admissions; "entire midwest" to V.A. Can- withtumorsotherthanlip,lung, questionnaires from Hines re- cer Center, Hines, Illinois, dur- larynx-pharynx. ferrals for 1942-44; records In- ing 1942-44: patientswith larynx- cluded smoking history. harynx turnors clinically or Eistologically diagnoseli. 13.7% non-smokers 23.9% non-smokers 79.5% cigarettes 59.2% cigarettes ' 3.7% cigars 10.0% cigars 6.8% pipe.s 11.5% pipes Valko 1952 (353) Czecho- M-_ F 226 Clinic patients with cancer of the 108 Clinic patients of same age group Medical history and questionnaire slovakia. iarynx. with other diagnoses: in clinic. 83.2% cigarettes 4.4% cigars 10.6% pipes - 7.5% non-smokers 22.2% non-smokers Sadowsky et al. (1953) (301) U.S.A. M -- 273 - Admissions to hospitals In N.Y.C. 615 - From same set of adrtlissions: Sample of 2605 out of 2847 lnter- Missouri; New Orleans, Chica- patients with illnesses -other views (including smoking his- go: patients with diagnosed than cancer, tory) by trained lay interviewers. laryngeal tumors, 1938-1943. - -- -- ---- - 4.0% non-smokers 13.2% non-smokers 60.1% cigarettes only 63.3% cigarettes only 2.2% cigars only 3.4% cigars only ' 4.8% pipe only 7.0% pipe only 28.9%soine combination 23.1%sonie combination Bl9mlein 1955 (30) Germany M 241 - Clinic patients with cancer of the 200 Paticnts with no laryngeal disease. Personal history taken in cllnia. larynx. 0.8% non-smokers 18.0% non-smokers 79.3% heavy smokers 4.3% heavy smokers 95.0%,; inhalers - - 17.0% inhalers Wynder et al. 1956 (376) U.B.A. M 209 Inpatients Memorial Cancer Re- 209 Patients with other than epider- Trained lay Interviewers. search Center during 1952 to mold cancer, individually 1954, with benign or malignant matched eontrols in same insti- epidermoid tumors of larynx. tutions.- 0.b% non-smokers - 10.5% non-smokers 86.0% cigarettes 73.7% cigarettes 7.5% cigars 10.1% cigars 5.0% pipes 3.8% piix' 1.0% 0igarslpipes 1.9% aigarsipipes E8GS9C.E0

India M 132 Laryngeal cancer patients at Tata 132 Controls Individually matched as Interviews for smoking and medi- MemorialIlospital, 1952-1954. - for U.S.A. data above. eal histories. 13.6% non-smokers 30.3% non-smokers - - - 78.8% bldis 62.1% bidis 5.3% clgarettes 4.5% cigarettes 1.5% hookah 0.8% hookah 0.8% chilum 2.3% chilurn Schwartz et al. 1957. - (314) France M - 121 -- Patients hospitalized from 1954 242 - ---- Same time and sources; patients - - - Cases and controls indfvidually throuFh 1956 with laryngeal can- hospitalized for non-cancerous matched within institutions; cer, in Paris and other large conditions s or trauma. each member of a set questioned cities. by the same trained lay inter- 96°5 smokers 84% smokers viewer. 58% in halers 47% inhalers 44% roll their own cigarettes 31% roll their own cigarettes Wynder et al. 1957--_- (385) Sweden M-F__ 63 - -- Patients at Radiumhemmet with 271 -- - - --- -- - - - Patients from same source and - - By trained lay Interviewers in squamous-cell cancer of larynz, tirne, with cancer other than hospital. from 1952 through 1955. squamous-cell of larynx. - - Males: - Males: 5% non-smokers 24% non-smokers 47% cigarettes 36% cigarettes 17% cigars - 9% cigars 15% liipes 16% pipes 17% maxed 18%nifxed Wynder et al. 1958. (388) Cuba M 142 Clinic patients In Havana during M 220 Same source and time; apparently Interview of patients in clinic. F 32 1956, 57, with histologically di- F 214 patients with cancers other than agnosed epidermoid cancer of larynx, lung, or oral cavity, larynz:- - - -- - matched for age. - - 1%a non-smokers, M; 13% F 16%non-smokers; M; 66% F 62% cigarettes, M; 72% F 45% cigarettes, ad ; 27% F 20%cigars,M;6%aF 22% cigars,M;6%F 1%pipes, M - - l%pipes, M . - 16% mixed, M; 9% F 16% mixed, M; 0% F Dutta-Choudhurl et - (100) India - M-F ~ 582 - - ----- Patients in Calcutta cancer hos- - 288 _ _ Not speci0ed. _------ Tobacco histories obtained during 81.1959. - - pital during 195o-54, with laryn- -- - 1951-54, apparentlybyinterv9ewy geal tumor diagnosed and con- firMed by biopsy or smear. 14.1% non-users 41.7% non-users 77.8% cigarettes or bidi 52.1 % cigarettes or bidl 3.1%chew. 3.8% chew 5.0% both 2.4% both

TABLE 11.--Outli.rce o f retrospective studies o f tobacco use and cancer o f the larynx-Continued Ref- Cases Controls Inveetigator and year er- Country Sex - Collection of data ence Num- Method of selection Num- Method of selection ber ber Bteacewskl 1960. (327) Poland M 207 Patients admitted to chronic dis- M 912 Patients admitted during 1957 & Author interviewed patients aua F 13 ease hospital during 1957 & F 1813 1958 to chronic disease center pected of lung cancer [or smoking 1958 with histologically con- for cancerous and non-cancerous history and background. firmed squamous-cell carcinoma conditions presumably not re- of the larynx, lated to tobacco consumption. 0.5% non-smokers 17.3% non-amokers 87.9% cigarottes only 60.5% cigarettes only 1.9% pipes and/or cigars 11.1% pipes and/or cigars 88.4%° heavy smokers" 49.0%"heavy smokers" 98.1% inhalers 08.8% inhalers 30.8% smoke, F 8.4% smoke; F

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 laryngeali 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) found an association with inhalation among light cigarette smokers and among, pipe and cigar smokers. For botL 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 materiaU 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 smalli as to weaken the stability of any calcu- lable ratios, in the three maj or studies, the number of observed' cases among, cigarette smokers is reasonably large and yields ratios of 3.7 [current Ham- mond study (157) ], 5.8 [Dorn (88) ], and 13.1 [Hammond and Horn (163) ]. 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 casess observed and 3.2 expected (Table 24,,Chapter 8)i. None of the studies currently in progress has yielded a sufficient number of cases of laryngeal! cancer to permit analysis of smoking class categoriess 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 1'0, Non-Neoplastic Respiratory Diseases. Evaluation of the Evidence The 10 retrospective studies have a high d'eg,ree 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 t'hese all show consistency in designating cigarette smoking as the significant' associative class. The fact that each of the prospective studies yielde& an excess of cases among cigarette smokers over the number expected from the incidence among non-smokers adds to the level of consistency noted. The 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 he for oral cancer, is reasonable because alcohol consumptions 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. Thee 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. I TIME TRENDS Although~ laryngeal cancer mortaliUy 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 mentione& that in at least one d'e- 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 (as a combined group). 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 other factors may play a significant role in the productioni of laryngeal cancer, such! as alcohol and inadequate nutrition (1376). 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 ini this country that adequate case materiall among chewers is not available for analysis. However, evidence derived f'rom, studies amona betel nut chewers in India indicates that even among smokers of cigarettes, cigars, pipes or bidis * the addition of tobacco to the material chewed is associated with an even greater risk of laryngeal cancer (100, 376). The evidence from the retro- spective andl prospective st'udies is compatible with the small rise in laryngeal cancer 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 would 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 (WM: WF'= 1!0.8) but also with a lower sex ratio 30 years ago (WM: WF=6.3) (130). Assuming a reasonable induction period, the mortality rates W years ago could have been a reflec- tion of the much lbwer consumption of tobacco even among males between 1900-1910 (239). One cannot overlook the role of alcohol consumption in, this differential. The greater alcohol consumption among males and a strong association be- lween laryngeal cancer and alcohol consumption (376, 377) must be con- sidered as contributing to the excess ratio of male to female laryngeai cancer mortality. The role of inherent sex differences (e.g., hormonal, laryngeal anatomy)' as determinants in the difference in mortality related to smoking cannot be fully evaluated from the limited information available. LOCALIZATION OF LESIONS'. Two studies have dealt analytzcally with laryngeal cancer from the stand- point of specific locallzation, i.e., extrinsic vs. intrinsic laryngeal cancer (327, 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 varietyof 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 interpretatiom 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 whi& 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, finalHy„ the obvious exposure to such juice from tobacco chewing, is compatible with the preponderance of extrinsic typess among such users of tobacco. is a significant factor in the causation of laryngeal cancer in the male. Evaluation of the evidence leads to the judgment that cigarette smoking, Conclusion. ESOPHAGEAL CANCER were collected in the period 1938-43. These investigators found associa- 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 of the two variables as early as in 1937. Ahlbom (1) studied a group of tween~ smoking and esophageal cancer led to more or less controlled studies As with cancers of other sites, clinical impressions of an association be- Epidemiologic Evidence RETRQSPECTIVE STUDIES 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 (329')~ 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 rerraining 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 thee 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- strated excess frequencies of cigarette and cigar smokers among the esopha- geal cancer cases not to be statistically significantS 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 significantly more smokers among cases than among controls. However, the difference 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 gradiea 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 (325, 374). The Polish data revealed a: relative risk ratio of 16:1 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 Bross (374) tested 213 -,a

TASL>; 12.-Summary of methods used in retrospective studies ol tobacco use and cancer of th.e esophagus - C ases I Con trols Investigator year and , , reference Country Sex N - ' - Collection of data tiem Method of selection be~ Method of selection Badowskyeta1.1953 (301) U.S.A. M 104 White patients admitted during 615 White patients with illnesses other (1) Obtained by 4 especially trained 193t}-43 to selected hospitals in than cancer admitted to same lay lnterviewers. N.Y. City Missouri, New Or-_ < group of hospitals during same i d (2) 242 records out of a total of 2,847 te d d b f in o l l leans, and ( hicago. o . per c mp exc u ecause o e or e questionable smoking histories. Sangbvl et al. 1955 (306) India M - 73 Consecutive clinic admissions to (1) 288 - --- - - -- Consecutive clinic admissions of - - By means of 'detailed qucstlonary'. Tata Memorial Hospital, Bom- patients withouEcancer No-other detafls given. bay. (2) 107 Coasecutive admissions of patients with cancers other than intraoral or esophagus. Steiner 1956 (329) U.S.A. M+ 116 Consecutive cases studied at aa- 464 Autopsy eases comprising: Not clear how smoking histories were F topsy in University of Chicago - 116stomach cancer obtalned-from hospital records, Dept. of Pathology during 1901- 1161ung cancer - probably, which indicates they 1954. 116 malignant lymphatic dis. may be inadequate. 116 cases without any malignant neoplasm. Matched by age, sex, race and year of autopsy. Wynder et al. 1957 (3&5) Sweden M 39 Patients admitted to Badlumhem- 115 Patients admitted to same hospital met, Stockholm during 1952-1955. with cancer of skin, and bead and - ncc.k region other than squamous cell cancer, leukemia, colon, other sites. No matching. Staszewskl 1960 (326, 327) Poland M 24 Patlents admitted to Oncolog ical 912 Other patients sent to Institute with No details given on method of data _ _ Institute during 1957-59. syinptoms probably not etiologi- collection. No age adjustment or cally connected either with smok- matching. Average age of cancer Ing or with diseases of esophagus, patients=60.5 an l-of control_s=53: stomach or duodenum. Schwartz et al. 1961 (315) France M 362 Admissions to hospitals in Paris and 362 Ilealthy indlviduals admitted to Interviewed by team of spcclal inter- a few large provincial cities since same hospital because of work or viewers who interviewed the 1954. trafllc-acciilents-matched by 5 largest proportion possible of al: yr.~igegrbup and time oCadmis- cancer - patients. Cases and slon. matched coYitrols-Intervlewed by - same person. t64S9GE0

Wynder and Bross, 1961 U.S.A. M 150 Cancer patients seen in Memnrial 150 Patients seen In same hospitals dnr- Data collected by trained inter- (374). Hospital, N.Y.C. and Kings- iug same time period with other viewers. bridge and Brooklyn VA Ilospi- tumors. fit%-malil;nanG tumors; tals during i950-69 (8fi% white). 36%-lienign conditions. Matched hy age with cancer patients F 37 Same hospitals and same time period 37 Same as with regard to male con- as male patients (86% whit2+)e trols. 43% had malignant and 37% t enign tumors. Wynder and Bross 1961 India M 67 Admitted to Tata Memorial Hospi- 134 Patients with other forms of cancer (1) Interviewed by one person. (374). F 27 tal, Bombay. except for oral cavity and lungs; a.c (2) 10% of male cancer cases histolog- well as various benign diseases. ically confirmed and 4%bf female cancer cases. ~61•S9c,Fb

TABLE 13.---Summary of results of retrospective studies of tobacco use and cancer of the esophagus Percent non-smokers Percent heavy smokers Percent Inhalers among Relative risk: ratio to smokers - - non-smokers - Investigator, year, and reference - - Cases Controls Cases Controls Cases Controls All smokers Heavy smoker9 - 8adowcky et al. 1953 (301) ---------------------------------- 3.8---------- 13.2--------- -- - ------------- -°--------°• - -------------- - ------------° 4.0 ---------°--- - 8angvhtet al. 1955 (308)------------------------------------- 6.5 ----•---•- 17.3--------- Average num ber of bidis - -------------- -------------- 3.6 - -------------- emoked _ -------- 15.3 14.1 Wynderet al. 1957 (385): M----------------------------------------------------- 13----------- 24----------- --'-'--------- -- •----------- -------------- -------------- 2.1 ----------•-•_ --- r--------°---°---------°-------^---------°------- atioat 65----- about 92-^-- -------- ^------------ -------------- -------------- - - -----^°°- 2.0 -- - -°°--°----- - -- Btasrewski1@6(1(328,327)---------------------------'------ 0------------ -- 18----------- 95.8 59 87.5 80 -- -------------- 16 8chwartL et a1.1981 (315)-------------------- ---------------- 3------------ 1Z----------- Total am ountsm oked 39 38 - 6.6 -------------- daily (cigarettes) 16.8 16.0 Wynder and Bross 1981 (374): (1) Am erican males----------------------------------- 5------------ 15----------- 48 33 -------------- ---------- ---- 3.4 1.8 (2) American feitialee------'--------------------------- 41----------- 78-°------° 27 16 ---.-.. . -------------- -------------- -4:1 ' (3) Indian maies--------------------------------------- - 13----------- 28 ---------- -------------- -- ° --- ---------- ------•'------ 2.6 -----°------- (4) Indian femules------------------ ----------------- 78 --'------- 94 -----•--'-- ------------ - ------ ---'- - ---'---------- - -------------- 4-b -----------'-- C6Z.S9G£0

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 smoke& 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) some deathss 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 f'rom, 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 witLso few cases to date, further cross-classification by duration of smoking, inhalation practices, and discontinued smoking is not feasible ati the present time. Cdreinogenesis 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 skim No data are presented in evidence. Evaluation o f Evidence Five of the seven retrospective and six of the seven prospectYve studies show sigpificant associations between esophageal cancer and tobacco con- sumption. One prospective study showed a mortality ratio less than unity (96) but this is base& 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 thee prospective studies. This level of consistency is not to be ignored although few of the studies revealed increasing gradients of risk with amount smoked.

I H'ere, only two studies (301, 374) and possibly a~ third retrospective study (i385) 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„revealedi sueh 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. Inhalhtion 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 hypothesisthat 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'forrns of tobacco use„ viz., cigarette, cigar and pipe smoking and tobacco chewing, would support such an hypothesis. It is also supported by the fact that the mortalfity 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. :?•.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 d'oes not negate the significance of an association with tobacco:use, some forms of which have been concurrently rising. This has been discussed earlier but it should be emphasi7ed that declines im other environment'al 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 om 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 t'obaeco: juice, then the time trends im 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 beliefi 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 al "mixed known strain" were painted with tobacco tar daily for fivee 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 (2i5) 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 stud~~, though carefullyy 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 smokeds age: at onset of! smoking, duration of smoking, and inhalation was either not collected or not analyzed. Only three additional retrospective studfies (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 andi 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 foun& no relationship between smoking and' urinary bladder cancer in females, but one study (389) found the relationship to bee signific.ant.Three of the studies examined otherr forms of smoking. Schwartz et al. (315)~, 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 (2201 found sig- nificant associations between both pipe and cigar smoking and urinaryy bladder cancer in the male. Wynder and co-workers (389'): 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 o f smoking. In each, a significant excess, of heavyy 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). Inhalation was examined in two studies, the French and the Danish (220, 315)'. Schwartz et al. (315) found a profound! effect of inhalation on~ the associratiom 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 showe& a greater frequency of inhalers in each class. When inhalation was controlled, the eff'ect ofl 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)1 found statistically signifi- 219. ~,_.~. ..~.......... . ...--.... . .., - . .-., w?4...~.i'sFv::.x.+.1~...-.iM~.'.~urr+

M "Z,s9c,eo TABLE 14.--Sruwnary of methods used in retrospective studies of smoking and cancer of the bladder- _ Cases Controls Investigator year and - , , relerenoe Country 8ez - -- -- Collection of data Num- Method of selection Number Method of selection ber Lilienteld et al., 1958 U.B.A. M 321 AdmLssions to Roswell Park 337 Notiisease patients. Interview of patients by groups of (215). - -- ---- - -- - Memoriul Institute.--1945-55 over 287 Prostate cancer. interviewers-at time of Ist vislt to 45 yrs: oi age: Institute beTore seen and diagnosed by hy i ians: ^ F - 116 Same as males 109 Benign bladder conditions. p s c 317 No-disease patients. 763 Breast cancer - Schwartz et al., 1961 France - M - 214 -- - Admissions to hospitals in Paris and 214 IIeEilthy individuals admitted to Interviewed by team of specialized (315): a few large provincial citles since same hospital because of work or interviewers who intervfewed the 1954. --- traffic accident-matefied by 5 yr: largest-proportlonpossibie-of all age group, & admitted during cancer patients admitted to these same time to same hospital as hospitals. Cases and matched cases. controls Interviewed by same person. Lockwood 1961 (220). Denmark - M - 282 All bladder tumors reported to 292 - ----- --- - -- - A. From election rolls matched with - - -- - Cases-59 cases Interviewed by F 87 -Danish- Caneer Register during 87 cases according to ser, age, marital Clemrtiesen and 310 by Lockwood 1942-1958 and living at time of i C i t ie h d status; occupation and residence. Election Itoil Controls-2 inter- view Cl mm d b d 367 b erv w agen an open n n Fredericksburg. B. Another control group obtained e y y e esenim Lockwood. from sample of Danish Morbidity Survey (1952-53 & 54) compared 'with respect to smoking histories. Wynder 1963 (389). U.S.A. First Phaae M 200 Admission to several hospitals in 200 Admission to same hospitals (ex- Trained tntervlewers. N.Y.C. during January, 1957- cluded cancer of respiratory sys- (To be published). F 50 December, 1960. 50 tern, upper alimentary, tract, myocardlalinfarction). Matched by sex and age. Second Phase - M 100 Admission to same hospital during 100 Same as above. F 20 1961. 20 t

TABLE 15.-Summary of results of retrospective studies of smoking (irrespective of 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 Cases Controls All smokers Heavy smokers Lillenfeid at al., 1958 (215)----------------------- --- jM lF 15 87 29 83 -------------- ------- -------------- - -------------- -------------- --- - - 2-3 I:4 -------------- -------------- -- Sehwartz,1961 (315)----------------------•---------- - M 11 20 - -------------- - -------------- - 54 - 37 - - 2.0 --- -------------- - Lockwood 1961 (220) - M ~ 9 17 30 15 -- 33 9 2.1 2.4 , -------------------------------- F 58 88 4 4 '------------- -_____-------- 1.5 1.0 Cancer Caves------------------------------•----- f M -lF 11 59 -------------- -------------- -------------- -------------- . -°-----°-'-- -------------- ~ 14 -------------- -------------- -------------- ... -------------- ----.--------- -------------- PaPilloma Cases--------------------- ------- {M 8 5 -------------- -- ---- ------ - ----------- -------°--- ------------ -- - 31 14 ------- ------ -------"--'-- -------------- ------------- -------------- '-------- Wynder et a1.,1983 (389) (Phase A and B combined) _ . . .. _ . .... - ~M F 7 61 ls SB 47 8 23 0 ___ --- ----•----- ------------- -------------- 2.9 3.9 3,0 --------- ss4s94co

cant relationships with inhalation also buty unf'ortunately; 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 tobacco1abits thanLockwood's: Only one study analyzed data on age at onset o f smoking. Lockwood (220) found that his patients began smoking larger amounts of tobacco at an earlier age thani did his controls. Other variables were examined in three studies, not only as a check on possible biases and inHuence of confounding variables on the association /'220, 315) but also as a means of eliciting other environmental factors (389). In the latter study by Wynd'er, which included analysis of occupation, an excess of leather workers andi 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. In one study of males (220) heavy smoking tended to increase the risk slightly (2.1 to 2.4). The female ratios were near unityy except for the finding of 3.9 from Wynder's data. Relative risk ratios for male cigarette smokers only ranged from 2.0 to 3.3. TABLE 1St1.-Summary of results of retrospectiv.e studies of cigarette smokingg and cancer of the bladder in males Rercrnt Cigarette Smokers Relative Risk: . lnvestieat'or, and ClassifiraUionof Cigarette Smoking Ratio of Ci¢a- rettc Smokers Cases Controls to Non-9mokerr [biliarnfCld (cigarette R'other). (2t5)1056 61 44. 2,0 Schµ-art'z(cigarettconly)~(31.5)1!tfi1 g3 70 2.1 Lockwood (,Ciqarette, is main inode oismoking) (Q2(1)' 1961 30 15 2.4 ltynder(ciearette Gother)(3R9)1963 85 63 3,3 PROSPECTIVE STUDIES Six of the seven prospective studies. showed bladder cancer mortality ratios ranging from 1.7 in the current study by Best, et al., in Canada (25)) to 6.0 in the Calif'ornia occupational study of Dunn et all (96). The only disparate finding is in the Doll and Hill study (84) where, oni the basis of 12 bladder cancer deaths among the physicians of the. study, the mortality ratio is 0:9(Table1)1. Two studies (96, 97) show relatively few deaths from urinary bladder cancer to date. If these studies are tentatively omitted and the:remaining four studies ('25; 88; 157i, 163) with significantly larger numbers of deaths are scrutinized, the range of the mortality ratios is narrow: 1.7 to 2.2. The mean mortality ratio for all seven prospective studies is 1.9: For smokers of cigars, and pipes the mean mortality ratio is 0.9 (Table 22, Chapter 8) . Further information on sub-classes of tobacco use, e.g., inhalation practices, age at onset of smoking, and duration of smoking are 222 . r :-, - a-w-~~ :

not presently available. Some information on a gradient' for amount of cigarette smoking was obtained from previously published data of Dorn 188) ; the mortality ratios by quantity of cigarettes were as follows: less than 10 cigarettes, 1.0; 10 to 20, 1.8;, more than 20, 2.75. In the original Hammondl and Horn study (163), a gradient with number of cigarettes smoked was perceptible for all cancers of the genito-urinary tract! (less than 10 cigarettes, 2'.0; 10-20, 2.0; more than 20, 3.1). Data for cancer of the bladder per se were not then available. In, the Dorn study, even at the 1959 mark in its progress, a distinct, gradient was noted. These data have recently been augmented by caleulations of up-to-date data from six of the prospective studies. These reveal a; distinct gradient by amount of cigarettes smoked daily. The mean mortality ratio for urinary bladder cancer among male smokers of one pack or less per day is 1.4, whereas thee iatio for smokers of more than a pack is 3'.1 (Chapter 8, Table 23)i. Carcinogenesis. In a studly whose original' aim was to determine the effect of tobacco tars on the tissues of the oral cavity in mice, Holsti and Ermala (1177) observed papillary carcinomas of the urinary bladder in 15 percent of the animals that survived, representing,10 percent of the 60 originally treated. The lesions were histologically classifie& as carcinomas, though no metastases were ob- servedl Benign papillomatoses were observed in 87.5 percent of the ani- mals. In a similar study, DiPaolo and 11Toore (7,5) observed only slight hyperplasia of the mucosa„ but in one mouse anaplhstic sarcoma of the uri, nary bladder was encountered. The significance of these experiments as well as earlier ones reported by Ro$'o (295) is obscure. Evaluation of the Evidence Relatively few retrospective studies of the smoking-urinary bladder cancer relationship have been undertaken. The four existing studies showed a consistency in association between cigarette smoking and cancer of the uri- narybladder ini males. Two investigators who studied the dose-ef]ect found a correlation of increasing risk with amount smoked. Those examining the practice of! inhalation of smoke have found an, even greater association and; although but one study dealt with age at onset of! smoking, this showed that patients with bladder cancer started heavy smoking at an earlier age than the.controls. The relative risks calculated from data available in the retrospective studies are of an almost similar order of magnitude not only among themselves but in comparison,to the mortality ratios derived from the larger of the prospec- tive studies. Two of three retrospective studies show, no association with other forms of smoking and' this is consistent with the findings of a bladder cancer mortality ratio of somewhat less than unity among cigar and' pipe smokers as elieited4rom the prospective studies. Because of this consistency in the male studies, only a brief discussion~ of the elements of observer-bias, misclassification, non-response bias, and other possible causes of error, willi be necessary. Suffice it to say, that in the 714-422 0-64-16 223 ~.

Lilienfeld study, aff interviewing for smoking history was done on all admis- sions for any complaint prior to diagnosis: In the Schwartz study, matched healthy controls were utilized; comparisons were made for area of residence, famil;v status, and! occupation; and these variables were tested for relation- ship to smoking and inhalation histories: Such relationships, when found, were slight and not to the degree of association of smoking to urinary bladder cancer. Information on histological confirmation of all cases of this study by Schwartz was lacking. Since the bladder cancer cases in this study had originally served as controls in a lung cancer study, some of the observer-bias arising from knowledge of the distinction between cases and controls was probably neutralized. Furthermore, the results of the early phase of the study were consistent with the findings in the entire study reporte& om later. The Lockwood study, executed to elicit environmental factors which might be operating to explain an increase in Copenhagen in incidence of bladder tumors both benign and malignant, included all bladder tumors, 24 percent of which were malignant. Since differences of opinion with respect to cri- teria of malignancy in these tumors exists, it' is possible that this type of tumor was similar to those diagnosed as cancers in other countries. Never- theless, Lockwood's group did analyze the material' separately and found the smoking, relationship to both benigni and, malignant tumors to be essen- tially the same. These authors also utilized al second control group derived from the Danish Morbidity Survey. Their study controli group and the probability sample from the survey were similar with respect to amount of smoking~ Both cases and controls were similar with respect to alcohol con- sumption, marit'alistatus, housing, history of pyelitis and cystitis, sulfonamide consumptioni and other variables. The Wynder study (389) involved controls matched by age and sex and liospital of adrnission. Variables of'comparison included race, marital status, religion, place oflbirth, dietary habits, education, residence, alcohotconsump- tion„ weight, orall hv.giene, blood' group, circumcision status, occupation, and genito-urinary diseases. Cases and controls were similar for all variables except for occupat'ion, and genito•urinary diseases. The excess of leather workers and shoe repairers among the blad'der cancer cases has been noted above. The bladder cancer cases also had a higher freq;uency of'~ bladder stones or cystitis. These conditions may have etiologic implications. Several conflicting findings do exist, however, in relation to the association between smoking and urinary bladder cancer. The first is the finding by Wynder of a highly significant association between smoking and bladder can- cer in females. This latter association is weakened, however, by the equivo- cal finding of only a slight excess of heavy smokers among the cases. A second inconsistent' finding is am association with cigar smoking, as reported for males by Lockwood. Inhalation was tested by him~ but it' is not clear whether the cigar smokers inhaled in sufficient amount and depth to charac- terize them as being different from cigar smokers in the United States. Fi- naldy, the urinary bladder cancer mortality ratio~ im the Doll and Hill pros- pective study is approximately unity, a finding inconsistent with the other six prospective studies. In addition to the finding of an association with smoking in female casesin a single study (389)~ is the fact that no associatiom exists for women in two other retrospective studies: If cigarette smoking is ac- 224

tually associated with male bladder cancer, should not an association be found in the female„as with lung, larynx, oral, and possibly esophageallcancer?' The clues to the solution of this dilemma may be first, that inhalation seems to be the more important factor in the relationship between smoking and bladder cancer, and'secondly„that other etiologic factors may have a"swamp- ing" effect in the female to counteract her lower frequency of inhaling. Evidence for support of this hypothesis is lacking at present. If correct. then the Wynder finding requires explanation, which may be looke& for in the disparities in smoking habits between cases and controls. The strength and specificity of the association are obviously of low order because the mean mortality ratio is 1.9. This also implies that factors other than smoking may be associated etiologically wit6 urinary bladder cancer. Little can be saidi regarding the coherence of the association beyond thee scanty data on d'ose-effect. Furthermore, adequate information is lacking for ani intelligent discussion oflf the sex differential, which is the lowest for any of the cancer sites for which an association, direct or indirect„with smok- ing has hitherto been suspected. An urban-rural differential is virtuallw non-existent in urinary bladder cancer. Since there: seem to be differences in patterns of smoking between rural and urban groups, additional factors must be sought to account for the lack of such a differential in the disease. The experimental work of Holsti and Ermala (177) has been described earlier. This is a solitary finding requiring repetition with the same strain of mice. DiPaolb and Moore utilizing different methods of preparation of the tobacco tar and different strains of mice obtained essentially negative results (75). Further retrospective studies of female cases, studies with large enough numbers of male cases to provide for further cross-classification by amount and duration of smoking and inhalation~ practices, and the ultimately forth- coming results on female subjects in the current Hammond prospective study will be necessary to provide more nearly adequate data: in urinary bladder cancer. ConclusionAvailable data; suggest an associatSon: between cigarette smoking and uri- narybladd'er cancer in the male but are not sudicient'tosupport a: judgment on the causal significance of this association. STOMACH CANCER Epidemiologic Evidence. RETROSPECTIVE STUDIES Very little interest in~ the relationship between smoking and gastric cancer seems to exist since only four (94, 193, 315, 325)' retrospective studies havee appeared in the literature since 19=16. The method'ology and findings of these studies have been summarized in Tables 16 and 17. Of the four studfies, two (94, 315) failed to find any association between smoking and' gastric 225

TABLE 16.-Summary of methods used in retrospective studies of smoking and cancer of the stomach r E08S9GE0 Cases Controls Investigator, year, and Country Sex - Collection of data reference - - - - No. Method of selection No. Method of selection -- Dunham & Brunschwig - U.S.A. - M&F 40 - - Not clear. Patients in Dept. of 40 - Not clear. Patients without gastric - - Not specified 1946 (94). Surgery, Univ. of Chicago. tumor. Kraus et al., 1957 (193). U.S.A. M 66 Admissions to Roswell Park Me- 677 Patients admitted to Roswcll Park Questioned by trained interviewers "-- - - -- modal Inst., 11/48-9/5 1, --- 25-74 during same time period in follow- - - --- _ years of age. -- Ing 4 diagnostic groups: - (1) Digestive cancer other than esophagus or stomach. - (2) Canccr-.other than diges- tive-respiratory, urinary, skin, hemat. (3) Non-tumor diag. of digestive system other than esophagus or storriach. (4) Non-tumor diag. other than --d i ge s t i v e-re s p i r a t or y; --u r i n s r y, skin, hemat. Each control Rroup matched to cancer group by age and popula- tion sizebf place of residence. Staszewski 1960 (327). Poland M 136 Patients admitted to Oncological 912 See'}`ABLE 11 See TABLE 11. Two-thirds of can- Institute during 1957-59. cer of stomach diagnoses were hi s- _ tologically contirmed. Schwartz et al., 1961 (315). France M 263 See TABLE 11 263 Patients hospitalized from 1954-1956 See TABLE II - -- - - ----- -- -- with gastric cancer in Paris and other large cities.

77 TABLE 17.-Summary of results of retrospective studies of smoking and cancer of the stomach Percent non-smokers Percent heavy smokers Percent inhalers among Relative risk: ratio to - - --- - -- - - -- - - smokers non-smokers reference and year Investigator , , Cases Controls Cases Controls Cases Controls A1l8mokers Heavy Smokers Dunham and Brunschwig 1948 (94) ------------------------ 47.5 47.5 -------------- -------- ------ - ------------ ---------------- ----- 0 -- ---- - Kraus et al. 1957 (193)-------------------------------------- ------ 19.2 - 24.2 - -- ----- - ---------------- .3 -1.3 - - ------------- --- ---- _ - 6taszewsk11980 (325) --------------------------------------- - 12.5 -- 18 - - 88.2 -- 80 - 1.5 ----- 2 1 - -- Schwartz et al. 1961 (315)----------------------------------- ------- -- 16 17 - Total cigarettes smoked -- 37 - - - 34 1.0 ---__-------- daily - 14.6 I 15.3 VOgS9L.E0

cancer. The other two studies, to date, suggested an association but these were not statistically significant (193, 325). Two of the studies did not approach the smoking variable specifically but as part of attempts to examine directed to the role of smoking (315, 325)~. The relative risks as calculated are not significantly different from unity. severall possible etiological factors (94, 193) ; the other two were specifically cancer mortality ratio~~ of'~ 1~~J (Table 29J, Chapter 8)~. For cigar and pipe smokers the combined studies provide a mean gastric smoked. In neither of these is any gradient apparent. or mortality ratios for the severall cigarette smoking classes by amount Two of the earlier reports (84, 88)' provi,de information on mortality rates ratio is not statistically significant (p=0.12) (163). and Horn study (163) (Table 1 of this chapter),. The Hammond and Horn Dunn, Linden, Breslow occupational' study (96) to 2.3' in the Hammond described earlier. The individual studies, however, with fairly adequate numbers for stability, show a range of mortality ratios from 0:8 in the calculated to be 1.4. This is obviously lower than for any of, the sites cancer. The mean gastric cancer mort'ality ratio for the seven studies is Hammond and Horn study) have yielded a total of 413 deaths from gastric The seven prospective studies brought up-to-date (except for the original PROSPECTIVE STUDIES condensates have not been successful (294). Attempts at production of cancer of the stomach with tobacco tars or into the glandular stomach wall between the serosa and mucosa (332, 333). rats by the intramural injection of carcinogenic hydrocarbons (17, 19, 187, 339) or by inserting a silk thread impregnated with 2-methylcholanthrene Adenocarcinoma has been produced in the glandular stomach of mice and oral administration~ of carcinogens (249). Rats also develop squamous cell tumors in the forestomach after prolonge& injecting 20-methylcholanthrene intramurally. Lorenz (333) produced the same type of' cancer in the forestomach by incidence of such cancers in~ mice varies with the strain used. Stewart and covered with squamous epithelium extending down from the esophagus. The 59; 276, 364). It should be noted that the forestomach of mice and rats is 19, 59, 113a, 223, 276, 308, 334, 364, 368) including benzo(a)pyrene (19, by the oral administration of various polycyclic aromatic hydrocarbons (8, Cdreir?ogenesis Squamous cell carcinoma has been produced in the forestomach of mice the fore- or glandular stomach. None of the retrospective studies shows an association between gastric cancer and smoking, Nor do the prospective studies yield gastric cancer mortality ratios significantly higher than the total mice with benzo(',a)pyrene and'dibenz (a,h) anthracene ihjected directly into Squamous and adeno-carcinomas have been produced experimentally in Eual'uation, o fthe Evidence 228

mortality ratio, In fact, the mean gastric cancer mortality ratio for ciga- rette smokers is below the mean total mortality ratio, and for cigar and pipe smokers it is approximately the same. Even a gradient by amount smoked is lacking in~ at least two of~ the prospective studies. Conclusion. No relationship has been established between tobacco use and stomach~ cancer. SUMMARIES AND CONCLUSIONS Cancer deaths per year increased seven-fold (,in the United States death registration area: of 1900) between 1900 and 1960-from 10,000 in 1900 to 80;000' in 1960. Less than half of this increase was due to aging and growth of the population. A large part of the increase was due to lung cancer. LUNG CANCER' While part of the rising trend for llmg cancer is attributable tb improve- ments in diagnosis, the continuing experience of the State registers and the autopsy series of large general hospitals leave little doubt! that a true increase in the lung cancer deatL rate has taken place. About 5,700 women and 33,200 men died of lung cancer in the United States in 1961; as recent'lyas 1955, the corresponding totals were 4,100'women and 22;700 men. This extraordinary rise has not been, recorded for cancer of any other site. When any separate cohort (a group of persons born during,the same ten- year period) is scrutinized over successive decades, its lung cancer mortality rates vary directly with theaecency of the birt6 of the group: the more recent the eohort, the higher the risk of lung cancer throughout life. Within; each cohorts lung cancer mortality apparently increases unabated to the end of the life span. The pattern~ would sug~esG that the mortality differences may be due to differences in exposure to one or more factors or to a progressive change in population composition among the several cohorts. A considerable amount of experimental work in many species of animals has demonstrated that certain polycyclic aromatic hydrocarbons identified in~ cigarette smoke can produce cancer. Other substances in tobacco and smoke, though not carcinogenic: tliemselves, promote cancer production or lower the threshold to a known carcinogen. The amount of known carcinogens in cigarette smoke appears to be too small to account for their carcinogenic activity. There is abundant evidence, however, that cancer of the skin can be in- d'uced in man by industrial, exposure to soots, coal tar, pitch and mineral oils; all of these contain various polycyclic aromatic hydrocarbons known to be carcinogenic in many species of animals. Some: of these compounds are also present, in tobacco smoke. Although it is noted that the few attempts to produce bronchogenic carcinoma directly with tobacco extracts, smoke, or 229

condensates applie& to ~ the lung or the tracheobronchial tree of experimental animals have not been successful, the administration of polycyclic aromaticc hydrocarbons, certain metals, radioactive substances, and certain viruses have 1 of the association between tobacco smoking and lung, cancer (summarized in Tables 2 and 3 of Chapter 9), varied considerably ini design and method. Despite these variations, every one of the retrospective studies showed an association between smoking and lung cancer. All showed that proportion- ately more heavy smokers are found among the lhng cancer patients than in the control populations and proportionately fewer non-smokers among, the cases than among the controls. The differences are statistically significant in all the studies. Thirteen of 7 prospective studies (described in Chapter 8). The 29 retrospective studiess with~ lung cancer and appropriate "controls" without lung cancer and from cancer comes primarily from 29 retrospective studies of groups of' personss to fix a safe dose of chemical carcinogens for men. The systematic evidence for the association between smoking and lung Neither the available epidemiologicall nor the experimental deta is adequate aromatic hydrocarbons that produce cancer in~ experimental animals. man are susceptible to the carcinogenic action of some of the same polycyclic been shown to produce such~ cancers. The characteristics of the tumors pro- duced are similar to: those observed in man. Since the response of most human tissues to carcinogenic substances is qualitatively similar to that observed in experimental animals, it is highly probable that the tissues of the studies, combining all forms of tobacco consumption, found a significant association between smoking of any type and lung cancer; 16 studies yielded an even stronger association with cigarettes alone. The degree of association between smoking, and lung cancer increased as the amounts of smoking, in- creased. Ex-smokers generally showed a lower risk than current smokers but greater thani non-smokers. Relatively few of the retrospective studies have dealt with "age started smoking," but alli except one of these studies found that; male lung cancer patients began tol smoke at a significantly younger age than the controls. Except at the highest cigarette consumption levels, the relationship: of inhalation to lung cancer was significant for those smoking cigarettes alone. Several investigators have utilized mathematical techniques to calculate,, fromi retrospective studies, the relative risks of lung cancer f'or smokers as compared with non-smokers. All of the 9 studies in which relative risk ratios were derived showed' a significantly greater risk among smokers, ranging from as low as 2,d-to-1! for light smokers to as much as 34.1-to-1 for heavy smokers, with most of the ratios betweeni these two extremes. All seveni of the prospective studies show a remarkable consistency in the higher mortality of smokers, particularly from lung cancer. Of' special interest is that the size of the association between cigarette smoking and! totall lung cancer death rates has increased with the ongoing progress of the studies. Depending oni the kind of population studied'y the relative risks of lung cancer for current cigarette smokers in America comparedl with, non-smokers range from 4.9'in one study to 15.9 in another. A study among British doctors showed a ratio of 20.2. For the studies as a whole; cigarette smokers have a risk of developing lung cancer 10.8 times greater than non- 230

smokers. The mortality ratios increase progressively with amount of smok- ing; the pivot levell appears t'o be 20 cigarettes a day. For those who smoke pipes andl/or cigars (to the exclusion of ciaarettes ), the lung cancer ratioss are lower than for any of the cigarette smoking classes includinr, combina- tions of cigarettes with pine and /or ciaars. In extensive and controlled blind studies of the tracheobronchial tree of 402 male patients, it' was observed that several kinds of changes of the epithelium were much more common in the trachea and bronchi of cigarette smokers and subjects with lung cancer than in nonrsmokers and patients without lungcancer. 'liheepithelia] changes observed are (1) loss of ciliated cells, (2) basallcell hyperplasia (more than two layers of basal cells), an& (31 presence of atypicali cells. Each of the three kinds of epitheliall changes was found to increase with the number of cigarettes smoked. Extensive atypical changes were seen most frequently in men who smoked two or more Uackss of cigarettes a day. Men who smoke pipes or cigarettes have more epithelia] changes than non-smokers but have fewer changes than cigarette smokers consuming approximately the same amount of tobacco. It may be concluded, on the basis of human and experimenCall evidence; that some of! the advanced epithelial lesions with many atypical! cells, as seen in the bronchi of cigarette smokers, are probably pre-malignant. Other pathologic studies show that squamous and oval~cell carcinomas are the predominant types associated withi the increase of lung cancer in the male population, and that a significant relationship exists between smok- ing and the epidermoid and anaplastic types. In several studies, adenocar- cinomas have also shown a definite increase, although to a lesser extent. Various studies have suggested that adenocarcinomas have little or less relationship to smoking. In general, the association between smoking and lung cancer may be measured by certain crrud'e indirect indicators as well as by the direct measures (retrospective and prospective studiesldescribed earlier. Indirect measures include: a parallel increase in lung, cancer mortality rates and in per capita consumption of tobacco; disparities between male and female lung cancer rates andi the corresponding differences bet'ween smoking habits of men and women by amounts smoked' and duration of smoking. The retrospective and prospective studies directly measure the occurrence and relationship of smoking and lung cancer in the same kinds ofl population. Careful analysis of these studies demonstrates that neitherdiarnostSc errorsnor classification errors in terms of amount smoked are of! sufficient size to invalidate the results. Possible bias due to selection of subjects is diminished by the fact that in the continuing studies, lung cancer death rate differentials increase with the passage of'~ time. Thus, it would appear that an association between cigarette smoking and ltrng cancer does indeed exist. No single criterion is sufficient to evaluate the causal significance of'~ this association; but a number of different kinds of criteria, considered together, provid'e an adequate test: the association is consistent; no prospective: study and no reasonably designed retrospective study has found results to the con- trary. In the nine retrospective studies, f'or which relative risks for smokers and non-smokers were calculated, and in the seven prospective studies, the relative risk ratios for lung cancer were uniformly high and remarkably 231

close in magnitude, attesting to the strength of the association. Moreover a dose-effect phenomenon is apparent in that the relative risk ratio increases with the amount of tobacco consumed or of cigarettes smoked. From the prospective studies, it is estimated that in comparison witL non-smokers, average smokers of cigarettes have approximately a 9- to 10-fold! risk of developing lung cancer and heavy smokers aEleast a 20:fold risk. An important criterion~ for the appraisal' of causal significance of an as- sociation is its coherence with known~ facts of the natural history and biology of the disease. Careful examination of the natural history of smoking and of lung cancer shows the relationship to be coherent in every aspect that could be investigate& The probability that genetic inflhences might under- lie both the tendency toward lung, cancer and the tend'eney to smoke weree also examined. The great rise in lung cancer recorded in man, that has occurred in recent decades, points to the introduction of new determinants without which genetic influences would! have had little or no potency. The genetic factors in man were evidently not strong enough to cause the develop- ment of lung cancer in large numbers of people under environmental' condi- tions that existed! half a century ago: The assumption that the genetic constitution of man could have changed gradually, simultaneously, an& identically in many countries during this century is most unlikely. More- over, the risk of developing lung cancer diminishes when smoking is dis- continued; although the genetic constitution must be assumed to have remained the same. It has been reeognized that a: causal' relationship between cigarette smok- ing and lhng cancer does not exclude other factors. Approximately 10 percent of lung cancer cases occur among non-smokers. The available evi- dence on occupational hazards, urbanization or industrialization and air pollution, and previous illness was considered for possible etiologic factors. A significant excess of lung cancer deaths was found among workers in certain industzies-notably chromate, nickel processing, coal gas, and as- bestos-but the population exposed to industrial carcinogens is relatively small; these agents cannot account for the increasing lung cancer risk in the general population. The urban-rural diff'erences in lung cancer mortality risk, though small and accounted for in part by differences in smoking habits,, imply that intensity of urbanizationi or industrialization and' air pollution may have a residual influence on lung cancer mortality. Observations on, previous respiratory illness are too few in number to place any degree of assurance on relat'ionship with lung cancer. Conclusions 1. Cigarette smoking is causally related to lung cancer in men; the magni- tude 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. 232 . ... . ..,. ..~........... ... ,....-. _.x,;..:.~+a,. ...r,. :-.'.is- .~~+r•

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 insufficient to warranY a conclusion for each group individually.. ORAL CANCER The suspicion of an association between use of tobacco and oral cancer dates back to the early 18th century when cancer of the lip was first noted among users of tobacco. In modern times, 20! retrospective studies have shown a significant association of oral cancer with smoking or chewing of tobacco or use of snuff. Associations between oral cancer and smoking of cigarettes, cigars, and pipes were noted in nearly all of these studies, but in many, of them pipes and cigars seemed to exert a stronger influence. Im a study in which the sample size was large and controls adequate, it was possible to establish gradients for lip cancer by number of pipefuls smoked a day, for tongue cancer by amount of tobacco in pipes and cigars, and~ orall cancers by number of pipefuls. No gradientiby amount smoked was noted for cigarettes. The seven prospective studies show that cigarette smokers have propor- tionately 4.1 times as much mortality from, oral cancer as non-smokers. This is the third highest mortality ratio of cigarette smokers to non-smokers among the several specific types of cancer deaths and the fourth highest among all causes of death associated with cigarette smoking, For cigar and pipe smok- ers comparedl with non.smokers, oral cancer has the highest mortality ratio4 3.3, of all causes of death, exceeding cancer of the esophagus, larynx, and lung... Cancer of the orali cavity has not been, produced experimentallyy by the ex- posure of anin-ials to tobacco smoke or to carcinogenic aromatic polycyclic hydrocarbons except in the special case of benQo(a) pyrene and other hydFo- carbons oni the cheek pouch ofi the hamster. Leukoplakia was reported too have been inducedl by the injection of tobacco smoke condensates into the gingi'va! of rabbits. A strong, clinical impression links the occurrence of leukoplakia of the mouth with the use of tobacco in its various forms. Conclzcsions 1. The causall relation of'~ the smoking of pipes to the development of can- cer of the lip appears to be established. 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. LARYNX Retrospective studies with adequate sample size all designate cigarette smoking as the most significant class associated with cancer of the larynx. 233 I

In each of the seven prospective studies, laryngeal cancer has been observed among smokers in frequencies inexcess of the expected. A summation yields a mean mortality ratio of 5.3 for cigarette smokers. Recently calculated material from six prospective studies 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. Laryngeal cancer cases were also associated with cigar and pipe smoking, but the number of cases is not yet large enough for judgment. The relative strength of the association, as measured by the specific mor- tality ratio (as an average of combined experiences), is not as high~ as that noted for lung cancer, but two of the three major studies with adequate case loadsindicate that the reall value of the relative risk may approach that for lung cancer. As with lung cancer, a dose-effect of smoking is also demon- strable. The majority of the retrospective studies have shown a greater association with heavy smoking, So far as known, no attempts to induce carcinoma of the larynx by tobacco smoke or smoke condensates have been reported. 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. ESOPHAG'US Both, the retrospective and prospective studies show an association~ between esophageal cancer and tobacco consumption. In the seven prospective studies, smokers have died of esophageal cancer 3-4 times as frequently as non-smokers; the mortality ratio for pipe and cigar smokers (compared to non-smokers) is 12, second only to that for oral cancer. Recent data from six of the prospective studies show a gradient of risk ratios from 3.0 for smokers of one pack or less of cigarettes per dayto, 4.9 for smokers of more than a pack per day. So far as known, no attempts to induce carcinoma of the esophagus by tobacco smoke or smoke condensates have been reported. 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 In 1955, when~the lips and oral mucosa of mice were painted with tobacco tars for five months, 10 percent of the animal5 developed carcinoma of the urinary bladder. This experimental work led to four retrospective studies, all of whi& found a significant association between cigarette smoking and 234

urinary bladder cancer in males. Two of the studies also fbun& significant associations with pipe or cigarette smoking. Compared with non-smokers, the relative risk of smokers developing cancer of the urinary bladder varied from 2.0:to 2.9. The mean mortality ratio-cigaretrte smokers to non-smokers-for alll seven prospective studies is 1.9. Among smokers of one pack or less per day the mortality from urinary, bladder cancer is 1.4 times that of non-smokers; for smokers of more than a daily pack, it is 3,1. Conclusion Available data suggest an associatiom between cigarette smoking andl urinary bladder cancer in the male but are not sufficient to support! judgment on the causal significance of this association. STOMACH None of the retrospective studies shows an association between gastric cancer and smoking. The prospective studies show that cigarette smokers die of gastric cancer 1.4 times more ofteni than; non-smokers, buU this is below the total mortality ratio. No gradient of risk by amount smoked is apparent. Attempts to produce cancer of the stomach in experimental animals with tobacco tars have not been successful. Conclusion No relationship has been established between tobacco use and st'omach cancer. REFERENCES 1. Ahlbom, H. E. Pradisponierende Faktoren Fiir Plattenepithelkar- zinom in Mund; Hals und Speiserohre. Eine Statistische Unter- suchung am Material des Radiumhemmets, Stockholm. Acta Radiol 18: 163-85, 1937. 2. Alexander, P., Horning, E. S. Observations on the Oppenheimer method! of inducing tumours by subcutaneous implantation of plastic films., In Ciba Found'ation Symposium on Carcinogenesis. J & A Churchill, Ltd., Londony 1959. p. 12-25. 3. Andervont, H. B. Further studies on the suseeptibilfit'y of hybrid mice to induced and spontaneous tumors. J Nat Cancer Inst 1: 135-45, 1940. 4. Andervont, H. B. Pul'monary tumors in~ mice. VIII. The induction of pulmonary tumors in mice of strains D, M, C57 brown and C5 7 black by 1,2,5,6-dihenzanthracene. Pub Health Rep 54: 152-1-9; 1939. 235

5. Andervont, H. B. Pulmonary tumors in mice. The susceptibility of the lungs of albino mice to the carcinogenic action of 1,2,5;6• dibenzanthracene. Public Health Rep (WashJ 52: 212-21, 1937: 6. Andervont, H. B. Biological background for experimental work on tumors. Canad Cancer Conf 1: 2-24, 1954. 7. Arkins H. Relationship between human smoking habits and death rates. Current Med Digest 22: 37-44, 1955. 8. Armstrong, E. C., Bonser, G. M. Squamous carcinoma of the fore- stomach an& other lesions in mice following orall administration of 3,4,5,6-dibenzcarbazole. Brit J Cancer 4: 203-11, 1950. 9. Auerbach, 0. Special report to the Surgeom General's Advisory Com- mittee on Smoking and Health. 10. Auerbach, 0. The pathology of carcinoma: of the bronchus. New York State J Med 49: 900-7, 1949. 11. Auerbach, 0., Gere, J. B., Forman, J. B., Petrick, T. G., Smolin, H. J.,. Muehsam, G. E, Kassouny, D. Y., Stout, A. P. Changes in the bronchial epithelium in relation to smoking and cancer of the lung. New Eng, J Med 256: 97-104, 1957. 12. Auerbach, 0., Gere, J. B., Pawlbwski, J. M., Muehsam, G. E, Smolin, H. J., Stouts A. P. Carcinoma-in~situ and early invasive carcinoma occurring in the tracheobronchial trees in cases of bronchial car- cinoma. J Thorac Surg 34: 298-309, 1957. 13. Auerbaeh, 0.,, Petrick, T. G., Stout, A. P., Statsinger, A. L., Muehsam~ G. F., Forman, J. B., Gere, J. B. The anatomical approach to the study of smoking and bronchogenic: carcinoma. A preliminary re- port of 41 cases. Cancer 9: 76-83, 1956. 14. Auerbach, 0., Stout, A. P., Hammond, E. C., Garfinkel~ L. Bronchial epithelium in former smokers. New Eng J Med 267: 119-25, 1962. 15. Auerbach, 0., Stout, A. P., Hammond, E. C., Garfinkel, L. Changes in bronchial epithelium in relation to cigarette smoking and in rela• tion tolung,cancer. NewEngJ Med 265:253-67, 1961. 15a. Auerbachy 0., Stout, A. P., Hammond, E. C., Garfinkel, L. Changes in bronchial epithelium~in relation to sex, age, residence, smoking,and pneumonia; New Eng J Med 267: 111~-9; 1962. 16: Auerbach, 0., Stout, A. P., Hammond, E. C., Garfinkel, L. Miero- scopic: examination of bronchial epithelium in children. Amer Rev Resp Dis 82 : 640-8;,1960: 17. Barrett, M. K. Avenues of approach to the gastric-cancer problem, J. Nat Cancer Inst 7: 127-57, 1946. 18. Barry, G., Cook, J. W., Haslewood, G'. A. D., Hewett, C. L., Hieger, I.,, Kennaway, E. L. The productiom of cancer by pure hydrocarbons part 3. Proc Roy Soc [Biol] 117: 3'18-51, 1935: 19: Beek„ S. The effect of feeding carcinogenic hydrocarbons dissolved in aqueous soap solution on the stomach of CBA mice. Brit J Exp Path 27: 155-7, 1946. 20. Beebe, G. W. Lung cancer in World War I veterans. Possible rela- tion to mustard-gas injury and 1918 influenza epidemic. J Nat Cancer Inst, 25: 1231-52, 1960: 236

21. Berenblum, I. A speculative review. The probable nature of promot- ing action and its significance in the understanding of the mecha- nism of carcinogenesis. Cancer Res 14: 471-7, 1954. 22. Berkson, J. Smoking and lung, cancer: Some observations onI two recent reports. J Amer Stat Ass 53: 28-38, 1958. 23, Berkson, J. The statistical investigation of smoking and cancer of the lung. Proc Mayo Clin 341: 206-24a, 1959. 24. Berkson, J. The statistical study of association between smoking and lung cancer. Proc Mayo Clin 30: 31911$, 1955. 25. Best, E. W. R., Josie, G. H., Walker, C: B. A Canadian study of mor- tality in relation to smoking habits. A preliminary report. Canad J Public HealYhi52: 99-106, 1961. 26. Bigelow, G. H.,, Lombard, H. L. Cancer and other chronic, diseases in Massachusetts. Boston, Houghton MifHin Co.,,1933. 355 p. 27. Bittner, J. J. Spontaneous lung carcinoma in mice. Pub Health Rep 53: 2197-2202, 1938. 28. Black, H., Ackerman, L. V. The importance of epidermoid carcinoma- in-situ in the histogenesis of carcinoma of the lung. Ann Surg 136: 44-55, 1952. 29. Blacklock, J. W. S: The prodtlction of lung tumors in rats by 3:4 benzpyrene, methylcholanthrene and the condensate from cigarette smoke. Brit J Cancer 111: 181-91, 1957. 30. Bliimlein, H. Zur kausalen Pathogenese des Larynxkarzinoms unter Beriicksichtigung des Tabakrauchens. Arch Hyg Bakt Miichen, 139: 404, 1955. 31. Bock, F. G., Moore, G. E: Carcinogenic activity of cigarette smoke condensate. 1. Effect of trauma and remote X-irradiation. J Nat Cancer Inst 22: 401-11, 1959. 32. Bonnet, J. Quantitative analysis of benzo[a]pyrene in vapors coming from melted tar. Nat Cancer Inst Monogr No. 9: 221-3, 1962. 33. Boutwell, R. K.,, Bosch, D., Rusch, H. P. On the role of croton oil in tumor formation. Cancer Res 17: 71-5, 1957. 34. Bowery, T. G., Evans, W. R., Guthrie, F. E., Rabb, R. L. Insecticidee residues in tobacco. Agric & Food Chem 7(10) : 693-702, 1959. 35. Bowery, T. G., Guthrie, F. E. Determination of insecticide residues on green and flue-cured tobacco and in mainstream cigarette smoke. Agric & Food Chem 9(3)~: 193-7, 1961. 36. Breedis, C.,, Robertson, T., Osenkop, R. S., Furth, J. Character of changes occurring in course of transplantation of two st'rains of lung tumors in mice. Cancer Research 2: 11'6-124, 1942. 37. Breslbw, L. Special report to the Surgeon General's Advisory Com- mittee on Smoking and' Health. 38. Breslow, L., Hoaglin, L., Rasmussen, G.,, Abrams„ H. K. Occupationss and cigarette smoking as factors in lung, cancer. Amer J Public Health 44: 171-81, 1954. 39. Bridge, J. C., Henry, S. A. Industrial Cancers. In: Report of the In- ternational Conference on Cancer, London, July,,1928, p. 258-68. 237 P ...... . ,.,.. .._ . _. , _ .... - ".ait.~ ..c>-.. _..o,. vw S:`k~: .. .........,

40. Brill, A. B., Tomonaga, Ms, Heyssel, R. M~ Leukemia in man follow- ing exposure to ionizing radiation: A summary of findings in, Hiro~ shima and Nagasaki, and a comparison with other human experience. Ann Int Me& 56: 590-609, 1962. 41. Broders, A. C: Squamous-cell epitheliomal of the lip, JAMA 74: 656- 64, 1920. 42. Brosch,,A. Theoretische und experimentelle Untersuchungen zur Patho- genesis und Histogenesis der malignen Geschwiilste: Virchow's Arch Path Anat 162: 32-84, 1900. 4.3: Brues, A. M. Critique of the linear theory of carcinogenesis. Science 128: 693-9, 1958. 44. Brusevich, T. S. On occupational dermatoses caused by crude oil pyrolysis products and the possibility of their degenerating, into can- cer of the skin. Gig Tr Prof Zaho16: 38-43, 1962. 45. Buechley, R. W. Epidemiological consequences of! an arsenic-lung can, cer theory. Amer Ji Public Health 53: 1229-32, 1963. 4i6. Burdette. W. J. Gradient in susceptibility of the bronchopulmonary tract to tumors. Surgery 38~ (11) :?79-86, 11955. 47. Burdette, W. J. Induced pulmonary tumors. J Thorac Surg 24: 427=3291952. 48. Burd'ette, W. J. Oncogenetics. Surg Clin N Amer 42: 289-303; 1962. 49. Burdette, W. J. Significance of mutation in relation to the origin of tumors. Cancer Res 15: 201, 1955. 50. Butlin, H. T. Three lectures on cancer of the scrotum in chimney- sweeps and others: Brit :11ed J 1: 1341-6, 1892; 2: 1-6, 66-71, 1892. 51. Cahnmann; H. Detection and quantitative determination of benzo(a) pyrene im American shale oil'. J Anal Chem 27: 1!235--40, 1955. 52. Carnes, W. H. The respiratory epithelium of patients with lung can, cer. The Morphological Precursors of Cancer. Proceedings of an International Conference held at the University of! Perugia, June 1961. A publication of the Division of Cancer Research, Uhiversity of Perugia, Italy. 53, Case,, R. A. M., Lea, A. J. Mustard gas poisoning, chronic bronchitis and lung cancer; an investigation into the possibility that poisoning by mustard gas imthe 1914-18 war might be a factor in the produc- tion of neoplasia. Brit J Prev Soc Med' 9: 62-72, 1955. 54. Castleman, B. Personal com,muniaation~ to the Surgeon General's Advisory Committee on Smoking and Health. 55. Clemmesen, J, Nielsen, A. The social distribution of cancer in Copen- hagen, 1943-1947. Brit J Cancer 5: 159-77, 1951. 56. Clemmesen, J., Nielsen, A., Jensen, E. Mortality and incidence of' ean- cer of the lung, in Denmark and some other countries. Acta Un Int Cancr 9: 603-36, 1953. 57. Cohart, E. M. Socioeconomic distribution of cancer of the lung im New Haven. Cancer 8: 1126-9, 1955. 58. Cohen, J.,,Heimann, R. K. Heavy smokers with low mortality. Indtistr Med Surg, 31: 115-20, 1962. .238 Q4~

1 59. Collins, V. J., Gardner, W. U., Strong, L. C. Experimental gastric tumors in mice. Cancer Res 3: 29-35, 1943. 60. Cooper, A. P. Observations on the structure and diseases of the testis. London, 1830. 55, 245 p. 61. Cornfield, J. A method of estimating comparative rates from clinical data; applications to cancer of the lung, breast, and cervix. J Nat Cancer Inst 11: 1269-75, 1951. 62. Cornfield, J., Haenszel~ W., Hammond, E. C:, Lilienfeld, A. M., Shim- kin, M. B.,,Wynder, E. L. Smoking and lung cancer: recent evidencee and a discussion of some questions. J Nat Cancer Inst 22 : 173'-203,. 1959. 63. Cottini, G., Mazzone, G. The effects of 3:-4,benzpyrene on human skin. Amer J Cancer 37: 186-95i 1939. 64. Cunningham. G. J., Winstanley, D. P. Hy.perplasia and metaplasia in the bronchial epithelium. Ann Roy Coll Surg Eng 24: 323-30, 1959. 65. Cutler, S. J., Ederer, F:, Gordon, T., Crittenden, M., Haenszel, W'. Part I: End results and mortality trends in cancer. Nat Cancer Inst Monogr No 6: 1-67, 1961. 66. Davidson, J. Betel chewing and cancer. Brit Med J 2: 733-4, 1923. '67. Davis, G. G. Buyo cheek cancer. JAMA 64: 711-8, 1915. 68. Davis, K. Ji., Fitzhugh, 0. G. Tumorogenic potential of aldrin and dieldrin for mice. Toxicoll Applied Pharmacol 4: 187-9, 1962. 69. Dean, G. Lung cancer among white South Africans: Brit Medl 12: 852-7, 1959. 70: Dean, G'. Lung cancer among white South Africans. Report on a further study. Brit Med' J 2: 1599-1605, 1961. 71. Dean, G. Lung cancer in Australia. Med J Aust 1: 1003-6, 1962. 72: Denoix, P. F., Schwartz, D., Anguera, G. L'enquete franqaise sur 1'etiologie du cancer broncho•pulknonaire. Analyse detaillee. Bull Ass Franc Cancer 45: 1-37, 1958. 73. de Vries, W. M. Pitch cancer in the Netherlands. Rep Int Conf Cancer Bristol, 1928, p. 290-2. 74. Dickens, F., Jones, H. E. H. Carcinogenic activity of a series of reactive lactones and related substances. Brit J Cancer 15: 85-100; 1961. 74a. Dickens, F:, Jones, H. E. H. Further studies on~ the carcinogenic and growth-inhibitory actnvity of lactones and related substances. Brit J Cancer 17: 100-8, 1963. 75. DiPaolo, J. A., Moore, G. E. Effect on mice of oral painting,of cig4rette smoke condensate. J Nat Cancer Inst 23: 529-34, 1959. 76. Doll,R. Etiology of lung cancer. Advances Cancer Res 3: 1-50, 1955. 77. Doll,, R. Mortality from lung, cancer in asbestos workers: Brit J Industr Med 12: 81-6, 1955. 78. Doll, R. Mortality from lung cancer among non-smokers. Brit J Cancer 7: 303-12; 11953. 79. Doll, R. Occupational lung cancer: A review. Brit J Industr Med 16: 181-90; 1959. 80. Doll, R. Personal communication to: the Surgeon General's Advisory Committee on Smoking and' Health. 714-422 0-64-17 239

118. Fisher, R. A. Smoking, the cancer controversy. Some attempts to assess the evidence. Oliver and Boyd. London. 1959, pp. 47: 119. Foulds, L. Progression of careinogenesis. Acta Un Int Cancr 17: 148-56, 1961. ]20. Freedlander, B. L., Freneh„ F. A. Absence of co-carcinogenic action of oxidation products of nicotine in initiation of pulmonary ade- nomas in mice with urethan. Proc Amer Ass Cancer Res 2: 109, 1956. 121. Freedlander,, B. L., French, F. A:, Furst, A. The nonadditive effect of! nicotine and nicotine N'~ oxide on the carcinogenicity of ultra-violet! light. Proc Amer Ass Cancer Res 2: 109, 1956. 122. Friberg. L., Kaij, L., Dencker, S. J., Jonsson, E. Smoking habits in, monozygotic and dlzvgotictwins: Brit Med J 1: 1090-2, 1959. 123: Furth; J. Influence of host factors on the growthi of neoplastic cell's. Cancer Res 23: 21-34, 1963. ].24. Furth. J~, Furth. 0. B. Neoplastic diseases produced ini mice by gen- eral irradiation with x-rays. I. Incidence. Am J Cancer 28: 54- 65; 1936. 125. Gates, 0., Warren, S. The product'ion of bronchial carcinomas in mice. Amer J! Path 36: 653-71, 1960. 126. Gellhornti A. The cocarcinogenic activity of cigarette tobacco tar.Caneer. Res 18: 510-7, 1958. 127. Geminus [It seems to me.] Edfit'orial on article by Sir Ronald FishAr (114)~. New Scientist 4: 440. 1958. 128. Gilliam, A. G. Trends of mort'alnt'ry- attributed to carcinoma of the S L l'ung; possible effects of faulty certification of deaths to other respira- tory diseases. Caneer8~: 1130-6. 1955:1129: Goldhlatt, NL W. Occupational carcinogenesis. Brit Medl Bull 14: 136--40, 1958. 130. Gordon, T., Crittenden„ M.,, Haenszel,, W. Cancer mortality trends in the United States, 1930-1955; Part II: End Results and Mortality Trends in Cancer. Nat Cancer Inst Monogr No, 6: 131-355, 1961. 131. Grady, H. G., Stewart; H. L. Histbgenesis of induced pulmonary tumors in strain A mice. Amer J Path 16: 417-32, 1940. 132. Graham, E. A.,, Croninger, A. B., Wynder, E: L. Experimental pro- duction of carcinoma with cigarette tar. IV. Suceessfull experi- ments with rabbits. Cancer Res 17„ 1058-66, 1957. 133. Graham, Saxon. Special report to the Surgeon GeneralPs Advisory Committee on Smoking and HealthL 134. Gray, S. H., Cordonnier, J. Early carcinoma of the lung. Arch Surg. 19: 1618-26, 1929. 135. Great Britain General' Register Office. The Registrar-General's Decen- nial Supplement. Part IIa Occupational mortality. London, H.M.S:O., 1938. 156 p. 136. Griswold, M. H., Wilder, C. S., Cutler, S. J.,, Pollack, E: S: Can¢er in Connecticut 1935-1951. Hartford, Connecticut State Department of Health, 1955. 141 p. 137. Gross, L. Oncogenic viruses. Oxford, Pergamon, 1961. 393 p. 242

138. GselL„ 0. Carcinome bronchique et tabac: Med Hyg 12: 429-31, 1954. 139. Guerin, M., Cuzin, J. L. Action carcinogene du goudron de fumee de cigarette sur la peau de souris. Bull Ass Franc Cancer 44: 387-108; 1957. 140. Guerin, M., Oherling, C: Neoplasies et cancers a virus. Paris, Amedee Legrand 1961. 322 p. 141. Haag, H. B., Hanmer, HL R. Smoking habits and mortality among workers in cigarette factories. Industr Med Surg 26: 559-62, 1957. 142. Haase, G. Zur Kenntnis der Leukopl'akial oris und der Lippen- und Zungenkrebse bei~ Rauchern. Deutsch Mschr Zahnk 49: 881-913, 929-76, 19311. 1143. Haddow, A. The chemical and genetic mechanism of carcinogenesis. I. Nature and! mode of actioni II. Biologic alkylating agents. In: Homburger, F:, ed. The physiopathology of cancer. 2 ed. NY, Hoe- ber,, 1959. p: 565-685. 144. Haenszel, W: Cancer mortality among the foreign-born in t'he United States. I Nat Cancer Inst 26: 37-132, 1961. 145. Haenszel, W. Special report~ to the, Surgeon General's Advisory Com- mittee on Smoking and Health. 114'16; Haenszel,,W: Mortality and morbidity statistics oni all forms of cancer. Acta Un Int Cancr 17: 837-47, 1961. 147. Haenszel, W., Loveland, D. B.,, Sirken; M. G. Lung-cancer mortality as related to residence and' smoking histories. 1. Whit'e males. J Nat Cancer Inst 28: 947-1001, 1962. 148! Haenszel. W., Marcus, S. C., Zimmerer, E. G: Cancer morbidity in urban and rural Iowa. Pub Health Monogr No. 37: 1-85, 1956: 149. Haenszel, W., Shimkin, M. B. Smoking patterns and epidemiology of lung cancer in the United States: Are they eompathble? J N'at, Cancer Inst 16: 1417-41, 1956. 150. Haenszell W.,, Shimkin, M. B.,, Mantel, N. A retrospective study of lung cancer in women. J Nat Cancer Inst 21: 825-42; 1958. 151. Haenszel, W.,, Shimkin, M. B., Miller, H. P. Tobacco smoking, pat- terns in the: United States. Pub Health Monogr No. 45: 1-111, 1956. 152. Haenszel. W., Taeuber, K. E. Special report! to the Surgeon General's Advisory Committee on Smoking, and Health. 153. Halver, J. E., Johnson, C. L:, Ashley, L. M. Dietary carcinogens induce fish hepatoma: Fed Proc 21: 390;,1962. 154:. Hamer, D., Woodhouse, D. L. Biological tests for carcinogenic action of tar from cigarette smoke. Brit J Cancer 10: 49-53, 1956. 155. Hamilton, J. D., Sepp, A., Brown, T. C., MacDonald, F. W. Morpho- logical changes in smokers' lungs. Canad Med' Ass J 77: 177-82, 1957. 156. Hammond, E. C: Lung cancer death rates im England and! Wales com- pared with those in the United States. Brit Med! J 2: 649-54, 1958. 157. Hammond, E. C. Prospective study of 1,085,000 men and women in 25 of the United States aged 35--84. Unpublished data. ; L 243 I

I 158. H'ammond„ E. C. Smoking in relation to lung cancer. Conn Med J 18: 3-9, 1954. 159. Hammond,, E. C. Special report to the Surgeon General's Advisory Committee on Smoking an& Health. 160. Hammond, E. C., Garfinkel, L. Smoking habits of men and women. J Nat Cancer Inst 27: 419-42, 1961. 161. Hammond, E. C.,,Garfinkel! L. Special report to the Surgeon General's. Advisory Committee on Smoking and Health. 162. Hammond, E. C.,, Horn„ D. Smoking and death rates-report on forty- four months of follow-up.of 187,783 men. I. Total mortality. JAMA 166: 11159-72, 1958. 163. 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: 1294-11308, 1958'. 164. Heller, I. Occupational cancers. J Industr Hyg, 12: 169-97, 1930. 165. Hendricks; N. V., Berry, C: M., Lione. J. G., Thorpe, J. J. Cancer of the scrotum in wax pressmen. AMA Arch Industr Health 19: 524- 39, 1959. 166. Henry, S. A. Occupational cutaneous cancer attributable to certain chemicals in industry. Brit Med Bull 4: 389-401, 1947. 167. Herman, D. L., Crittenden, M. Distribution of! primary lung carci~ nomas ini relatroni to time as determined by histochemical techniques. J'. Nat Cancer Inst 27: 1227-71, 19611. 168. Heston, W. E. Effects of genes located on chromosomes III, V, VII, IX, and''XIV on the occurrence of pulmonary tumors in the mouse. Proc Ihiternat Genetics Symposia, Cytol'ogia suppl 219: 224, 1957. 169. Hestbn, W'. E. Genetic analysis of susceptibility to induced pultnonary tumors in mice. J Nat~ Cancer Inst 3: 69-78, 1942. 170. Heston, W. E, Inheritance of susceptibility to spontaneous pulmonary tumors in mice. J Nat Cancer Inst 3: : 79-82, 1942. 171. Heston, W. E., Dunn, T. B. Tumor development in susceptible strain A and resistant strain L lung transplants in La F1 hosts. J Nat Can- cer Inst 5: 1057=71„ 1951. 172. Heston,, W. E., Schneidernian„ M. A. Analysis of dose-response in re- lation to mechanism of pulmonaryy tumor induction in mice. Science 117: 109-11, 1953. 173. Hest'on, W: E., Steffee, C. H. Development of tumors in fetal and' adult~ lung transplants. J>\at Cancer Inst 18: 779-93, 1957. 174. Hobsons J. W., Henry, H. eds. Pattern, of Smoking, Habits. H'ulton research studies of the British social patterm London. Hlulton Press, 1948; 175. Hoffman, E. F., Gilliam, A. G. Lung cancer mortality. Public Health Rep 69: 1'033-42, 1954. 176. Holland, J. J. Dissertatio inaugur. med. chir. sistens Carcinoma labii inferioris, absque sectione persanatum. In~: Wolff, JI. Die Lehre von der Krebskrankheit Jena, 1911. Vol. 2, p. 52-78. 177. Holsti, P., Ermala,,L. R. Papillary carcinoma of the bladder in mice, obtained after peroral administration of tobacco tar. Cancer 8: 679-82, 1955. 244

178. Hueper, W. C. A quest into the environmental causes of cancer of the lung. Public:Health Monogr No. 36: 1955, 45 p. 179. Hueper, W. C. Environmental factors in the production of human can- cer. In: Raven, R. W., ed., Cancer. 180. Hueper, W. C:Experimentall studies in metal carcinogenesis. IX. Pultnonary lesions in guinea pigs and rats exposed to prolonged in- halation of powdered metallic nickel. AMA Arch Path 65: 600-7, 1958. 1181. Hueper, W. C. Experimental studies in metal carcinogenesis. VI. Tissue reactions in rats and rabbits after parenteral introduction of. suspension of arsenic, beryllium, or asbestos in lanolin. J Nat Can- cer Inst 15: 11!3-29; 1954. 182. Hueper,, W. C:, Payne, W. W. Experimental cancers in rats produced by chromium compounds and their significance to industry and public health. Amer Indhstr Hyg Ass J 20: 279-80; 1959! 183. Hueper, W. C'., Payne, W. W. Experimental studies in metal' car- cinogenesis. Chromium, nickel, iron, arsenic. Archi Environ Health 5 : 445-62. 1962. 184. Kennawav, E: L., Kennaway, N. M. A further study of'the incidence of cancer of the lung and larynx. Cancer 1: 260=98, 1947. 185. Kennaway,,N. M.. Kennaway, E. L. A study of the incidence of' cancer of the lung and1arynx. J Hyg 36: 236-67; 1937: 186. Khanolkar, V. R. Cancer in India in relation to habits and customs. In: Raven, R. W., edl Cancer. London, Butterworth & Co. Ltd, 1958. Chapter 11, p. 272-80.. 187. Kirby. A. lI. M. Attempt's to induce stomach tumors. I. The effects of cholesterol heated to 300° C. Cancer Res 3: 519-2,5; 1943. 188. Klar, E, fJber die Entstehung eines Epithelioms Beim, Menschen Nach Experimentellen~ Arbeiten mit Benzpyren, Klin, Wschr 17: 1279-80. 1938 . 189. Knudtson. K. P. The patholbgic: effects of smoking tobacco on the tracheai and bronchial mucosa. Amer J Clin Path 33: 310-7, 1960. 190. Kotin, P. The role of atmospheric pollution in the pathoYenesis of pulmonary cancer: A review. Cancer Res 16c 375-93, 1956. 191. Kotin. P.,, Wiseley, D. V. Production of lung cancer in mice by in- halation exposure to inflbenza virus and aerosols of hydrocarbons. Progr Exp Tumor Res 3: 186-215, 1963. 1192: Koulumies, M, Smoking and pulmonary carcinoma. Acta Radiol ( StockholYn )' 39: 255-60, 1953. 193. Kraus, A. S., Levin3 M. L,, Gerhardt, P. A study of occupational associ- ations with gastric cancer. Amer J Public Health 47: 961-70, 1957. 194. Kreshover, S'. J., Salley. Ji. J. Predisposing factors in orall cancer. J Amer Dent Ass 54: 509-14, 1957. 195. KreyberC, L. Histological lung cancer types; a morphological and biological correlation. Norwegian Uhiversities Press, 1962. 92p. Also: Acta Path 14licrobiol Scand Suppl 157, 11962. 92 p. 196. Krey.berg, L. The significance of histological typing, in the study of the epidemiology of primary epithelial!lting tumours; a study of 466 cases. Brit J Cancer 8: 199-208, 1954. 245

197. Kuschner, M., Laskin, S., Cristof'ano; E., Nelsons N. Experimental car- cinoma of the lung. Proc Third Nat Cancer Conf Detroit, 1956. Phil'adelphia, Lippincott, 1957. p: 485-95. 198: Kuschner, M., Laskin, S., Nelson, N., Altschuler, B. Radiation in- duced bronchogenic carcinoma in rats. Amer J Path 34: 554, 1958. 199. Lancaster, H. 0. Cancer statistics in Australia: Part II. Respiratory tracheobronchial tree and lungs of mice exposed to cigarette smoke. II. Varying responses of major bronchi to cigarette smoke. Ab- sence of'~ bronchogenic carcinoma after prolonged exposure, and disappearance of bronchial lesions after cessation of exposure. Cancer 13: 721-32, 1960: 2061 Leuchtenberger, R., Leuchtenberger, C;, Zebrun, W., Shaffer, P. A correlated, histological, cytological and cytochemical study of: thee tracheobronchial tree an& lungs of mice exposedl t'~oeigarette smoke. III. Unaltered incidence of grossly visible adenomatous lung tumors in female CF mice after prolonge& exposure to cigarette smoke. Cancer 13': 956-8, 1960. 207. Levin, M. L., Goldstein, H., Gerhardty P. R. Cancer and tobacco smoking. A preliminary report. JAMA 143: 336-8;, 1950. 208. Levin, M. L., Haenszel~ W., Carroll, B. E., Gerhardt, P. R., Handy, V. H., Ingraham, S. C. IL Cancer incidence in urbani and rural areas of New York State. J Nat Cancer Inst 24: 1243-57, 1960. 209. Levy, B. M. Experimental oral carcinogenesis. J Denti Res Suppl to No. 1 42: 321-7, 1963. 210. Lewis, E. B. Leukemial and ionizing, radiation. Science 125: 965-72, 1957. 211. Lickint, F. Atiologie und Prophylaxe des Lungenkrebses. 2. Sta- tistische Voraussetzungen zur Klarung, der Tabakrauchatiologie des Lungenkrebses. Dresden and Leipzig, Theodor Steinkopff, 1953, 76-102. system. Med J Aust 1: 1006-11, 1962. 200. Landy, J. JL, White,, H. J. Buccogingival carcinoma of snuff dippers. Arch Surg, 27: 442-7, 1961. 201. Larson, P. S:, Haag, H. B., Silvette, H. Tobacco. Experimental and Clinical Studies. Williams and Wilkins, Baltimore, 1961. Leuko- plakia, p: 629-32. 202. Ledermann, S: Cancers, Tabac, Viny et Alcool. Concours Me& 77: 1107,1109-11, 1113-4, 1955. 203. Leitch, A. Paraffin cancer and its experimental production. Brit Med J 2: 1104-6, 1922. 204, Leitch, A. Notes on chimney-sweeps' cancer. Brrit Med J 2: 94.34, 1924. 205. Leuchtenberger, C., Leuchtenberger, R., Doolin, P. F. A correlated his- tological, cytological, and cytochemicallstudy of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. I. Bronchitis with atypical epthelial changes in mice exposed to cigarette smoke. Cancer 11: 490-506,,1958! 205a. Leuchtenberger, C., Leuchtenberger, R., Zebrun, W., Shaffer, P. A correlated' histological, cytological, and cytochemical study of the 246 ,..f. __. .;v. :... I 4

212. Lickint, F. Tabak und Tabakrauch als Etiologische Faktor des Car- cinoms. Zeit f Krebsforschung,30: 349-65, 1929. 213. Liebe, G. B. Originalabhandlungen undl Uebersichten. XIL U6er den Theer oder Paraffinkrebs. Schmidts Jahrb Ges Med 236: Heft 1, 65-76; 1892. 214. Lilienfeld, A. M. Emotional and other selected characteristics of cigarette smokers and non,smokers as related to epidemiological studies of lung cancer and other diseases. J Nat Cancer Inst 22: 259-82, 1959. 215. Lilienfeld, A. M., Levin, M., Moore, G. E. The association of smoking with cancer of! the urinary bladder in humans. AMA Arch Intern Med 98: 129-35; 1956. 216, Lindberg, K. Uber die formale Genese des Lungenkrebses. Arb a; d path Inst d Univ Helhingfors 9: 1-400, 1935. [cited by Nis- kanen (6)~] 217. Lisco, H., Finkel~ K P. Observations on lung pathology following the inhalation of radioactive cerium. [Abstract] Fed! Proc. 8: 360-1, 1949. 218. Little, C. C. Statement of Dr. Clarence Cook Little representing the Tobacco Industry Research Committee. In U.S, Congress 85th House Committee on Government Operations Legal and Monetary Affairs Subcommittee-Hearings on False-and 1Vlisleading Advertis- ing, (ifilter-tip cigarettes) July 18-26; 1957. Govt Print Off, 1957,. p. 34-61. 219. Little, C. C. 1957 report of the Scientific Director. Tobacco Industry Research Committee, N Y 1-62, 1957. 220. Lockwood, K. On the etiology of bladder tumors in Copenhagen- Frederiksberg. An inquiry of 369 patients and 369 controls. Acta Path Microbiol Scand Suppl 51: 145, 1-161, 1961. 221. Lombard, H. L., Doering, C. R. Cancer studies in Massachusetts. 2. Habits, characteristics and environment of individuals with and! without cancer. New Eng J M 198: 481-7, 1928. 222. Lombard, H. L, Snegireff, L. S. An epidemiological study of lung cancer. Cancer 12: 406-13, 1959. 223. Lorenz, E., Stewart, H. L. Squamous cell carcinima and other lesions of' the forestbmach in mice, following oral administration of 20- methylcholanthrene and 1,2,5,6-dibenzanthracene (preliminary re- port). J Nat Cancer Inst 1: 273-6, 1940. 224. Lorenz,, E., Stewart, H. L., Daniel~ J. H., Nelson„ C. V. The effects of breathing tobacco smoke on staim A mice. Cancer Res 3: 1231I, 1943. 225. Lynch, C. J. Influence of heredity an& environment upon number of tumor nodules occurring in lungs' of mice. Proc Soc Exper Biol Med 4,3: 186-9, 1940. 226. Lynch, C. J. Studies on the relations betweeni tumor susceptibility and heredity. VI. Inheritance ofI susceptibility to tar-induced tumorsin, the lungs of mice. J Exper Med 46: 917-33, 1927. 247

227. Lynch, R. M., McIver, F. A., Cain, J. R. Pulmonary tumors in mice exposed to asbestos dust. AMA Arch~ Ind'ustr Health 115: 207-14, 1957. 228. MacDonald, I. G. Chinks in the statistical armor. CA 8: 70, 1958: 229.b'IacDonald, I. G. Statement of Ian G. MacDonald, University of Southerni California. In: U.S. Congress 85th House. Committee on Government Operat'ionsLegal and' Monetary Subcommittee, Hearings on False and Misleading Advertising (filter-tip cigarettes). July 18-26, 1957. Govt Print Off, 1957,,p. 34-61. 230. Mainland, D., Herrera, L. The risk of bias4 selection in forward- going surveys with non-professional interviewers. J Chron Dis 4: 240-4, 1956. 231. Manouvriez, A. Maladies et Hygienedes Ouvriers Travaillant a la Fabrication des Agglomeres de Houillo et de Brai. Ann Hyg Publ Med e- ser. 2, 45: 459-81, 1876. 232. Mantel, N., Heston, W. E., Gurion, J. M. Thresholds in~ linear dose- response models for carcinogenesis. J Nat Cancer Inst 27: 203-15, 1961. 233. Marsden, A. T. H'. Betel cancer in Malaya. The Med I Malayal 14: 162-5, 1960. 234. Maxw-ell, J. L. Betel-chewing and cancer. Brit Med J 11: 729, 1924. 235. McArthur, C., Waldron, E., Dickinson, J. The psychology of smokinb. J Abnorm Soc Psycholi56: 267 '5; 1'958. 236. McConnell, R'. B., Gord'on, K. C. T., Jones, T: Occupational and, per- sonall factors in the etiology of carcinoma of the lung. Lancet, Lon- don, 2: 651-6, 1952. 237. Mills, C. A., Porter, M. M. Tobacco smoking habits and cancer of the mouth and respiratbry system: Cancer Res 10: 539-42, 1950. 238. Mills, C: A., Porter, M. M. Tobacco smoking, motor exhaust fumes, and general air pollution in relation to lung cancer incidence. Cancer Res 17: 981-90, 1'957. 239: b:tilmore, B. K.. Conover, A. G. Tobacco consumption in the United States, 1880-1955. Public Health Mongr No. 45: 1-111, 1956. 240. Mody, J. K., Ranadive, K. J. Biological study of tobacco in relation to oral cancer. Indian J Med Sci 13: 1023-37, 1959. 241. Muertel, C. G., Foss, E: L. Muiticentric carcinomas of the oral cavity. Surg, Gynec Obstet 106: 652-4, 1958. 242. Mold, J. B., Walker, T. B. Isolation of TDE from cigarette smoke. Tobacco Sci 1: 161-3', 1957. 243: Moore, C., Christopherson, W. M. The effect of' cigarette-smoke con- densate on hamster tissues. Exteriorized oral pouch~ and skin. Arch, Surg84i: 63-9, 11962. 244. Moore, C.,, Miller, A. J. Effect of~ cigarette smoke tar on the hamster pouch~ AMA Arch Surg,76: 786-93, 1958. 245. Moore, G. E., Bissinger, L. L., Proehl, E. C. Intraoral cancer and the use of chewing t'obacco. J Amer Geriat, Soc 1: 497-506, 1953. 246. Moore, G. E.,, Bock, F. G. A summary of research techniques for in- vestigating the cigarette smoking-lung cancer problem. Surgery 39': 120-30,1956. 248

247. Moriyama, I. M., Baum, W. S., Haenszel, W. M.,, Mattison, B. F. In- quiry into diagnostic evidence supporting medical certifications of death. Amer J Public Health 48': 1376-87, 1958. 248. Miihlbock, 0. Carcinogene Werking van Sigarettenrook bij Muizen. Nlederl T. Geneesk. 99: 2276-8, 1955. 249. Mulay,, A. S., Firminger, H. I. Precancerous and cancerous lesions of the forestomach and dermal-subcutaneous tumors in rats fed p-di'- methylaminobenzene-l-azo, 1-naphthalene. J Nat Cancer Inst 13: 57- 72, 1952. 250: Miiller, F. H. Tabakmissbrauch und Lungencarcinom. Z Krebsforsch 49: 57-84, 1939. 251. Murphy, J. B., Sturm, E: Primary lung tumors in mice following the cutaneous application of coal tar. J Exper Med 42'.: 693-698; 1925. 252. National Vital Statistics Division. National Center for Health Sta- tistics, U.S. Public Health Service. Special report to the Surgeom General's Advisory Committee oni Smoking and Health. 253. Nelson, A., Fitzhugh, 0. G. The chronic oral toxicity of DDT: J Pharmacol Exper Ther 89': 18-30, 1947. 254. Neyman, J. Statistics-servant of all sciences. Science 122: 401-406, 1955. 255. Nielsen, A., Clemmensen, J. Bronchial carcinoma-A pandemic. II. Incidence and tobaeco: consumption in various countries. Danish Med Bull 1: 194-9, 1955. 256. Niskanen, K. 0. Observations on metaplasia of the bronchial epit'he- lium and its relation to carcinoma of the lung. Acta Pat'h, 1Vlicrobiol Scand SuppI 80: 1949. 80 p. 257. Nothdurft'y H. fJber die Sarkomauslosung durch Fremdkorperimplan- tationen bei~ Ratten in Abhanaiekeit von der Form der Implantate. Naturwissenschaften~ 42:106„ 1955. 258. Ochsner, M., DeBakey, M. Symposium on Cancer. Primary pul- monary malignancy. Treatment by total pneumonectomy; analyses of 79 collected cases and presentation of 7' personal cases. Surg Gynec Obstet 68: 435-51, 1939. 259. 0'Donovan, W. J. Carcinoma cutitis in an anthracene factory. Brit J Derm 33: 291-7, 1921,. 260. O'Neal, R. M., Lee, K. T., Edw.ards„ D. Bronchogenic carcinoma. An evaluation from autopsy data, with special, reference to incid'ence, sex ratio, histological type, and accuracy of clinical diagnosis. Cancer 10: 1032-6, 1957. 261. Oppenheimer, B. S, Oppenheimer, E. T., Stout, A. P. Sarcomas in- duced in rodents by imbedding,various plastic films. Proc Soc Exp Biol Med 79: 366-9, 1952. 262. Orr, J. W., Woodhouse, D. L., Hamer, D., Marchant, J., Howell, J. S. Cigarette tobacco tars. Brit Einp Cancer Campaign Ann Rep 33: 238-9, 1955. 263. 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, 1958. 249

264'. Paget, J. Cancer of the penis in a chimney sweeper. Lancet 2: 265, 1850: 265. Papanicolaous G. Nl, Koprowska, I. Carcinoma-in-situ~ ofl the right lower bronchus. Cancer 4: 141-6,,1951. 266. Passey, R. D. Experimentall soot cancer. Brit Med J 2: 1112-3, 1922: 267. Passey; R. D., Bergel, F., Lewis, G. E., Roe, E. M. F., Middleton, F. C:, Boyland, E.,, Pratty B. M.G'., Sims,,P., Hieger, I. Cigarette smoking and cancer of the lung. Brifi Emp Cancer Campaign Ann, Rep 33: 59-61„ 238r9; 1955. 268. Passey, R. D., Roe. E. M. F., Middletom F. C., BergeL,F., Everett, J. L., Lewis, G. E., Martin. J. B., Boyland, E.,, Sims, P. Cigarette smoking and cancer. Brit Emp Cancer Campaigm Ann Rep 32: 60-2, 1954. 269: Paymaster, J. C. Cancer of the buccal mucosa;, a clinical study of 650 cases in Indian patients. Cancer 1: 431-5, 1956. 270: Payne,, W. W. Prodhction of cancers in mice and rats by chromium compounds. AMA Arch Industr Health 21: 530-5, 1960. 271. Peacock, E. E. Jr., Brawley, B. W. An evaluation of! snuffl and tobacco in the production ofl mouth~ cancer. Plast Reconstr Surg 23: 628- 35; 1959. 272. Peacock, E. E. Jr., Greenberg, B! G., Brawley, B. W. The effect of snuff and' tobacco on the production of oral carcinoma: An experi- mentat and! epidemiological study. Ann Surg151:542-50i1960. 273. Peacock, P. R. Cigarette smoking by laboratory animals. Seventh International Cancer Congress, Lond'on, July 6-12; 1958. Abstracts of papers. p, 153. 274. Peacock, P. R. Cigarette smoking experiments. Brit Emp Cancer Campaign. 35th Ann Rep, Part 2„1957. 303 p. 275: Peacock, P. R. Experimental cigarette, smoking by domestic fowls. Brit! J Cancer 9: 461. 1955: 276. Peacock. P. R.. Kirb-v,, A. H. M. Attempts to induce stomach tumors: II. The action of carcinogenic hydrocarbons on stock mice. Can- cer Res 41: 88-93; 1944. 2277. Pernu, J. An epidemiological study on cancer of the digestive organs and respiratory system. A study based on 7,078 cases. Ann Med Intern Fcnn 49 (Suppl. 33) : 1-117, 1960. 278. Poel, W. E. Skin as a test site for the bioassay of carcinogens and carcinogen precursors. Nat, Cancer Inst Monogr No. 10: 611-31, 1963. 279. Pobt, P. Chirurgical observations. London, 1775. Cancer Scroti, p. 63-8. 280. Potter, E. A., Tully, M. R. The st'athstical' approach to the cancer prob« lem in Massachusetts. Amer J Pub Health 35: 485-90, 1945. 281. Raascliou-Nielsen, E. Smoking habits in twins. Danish _lied Bull 7: 82-8, 11960. 282. Rabsons A. S., Branigan, W. J., LeCallais, F. Y. Lung tumors pro- dticed by intratracheal inoculation of polyoma: virus in Syrian hamsters. J Nat Cancer Inst 25: 937-65, 1960. 250

282a. Radford, Edward P., Jr., Hunt, Vilma R. Personal Communication to the Surgeon General's Advisory Committee on Smoking and Health. 283. Randig, K. Untersuchungem zur Atiologie des Bronchialkarzinoms. beff Gesundheitsdienst 16: 305-13, 1954. 284. Reddy, D. G.,, Rao, V'. K. Cancer of the palate in coastal Andhra: due to smoking cigars with the burning end inside the mouth. Indian J Med Sci 11: 791-8, 1957. 285. Reingold, I. M., Ottoman; R. E.,, Konwaler, B. E. Bronchogenic car- cinoma: A study of 60' necropsies. Amer J Clin Path 20: 515-25, 1950. 286. Rhoads, C. P., Smith, W. E., Cooper, N. S., Sullivan, R. D. Early changes in the skins of several, species, including man, after painting , with carcinogenic materials. Proc Amer Ass Can Res 1: 40, 1954. 287. Rigdon, R. H. Consideration of the relationship of smoking to lung cancer: With a review of the literature. Southern Med J 50: 524-32, 1957. 288. Rigdon, R. H. Statement of Dr. R. H. Rigd'on, Professor of Pathology, School of Medicine, University of Texas. In: U.S. Congress 85th House. Committee on Government Operations Legal and Monetary Affairs Subcommittee, Hearings on False and Misleading Advertis- ing (filter-tip cigarettes) July 18-26, 1957. Govt Print Off' 1957. p. 114-31. 289. Rockey, E. E., Speer, F. D., Thompson. A., Ahn, K. J., Hirose, T. Ex- perimentalistudy on effect ofcigarett'e smoke condensate on bronchial mu¢osa, JAMA 182: 1094-8, 1962. 290. Roe, F. J. C. The: action of cigarette tar om mouse skin. Britl Emp Cancer Campaign Ann Rep 36: 160, 1958. 291. Roe, F. J. C., Glendenning, 0. M. The carcinogenicity of~ ,Q-propio- lactones for mouse skin. Brit' J Cancer 19: 357-62, 1956. 292. Roe,, F. J. C., Salaman, M. H. Further studies on incomplete carcino- genesis: Triethylene melamine (T.E.M.)„ 1-2-benzanathracene and ,8-propiolactone, as initiators of skim tumor formation ini mouth. Brit J Cancer 9: 177, 203, 1955. 293. Roe, F. J. C;, Salaman, M. H., Cohen, J. Incomplete careinogens in cigarette smoke condensate. Tumor-promotion by a phenolic: frac- tion. Brit J Cancer 3: 623-33, 1959. 294. Roffo, A. H. Cancerizacion gastrica por ingestion de alquitran taba- quico. Bol Inst Med Exp Estud Cancer Buenos Aires 18: 39-fi8„ 1941. 295: Roffo, A. H. El tabaco en ell cancer de vejiga. Bol Inst Med Exp Estu& Cancer Buenos Aires 7: 130-44;,1930: 296. Roffo; A. H. Leucoplasie, experimentale produite par le tabac. Rev Sud-Amer Med Chir 1: 321-30, 1930. 297. Roffo, A. H. Leucoplasia tabaquica experimental. Bol Inst Med Exp Estud Cancer Buenos Aires 7: 130-44, 1'930. 298. Rosenblatt,, M. B. Correspondence to Dr. Burney, Surgeon General Public Health Service fromi Dr. Milton B. Rosenblatt. In: United States Congress 85th House Committee on Government Operations 251 1

Legal and Monetary Affairs Subcommittee, Hearings on False and MisleadingAdvertusing(ifilter-tip cigarettes) July 18-26, 1957. Govt Print'~ Off 1957. 753--4 pa 299: Rosenblatt, M. B., Lisa, J. R. Cancer of the lung; pathology, diagnosis, and treatment. New York, Oxford Univ Press 1956. 343 p. ;i00i Ross, P. Occupational skin lesions due to pitch and tar. Brit Med 12: 369-74; 194& 300a. Runeckles, V. C: Natural radioactivity in tobacco and tobacco smoke. Nature 191: 322-5, 1961. 301. Sadowsky, D. A., Gilliam, A. G., Cornfield, J. The statisticall associa- tion between smoking and carcinoma of the lung. J Nat Cancer Inst 13: 1237-58, 1953. 302. Saffiottis U., Cefis, F., Kolb, L. H., Grote, M. I. Intratracheal injection of particulate carcinogens into hamster lungs [Abstract], Proc Amer Ass Cancer Res 4: 59, 1963. 303. Salley, J. J. Experimental carcinogenesis in the cheek pouch of the. Syrian hamster. J Dent Res 33: 253-62, 1954. 303a. Salley, J. J. Smoking and oral cancer. J Dent Res 42: 328'-39, 1963. 304. Sanderud, K. Squamous metaplasia of the respiratory tract epithelium. An autopsy study of 214 cases. 2. Relation to tobacco smoking, oc- cupation and residence. Acta Pat'h; Microbiol Scand 43: 47-61, 1958! 305. Sanderud, K. Squamous metaplasia of the respiratoryy tract epithelium. An autopsy study of 214 cases. 3. Relation to disease. Acta Path~ Microbiot Scand 44: 21-32, 1958. 306. Sanghv.i, L. D., Rao, K. C. M., Khanolkar, V. R. Smoking, and chewing of tobacco in relation~ to cancer of the upper alimentary tract. Brit Med JI 1: 1111-4, 1955. 307. Sawicki„ E. Symposium analysis of carcinogenic air pollutants. Nat Cancer Inst Monogr No. 9: 201-20, 1962.. 308. Saxens E., Ekwall~ P., Setala, K. Squamous cell carcinoma of the forestomacli ini mice, foll'owing oral administration (cannula feed- ing) of 9,10-dimethyl-1, 2-benzanthracene solubilized in an aqueous solution of an associated colloid. Acta Path Microbiol Scand 27: 270-5, 1950: 309. Schairer, E., Schoeniger, E. Lungenkrebs und Tabakverbrauch. Z. Krehsforsch 54: 261-9, 1943. 310. Schamberg, J. F. Cancer in tar workers. J Cutan Dis 28: 644-62, 1910. 3111. Schrek, R.,, Baker, L. A., Ballard, G. P., Dolgoff, S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Res 10: 49-58, 1950. 312. Schurch, 0., Winterstein, A. Exper~imentelle Untersuchungen zur Frage Tabak und Krebs. Z Krebsforschi 42: 76-92, 1935. 313. Schwartz, D., Denoix, P.F: L'enquete frianeaise sur 1'etiologie du cancer broncho-pulmonaire. Role dii tabac. Sem Hop Paris 33: 3630-43, 1957. 314. Schwartz, D., Denoix, P. F., Anguera, G. Recherche des localisationss du cancer associees aux f'acteurs tabac et alcool chez l'homme. Bull Ass Franc Cancer 44: 336-61, 1957. 252 .

315. Schwart'z, D., Flamant, R., Lelloueh, J., Denoix, P. F. Results of a; French~ survey on, the role of tobacco, particularly inhalation,, im diff'erent; cancer sites. J N'at Cancer Inst 26: 1085-1108; 11961. 316. Segis M., Fukushima, I., Fujisaku, S., Kurihara, M., Saito, S:, Asano, K., Kamoi, M. An epid'emiological study on caneerinJapan. Gann 48: (Supplement)~ 1-63, 1957. 317. Segi, M., Kurihara, M. Cancer mortality for selected sites in 24: countries. No. 2 (1958-1959). Dept, of Public Health, Sendai, Tohoku i?hiversity School of Medicine, Japan 1962. 1:27 p. 3!1$. Seltser, R. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health~ 319. Shanta, V.,, Krishnamurthi, S. A study of aetiologicall factors in oral' squamous cell carcinoma. Brit J Cancer 13: 38!1~-8., 1959. 320. Shimkin, M. B. Induced pulmonary tumors in mice. I. Susceptibility of seven, strains of mice t'o, the action of intraveneously injected methylcholanthrene. Arch Path,29: 229-38, 1940. 321. Shubik, P., Saffiotti, U., Lijinsky: W., Pietra, G., Rappaport, H., Toth, B,, Raha; C. R.,,Tomatfis„L., Feldman, R., Ramahi, H. R. Studies on the toxicity of petroleum waxes. Toxic App Pharmacol 4: 1-62, 1962. 322. Soemmerring, S. Th. De Morbis Vasorum Absorbentium, Corporis Humani. Varrentrappii Venneri, Traiectic ad!Moenum, Publ'1795. 109 p. 323. Spain, D. M. Recent changes inrelativ.e frequency of varioushistologic types of bronchogenic carcinoma. J Nat Cancerr Inst 23: 427-38, 1959. 324. Stanton, M. F., Blaekwells R. Indhction of epidermoid carcinoma in lungs of' rats. A "new" method based upon the deposition of methylcholanthrene in areas of pulmonary infarction. J Nat' Cancer Inst 27: 375-407; 1961. 325. Staszewski, D. J. Smoking and its relation to carcinoma of the upper digestive tract (esophagus an& stomaehl and to peptic ulcer. Pol Tyg Lek 16: 287-92, 1960. 326. Staszewski; J. Smoking and cancer in Poland. Brit J Cancer 14: 419-36; 1960. 327. Staszewski, J. Smoking and its relation~to cancer of the mouth, tonsilss and larynx. Nbwotwory 10: 121'i-32, 1960. 328. Steiner, P. E. Symposium on endemiology of cancer of the lung; etiological implications of the geographical distribution of lung can- cer. Acta Un Int Cancr 9: 450-75, 1953. 329. Steiner, P. E. The etiology and histogpnesis of carcinoma of the esophagus. Cancer 9: 436-52, 1956. 330. Stewart„ H. L, Pulmonary tumors in mi,ce. In: Homburger, F. ed. The Physiopathology of Cancer. New York, Hoeber. 2 ed. 1959, chapter 2„ p. 18-37: 331. Stewart„ H. L., Herrold, K. M, A critique of experiments on attempts to induce cancer with tobacco derivatives. Bull Internatl Stat In- stitute 39: Rept No 135, 1962. 253 1 00

332. Stew.art, H. L., Lorenz, E. Adenocarcinoma of the pyloric stomach and other gastric neoplasms im miee induced with carcinogenic hydl-o- carbons. J Nat Cancer Inst 3: 175-89, 1942. 333. Stewart, H. L., Lorenz, E. Indhction of adenocarcinoma of the pyloric stomach in mice by methylcholanthrene. J Nat Cancer Inst 2: 193-6, 1941. 334. Stewart, H. L., Lorenz, E. Morbid anatomy, histopathology an& histo- pathogenesis of forestomach carcinoma in mice fed carcinogenic hydrocarbons in oil emulsions. J Nat Cancer Inst 10:: 147-66, 1949. 335. Stocks; P. Cancer, incidence in North~ Wales andl Liverpool region in relation to habits and environment. IX. Smoke and smoking. Brit Emp Cancer Campaign 35th Ann Rep Suppli to Part 2, 66-95, 1957. 336. Stocks, P. Statistical investigations concerning the causation of vari- ous forms of human cancer. In: Raven, R. W.,,ed.,,Cancer. 337. Stocks, P., Campbell, J. M. Lung cancer death rates among non- smokers and pipe and cigarette smokers: An evaluation in relation to air pollution by benzpyrene and other substances. Brit Med Ji 2: 923-9, 1955. 338. Sugiura, K. Experimental production of carcinoma: in mice with cigarette smoke tar. Gann 47: 243-4, 1956. 339. Sugiura, K. The relation of diet to the development of gastric lesionss in the rat. Cancer Res 2: 770-5, 1942. 340. Summary of ineeting, on pathogenesis of lung cancer (Toronto). Special communication to the Surgeon General's Advisory Committee on; Smokinb and Health. 341. Sunderman; F. W., Kincaid, J. F., Donnelly. A. J., West, B. Nickel poisoning. IV. Chronic exposure of rats to nickel carbony,h A report after one year of observation. AMA Arch Industr Health 16: 480-5, 1957. 34'2. Sunderman, F. W., Sunderman. F. W. Jr. Nickel poisoning. ZI. Implication ofl nickel as a pulmonary carcinogen in tobacco smoke. Amer J Clin Path 35: 203-9. 1961. 342a. Suntzeffi V., Croninger, A. B!, Wynd'er, E. L.,, Cowdry, E. V. and Graham, E. A. L?se of sebaceous-gland test of primary cigarette-tar fractions and of certain noncarcinogenic polycyclic hydrocarbons. Cancer 10: 250-254, 1957. 343. Tabahs E. J., Gorecki, Z.. Ritchie. A. C., Skoryna, S: C. Effects of saturated solutions of tobacco tars and& of 9, 10-dimethyl-1, 2- benzanthracene on the hamster's cheek pouch. [Abstract], Proc Amer Ass Cancer Res 2: 254, 1957. 344. Tobacco Manufacturer's Standing Committee. Statistics of smoking. Paper No. 1, London 1958. 345. Trentin; J. J., Yabe,,Y., Taylor, G. The quest for human cancer viruses. Science 137: 835-41, 1962. 346. Truhaut. R., DeClercq, M. Premiers resultats de l'etude chimique et biologique des produits obtenus dans la pyroly,sede la nicotine. Bull Ass Franc Cancer 44: 426-39, 1957. 254

347. Turner, F. C. Sarcomas at sites of subcutaneously implanted! bakelitee discs im rats. J Nat Cancer Inst 2: 81-3, 1:941. 347a. Turner, R. C., Radley, M. M. Naturally occurring alpha: activity of cigarette tobaccos [Letter to the Editor]. Lancet 1: 1I197-8, 1960. 348. Twort, C. C:, Twort, J. M. The carcinogenic potency of minerall oils. J Industr Hyg,13: 204-26, 1931. 349, Umiker, W., St'orey„ C. Bronchogenic earcinoma-io-situ: Report of a case with positive biopsy, cytological examination, and lobectomy. Cancer 5: 369-74, 1952. 350. University of Minnesota Hospital, Minneapolis. Personal communi- cation to the Surgeon General's Advisory Committee on, Smoking and Health. 351. Upton„A. C., Kimball, A. W., Furth, J., Christenberry, K. W., Benedict, W. H. Some delayed effects of atom.bomb radiations in mice. Cancer Res 20: 1-60; 1960. 352. Valentine, E. H. Squamous metaplasia of the bronchus: A study of metaplastic.changss occurring in the epithelium of the major bronchi~ in cancerous and noncancerous cases. Cancer 10: 272-9. 1957. 353. Valko, P. Smoking and occurrence of malignant tumors of~ the larynx. Cesk Otolar~yng 1: 102-5, 1952. 354. Van Duuren, Nelson N., Orris, L., Palmes, E. C., Schmitt, F: L. Car- cinogenicity of epoxides, lactones and peroxy compounds. J Nat Cancer Inst 31: 41-55, 1963. 355. Vogler, W. R.,, Lloyd, J. W., Milmore, B. K. A retrospective study of etiological factors in cancer of the mouth, pharynx, and larynx. Cancer 15: 246-58, 1962. 356: Von Verschuer, R. Twin research from the time of Francis Galton to the present day. Proc Royal Soc B 128: 62-81, 1939. 357. Vorwald, A. J. Ad Hoc, Conference on Lung, Carcinogenesis, Toronto, April; 1963. Sponsored by the Surgeom General's Advisory Com- mittee on Smoking and Health. 358, Vorwald; A. J., Durkan, T. M., Prat, P. C. Experimental studies of asbestosis. Arch Industr Hyg Oacup~ Me& 3: 1-43, 1951'. 359. Wagner, J. C. Asbestosis in experimental animals. Brit J Iindustr 1VIed 20: 1-12, 1963. 360. Wagoner, J. K., Archer, V. E., Carroll, B. E.,,Holaday, D. A., Lawrence, P. A. Cancer mortality patterns among United States uraniuM miners and millers, 1950 through 1962. J Nat Cancer Inst [In press] 361. Wagoner. J. K.,, Miller, R. W., Lundin, F. E., Jr.,, Fraumeni, J. F., Jr.,. Haij, M. E. Unusual cancer mortality among a group of under- groundi metall miners. New Eng J Med 269: 284-9, 1963: 362. Walpole, A. L. and' others. Cytotoxic agents; IV. Carcinogenic actions of some mono-functional ethyleneimine derivatives. Brit J Pharma- col 9: 306-23, 1'954. 363. Wassink, W. F. Ontstaansvoorwaarden voor longkanker. Nederl T Geneesk 4: 3732-47, 1948. 364. Waterman, N. Experimental production of carcinoma in the stomach of mice. Acta Cancrol 2: 375-88; 1936. 714-422 0-64-1e 255

365. Watson, W. L., Conte, A. J. Smoking and lung cancer. Cancer 7: 245-9;,1954. 366. Weller, R. W. Metaplasia of bronchial epithelium. A postmortem study. Amer J Clin Path 23: 768-74, 1953. 367. Wells, C: R. Betel' nut chewing and its effects. U.S. Nav Med Bulli 22: 437-9; 1925: 368. White, J., Stewart, H. L. Intestinall ad'enocarcinoma and intra- abdominal hemangio-endothelioma in mice ingesting methylcholan- threne. J Nat Cancer Inst 3: 331-4'7; 1942. 369. Wilkins, S: A., Vogler, W'. R. Cancer of the gingiva. Surg Gynec Obstet 105: 145-52, 1957. 370. Williams, M. J. Extensive carcinoma-in-situ in the bronchial mucosa associated with two invasive bronchogenic carcinomas. Report of case. Cancer 5: 740-7, 1952. 371. Winternitz, M. C:, Wason, I. M., McNamara, F. P. The pathology of influenza. Yale University New Haven Press. Conn., 1920. 61 p. 372. Wynder, E. L. Laboratoryv contributions to the tobacco-cancer prob- lem: Acta Medl Scand Suppl 369: 63-101, 1961. 373 Wynder, E. L. ed. The biolbgic effects of tobacco. Boston, Little, Brown, 1955: 215 p. 374. Wynd'er, E. L,, Bross, 1. J. A study of etiological fact'orsin cancer of the esophagus. Cancer 14- 389-413, 1961. 375. Wynder, E. L., Bross, I. J., Cornfield, JI., O'Donnell, W. E. Lung can- cer in women. A study of environmental factors. New Eng, J Med 255: 1111-21, 1956. 376: Wynder, E: L., Bross, 1. J., Day, E. A study of environmental factors in~ cancer of the larynx. Cancer 9: 86-110, 1956. 377. Wynder, E. L., Bross, I. J., Day, E: Epidemiologicall approach to the etiology of cancer of the larynx. JAMA 160: 1384-91, 1956. 378, Wynder, E, L., Bross, I. J., Feldman, R. M. A study of the etiological factors in cancer of the mouthL Cancer 10: 1300-23, 1957. 379. Wynder, E. L., Cornfield, J. Cancer of the lung in~ physicians. New Eng J Med 248: 441-4, 1953. 380. Wynder, E. L., Fritz, L., Furth, N. Effect on~ concentration of' benzo- pyrene in skin carcinogenesis. J Nat Cancer Inst 19: 361-70, 1957. 381. Wynder, E: L., Graham, E'. A. Tobacco smoking,as a possible etiologjc factor in bronchiogenic carcinoma. A study of six hundred and eighty-four proved cases. JAMA 143: 329-36, 1950. 382. Wynder, E. L., Graham, E. A., Croninger, A. B. Experimental produc- tion of carcinoma with cigarette tar. Cancer Res 13:: 855-64,, 1953. 383. Wynder, E. L., Graham, E. A., Croninger, A. B. Experimental produc- tion of carcinomal with~ cigarette tar. II. Tests with different mouse strains. Cancer Res 115: 445-8. 1955. 384. Wynder, E. L,, Hoffman, D. A study of tobacco carcinogens. No~ 8. Role of acidic fractions as promoters. Cancer 14!: 1306-15, 1961. 385. Wynder, E. L., Hultherg, S., Jacobsson, F., Bross, l. J. Environmental factors in cancer of the:upper alimentary tract. A Swedish study with special reference to Pllimmer-V,inson (Patterson-Kelly)~ Syndrome. Cancer 10: 47-87, 1957. 256

386. Wynder, E, L, Lemon, F. R. Cancer, coronary artery disease, and smoking. A preliminary report on differences in~ ineidence between Seventh-Day Adventists, and others: Calif Med 89: 267-72, 1958. 387. Wynder, E. L., Lemon, F. R., Bross, I. J. Cancer and coronary artery disease among Seventh-Day Adventists. Cancer 12: 1016-28, 1959. 388. Wynder, E. L.,, Navarrette, A., Arostegui, G. F.:, Llambes, J. L. Study of environmental' factors in cancer of the respiratory tract in Cuba. J Nat Cancer Inst 20: 665-73, 1958'. 389. Wynder, E., Onderdonk, J., Mantel, N. An epidemiologic investiga- tion of cancer of the bladder. Cancer 116: 1388-1407, 1963. 390. Wynder, E: L., Wright, G. A study of tobaeco: carcinogenesis. I. The primary fractions. Cancer 10: 255--71, 1957. 391. Wynder, E. L., Wright, G. Studies on the id'entification 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

Non-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pulmonary Emphysema I

Contents Page ALTERATIONS IN THE RESPIRATORY TRACT AND IN PULMONARY PAREN!CHYMA INDUCED BY TOBACCO SMOKE . . . . . . . . . . . . . . . . . . . . . . . . 263 Characteristics of the Exposure . . . . . . . . . . . . . 263 Composition of Tobacco Smoke . . . . . . . . . . . . 263 Regional Deposition or Retention of Tobacco Smoke ... 263 Mouth Retention of Tobacco Smoke . . . . . . . . . 264 Retention of Particles by the Trachea, Bronchiy and Pulmonary Tissue . . . . . . . . . . . . . . . . 264 Retention of Gases by the Trachea, Bronchi, and Pul- monary Parenchyma . . . . . . . . . . . . . . . 265 Metabolism and Toxicity of Specific Components in Tobacco Smoke . . . . . . . . . . . . . . . . . . 265 Clearance of Smoke Deposits . . . . . . . . . . . . . 267 Effects of' Tobacco Smoke on Defense Mechanisms of the Respiratory System . . . . . . . . . . . . . . . . . 267 Pulmonary IIygiene and Ciliary Activity .... ... 267 Mucus Secretion . . . . . . . . . . . . . . . . . 268 Alveolar Lining . . . . . . . . . . . . . . . . . . 269 Phagocytosis . . . . . . . . . . . . . . . . . . . 269 Other Mechanisms . . . . . . . . . . . . . . . . . 270 Histopathologic Alterations . . . . . . . . . . . . . . . 270 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- phy sema . . . . . . . . . . . . . . . . . . . . 260 275 275 275 276 277 278 278 278 279 I

RELATION OF SMOKING TO DISEASES OF TIIE RES- PIRATORY SYSTEM-Continued Chronic Bronchopulmonary Diseases-Continued Evidence Relating Smoking to Chronic Bronchitis and E'mphysema. . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . Prevalence Studies . . . . . . . . . . . . . . . ('1.) Smoking and Respiratory Symptoms . . . . (a.)' Chronic Cough . . . . . . . . . . . (b.) Sputum . . . . . . . . . . . . (c.) Cough and Sputum . . . . . . . . . (d.) Breathlessness. . . . . . . . . . . . (e.) Smoking, an& Chest Illness. . . . . . . (f.) ~ Combinations of Symptoms . . . . . . (g.) RelationsliipBet'ween Symptoms or Signs and Amount Smoked . . . . . (h.) Relationship Between Symptoms and~ Signs and Method of Smoking, . . . ('i,) Ventilatory Function. . . . . . . . . Prospective Studies . . . . . . . . . . . . . . Clinical Evidence . . . . . . . . . . . . . . . Relationship of Smoking, Environmental Factors, and Chronic Respiratorv Disease . . . . . . . . . . . . Atmospheric Pollution . . . . . . Basis for Interrelationship and Relative it'Iagnitude of Exposure . . . . . . . . . . . . . . . . (1.) Experimental Evidence . . . . . . . . . (2.) Relative Magnitude of the Exposure ... E pidemiologicall Evidence . . . . . . . . . . . . Occupational Factors . . . . . . . . .. . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . CONCLUSIOI S'. . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . Page 280 280 280 280 280 283 283 286 287 288 289 289 289 293 294 295 295 295 295 296 297 298 300 302 302 Figure FIGURE 1.-Black pigment and emphysema in lungs of 83' patients . . . . . . . . . . . . . . . . . . . 273 List of Tables, TABLE' I.-Summary of reports on the prevalence of cough in relation to smoking . . . . . . . . . .. 281 TABLE 2.-Summary of reports on the prevalence of sputum in relation to smoking . . . . . . . . . . . . . 283 TABLE 3.-Summary of reports on the prevalence of cough and sputum in relation to smoking . . . . . . . . 284' TABLE 4.-Summary of reports on the prevalence of breathless- ness, in relation to smoking . . . . . . . . . 285 TABLE S.-Summary of reports on history of chest illness in the past three years in relation to smoking ..... 28? TABLE 6.-Summaryof'reports on the prevalence of combinations of certain symptoms in relation to smok.ing . . . . 288 261 l

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I I Chapter 10 This chapter presents the evidence on smoking in relation to the develop- ment and progression of the non-neoplastic respiratory diseases. The chfonic bronchopulmonary diseases pose a healtLproblem~of substantial and steadily growing importance. Bronchiths and emphysema, in particular, severely disable large numbers of men of' working age, and have a considerable effect upon mortality as a direct or contributory cause of death. Because ofl the importance of these diseases to public health, they receive the most~ attention in this chapter, in accord with the fundamentall 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 EYPOSURE' 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 considere&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 (107, 116, 1'22). 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 03 microns (2). Some of the majpr classes of compounds which con- stitute the: particulate phase of cigarette smoke and notation of their tbxic 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 lting (2)1; Table 2 in Chapter 6 lfists 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 und'oubtedly exposes the airways and pulmonary parenchyma to smoke with 263

substantialNy different characteristics from the smoke that first enters the mouth. Insufficient direct evidence is available to characterize this exposure, and existing, information is derived largely from substances with analogous physicaliand chemical features. The retention or deposition of smoke constituents in the several regions of the respiratory system varies because many factors alter the characteristicss 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, themethod'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 an& the anatomic structure ultimately determine the pattern ofl regional retention (2). When cigarette smoke is inhaled, total retention of particles in the mouth, respiratory tract, and pulmonary parenchyma is about 80-90 percent', even when the smoke is held in~ the lung for a relatively short period, two-to.five seconds. When delfiberratelyy held for periods as long as 30 seconds, retention of particles is almost complete (135). MOUTH RETENTION OF TOBACCO SMOKE Removal of tobacco smoke constituents while in4he 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 fifi percent (18, 71, 135). Experiments utilizing, amod'el 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~tihe mouth and bronchi (57). The available information suggests that removal of smoke constituents in t'he mouth~ may be an important defense mechanism that prevents delivery of certain noxious agents to the tracheobronchial tree and lungparenchyma, but 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'pultnonary tissue is based on knowledge of physical factors which 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 twist'ing 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 inertiall impingement, except for very fine particles which diffuse onto the surfaee. The size of virtually all t'he individuali particles in inhaled smoke is probably less than two microns. Data from al number of laboratories indi- 264 O W ~ ~ Ctt 1 W CD

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 proportiom of deposition occurs f'or particless between 0.25-0.50 microns. Diffusion increases for particles belbw 0.25 microns, and extremely fine particles, approaching, molecular size, diffusee so rapidly that many probablyy remain om 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- pultnonary deposition derived from phy.siological' studies indicate that even for particles smaller t'han two microns, only about five percent are deposited along the bronchiali tree. Radioactive tracers in smoke have been used'' to study site deposition in animals. Deposition in a diffuse pattern was obtained in dogs inhaling smoke from cigarettes impregnated with K 42, Na 24, an& As 76 (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). In rabbits, cigarettes impregnated with As 76 produced deposition on the larynx, 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 andl are deposited on the surface of the terminal bronchioles, respiratory bronchioles, and pulmonary parenchyma: RETENTION OF GASES BY THE TRACHEA, BRONCHI, AND PULMO- NARY PAREITCHY1bIA Insufficient data are available on the intrapulmonary fate of gases of cigarette smoke to warrant detailledl consideration at~ present. Thorough re- vieww of the available information andithe known physical characteristics of gas absorption suggest that the speed and depth of inhalation may affect both the amount andi site of gas retention; moreover, while the distribution pattern may be diffuse, it seems possible, although not yet demonstrated, that a substantial portion of inhale& 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. ll'letabolismandToxicityofSpecific Components in Tobacco Smoke Little is known about the metabolismi of mostcompounds in tobacco smoke. The f'ragmentarydata have been thoroughly reviewed (2). Hydrogen cyanide is present in cigarette smoke in concentrations that would be fatal for mani were it not for a number of factors which accrue too 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 stbpping cellular respiration abruptly through inactivation of cytochrome oxid'ase. In sublethal exposures, the cyanide ion is gradually released from its combinationi with the ferric ion of cytochrome oxidase, converted to thiocyanate ion (SCN), and! excreted in the urine. Thiocyanate blood levels ini smokers are three times higher than in non-smokers and differences in relative urinary excretion are even more pronounced (46;, 127)i. 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 principali oxides of nitrogen, nitric oxide and nitrogen dioxide, are present ini cigarette smoke in tot'al concentrations varying from 145 to 665 ppm (123). Oxides of nitrogen are partially absorbed in the mouth; absorp- tion after inhalation, however, is almost complete(23, 811). Nitric oxide: one principal oxide of nitrogen in cigarette smoke, is mainly ani asphyxiant and! is only about one-fifth astbxic as nitrogen dioxide. There is no d'ocu- 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, coneentrations of nitro- gen dioxide produces injury sufficient in the human lung to result in pul- monary edema (187). Obliterating fibrosis ofl the bronchioles has also been observed ini man folloccing, moderately high exposures (126). In physiologic studies, changes which resemble those of pulmonary obstructive disease have beeni observed in men who are occupationally exposed to high concentrations of nitrogen oxides (I19'). Experimental studies indicate that nitrogen dioxide is capable also ofl 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 ri+-o-hour exposure to 80-1100; ppm. of nitrogen dioxide. Five daily exposures at 15-25 ppmL for two-hour periods produce similar but less severe results(109). It seems clear from environmental exposures of man to nitrogen dioxide that definite puhnonarydamage may result from such exposures. Whether nitrogeni dioxide alone, in inhaled cigarette smoke, is capable, ofl producing, such damage in man is less certain. Equal, amounts of nitric oxide and! nitrogeni dioxide in cigarette smoke have been reported (81), but recent w-orkindicates that~ the proportion of nitrogen dioxide is much lower (108)1. These divergent results and theuncertainty as to the level of nitrogen dioxide exposure necessary to produce pulmonary damage make it very difficult tol assess the role of nitrogen dioxide in cigarette smoke. Formaldehydegasispresent' in cigarette smoke in concentrations of 300 ppmL Chronic exposure to 50 ppm. of forma.ldehyde gas produces an irritant cellular response in mice similar to t'hat 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 thee major but not the smaller bronchi (102)',. Exposure of guinea pigs to lowconcentrations of acrolein, which is also~ present in cigarette smoke, caused! an increase in total respiratory flow re- sistance accompanied by decreased respiratory rates and increased tidal 266

volumes (143). It has been found also that acroliein 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 o f 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 f'rom~ the normal self-cleansingg mechanism of the lung described in the section om"Pulmonary Hygiene and Ciliary Activity" of this chapter. EFFECTS' OF TOBACCO SMOKE ON DEFENSE MECHANISMS OF THE RESPIRATORY SYSTEM Pulmonary Hygiene and Ciliary Activity The cleansing mechanism of the mammalian respiratory system is depend~ ent upomthe efflcient,,integrated functioning of a complex sy.st'em. Froni 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' byy deep: glands in the walls of the airways and by goblet cells. Clearance distall . to the terminal bronchioles has be- come more clearlyy 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 fltrids (2). Aft'er solution, absorption into the blood stieam~ or lymphatics may result in removal. Remaining particles may undergo phagocytosis or remain free. Some phagocytes enter the alveolnr~ lumen, become laden with foreign material, and are transported to the ciliated air passages tb be ex- pelled intact. Some disintegrate along the way and deposit their products on the surface lining. Still other phagocytes may enter interstitial tissues and' become sequestrated or be removed to regional ly.mph~ 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 ini the fluid lining produced by the mechanics of respiration andl re- plenishment, of the alveolar fluid lining. Inhibition of ciliary motility following exposure to: t~obaccot~ars; cigarette smoke, or it's constituents has been demonstrated frequently with experi'. mental use of respiratory epithelium from a«•ide variety of animal species (17,22; 39, 59, 79; 80, 96, 97, 98; 111, 112, 131, 147, 157, 158, 167,,178). 267 A"

Similar results have been obtained with ciliated human respiratory epi- thelium (17, 22). Although all investigations have been conducted in vitro, the uniformity of! the inhibitory effects in a numberofl different experimentali modela is impressive. Positive ions are present in cigarette smoke. Each cigarette yields about 1010 positive ions; negatively charged particles are also present (121). These thermally produced gaseous ions have considerable: energy and may pr~odtice effects in cells (190). In air free ofl cigarette smoke, positive ions decrease or abolish ciliary activity. The redtrction in ciliary motility which occurs after exposure to cigarette smoke is augmented and sustained by additional exposure to positive ions (112). Nicotine in high concentrations inhibits ciliary motility although eon- centrations of nicotine similar to those in tobacco smoke d'o not affect rabbit, chickeny or human ciliary function (22, 121). In addition, tobacco smoke from low-nicotine cigarettes produced no significant difference in ciliary response from that obtainedl with cigarettes whose nicotine content had not: been altered (1211. Hydrogen cyanide, ammonia, acrolein. fbrmaldehyde, nitrogen~ dioxide, all components of cigarette smoke, possess potent inhibi- tory activity (40). There seems to be little d'oubt that eigarette 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 effectss of cigarette smoke on ciliated respiratory tissue of man because of the many variables present in the complex experimental methods,, including, dosage of the particular agent. Ciliary 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 polllutants but are not found in si'g- nificant amounts in tobacco smoke, are also potent ciliary depressants. Morphologicalteration of cilia~~ of smokers has been described (31, 32, 104). The length, of cilia in the trachea and bronchial epithelium was meas- ured at autopsy and found to be shorter than in~ non-smokers. In addition the percentage of cells remaining ciliated is lower in smokers than in non- snrokers (~9;~ 10, 104Y. Mucus Secretion Definitive studies on the effect of cigarette smoking upon the quantity and quality of human respiratory tract mucus have not been performed. Alteration in, the appearance of mucus after exposure to cigarette smoke has been noted severali times. Followingexposure to sulfur dioxide, a g~s not present in cigarette smoke, changes in the physical properties of mucus have been observed ( 40):. Whether suchi changes resulti after exposure to gases present in cigarette smoke has not been, established. MorphologFcal changes observed in the goblet cells and mucous glands at post-mortem examination, however, support the possibility that mucus production may have been altered during life. In essence, little has been contributed in this regard since the observation about 11001 years ago; that a marked increase in mucous secretions in the trachea andl larger bronchi of the cat occurred after large doses of nicotine. 268' ~:

Atropinization blocked this effect, indicat'~ingthat thisaction of nicotine was mediated by stimulation of the mucous glands since goblet cells are not under nervous control (185 ). An increase in~ mucus-secreting cells af'ter exposure of rats to cigarette smoke has also been observed recently (130). Alveolar Lining The alveolar surface is covered by a secretion which stabilizes the alveoli' and is produced by the alveolar epithelium (79, 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, cause& a decrease in surface tension and an increase in surface comr pressibility. Lung extracts prepared from rats exposed to cigarette smoke during life also showed lower surface t'ension and increase in surface com- pressibilfity,. These findings differ markedly from results in non-exposed animals. Such changes during life would be expected t'o result in a de+ crease in the ef$cacyy of' surface forces stabilizing, the alveoli (134). Fur- ther interpretation of the results of this single study does not appear war- ranted; however, because of the great potential significance of thealterat'ion described, further studies should! beencouragedL Phagocytosis 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 phagocyt'es is well' documented in~ experimentall studies. On the basis ofl solubility, fluorescence, and pigment characteris- tics ofl 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 ofl exogenouspigment'ed material in mice has been shown to be directly proportional to both the leveli and' duration of cigarette smoke exposure (119, 121). Similar fluorescent materiial 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 (121). Ear1y in the exposure period, the clearance mechanism of the lungs is ade- quate to the task of aggregating andl removing pigmented material and pigment-laden phagocytes; 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 si¢nilar suppression~ of the effectiveness of the phagocytic clearance mechanism for the human lung has been~ described in pneumoconiosis (41). Fluorescent histiocytes have been found in thesputum of cigarette smokers but were not detected in the induced sputum of non-smokers (188). The intensity of fluorescence and the number of histiocytes were in~ direct propor- tion to the number of cigarettes smoked. These fluorescent histiocytes 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 fbr 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 ofi this, fhinction, however, cannot be dismissed since it might be expected to result in lung,injury. Other Mechanisms Little is known about the role of lymphatics in the removall of tobacco smoke deposits. The eval uation 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 tbbacco smoke and certain of its components, like many other substances, can reduce or abolish ciliary motility, ati least temporarily, and can slow mucus flow. Impairment of this mechanism in man has not beeni demonstrated under conditions of cigarette smoking; although it seems,lbgi- 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. Decreaseini the number ofl ciliated cells and! shortening of remaining, cilia have been described in post-mortem examinations of bronchi' from smokers, with implied functional impairment. Alterations in bronehial' mucus havee been suggested by changes in goblet cells and mucous glands after cigarette- smoke exposure. Increased amount! ofl secretions in the tracheobronchial tree is a frequent observation afterexposur~eto cigarette smoke. Alterationoftheflnid lining of the alkeoli ini rats as ai consequence of ciga- rette smoke exposure has been~ reported in the only study of this aspect. The dccrease in surface tension and the increase in surface compressibility obd served in this studycouldihave great potential significance in terms of human respiratory disease. That tobacco products are ingested by alveolar phagocytes of the experi- mentat animall and of man seems fairly welldocument'ed. Ezperimental 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 14arge for respiratorv disease in man but further definition of these effects and qµantitatiion willlbe necessary before their full significance can be understood. HISTOPATHOLO(;IC ALTERATIONS INDtiCED IN THE RESPIRATORY TRACT AND IN PUL1t0\:4R7pARE1CIdY17A BYTOB:ACCO: SMOKE A variety of histopathologic studies from diverse points of view indicate clearly that smoking is associated with abnormal changes in, the st'~ructure of 270 .;t ,~.. .. ~. .~.

both the surface epithelium and wall of the airways,, including the mouth. Many of the studies are open t'oi criticism because of inadequate numbers, lack of proper controls, and defects of experimental design, but specific criticisms, are different for each study, an& 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 etiolbgic agent im 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 stbmas of the salivary g)ands, leading to blockage andisubsequent dilata- tiom 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 lhrvnx that correlates closely with the cigarette smoking history (45, 170). Epi- thelial hyperplasia with liyperkeratosis and variable degrees of chronic in- flammation and' squamous metaplasia are present ini the true vocal cord's, false cords, andlthe suhglottic area. The trachea and bronchi show many morphological changes inithecigarette smoker as compared to the non-smoker (9'; 10;,11i, 31, 33, 35. 38, 1711). Var- ious degrees of hyperplasia, with and without overt atypical change;, and metaplasia ofl 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 ini the number of goblet cells and in the degree of mucous distension of the goblet cells were present in whole mounts of bronchiall epithelium of smokers (31). Hyperplasia and' hypertrophy of mucous glands andi a higher proportioni of cells with shorter cilia also were observed more frequently in smokers (33, 171). 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 gland's in smokers and non-smokers are especially important when considered in the light of current concepts of 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, 1$-1)1. Althoughi manyy cases of chronic bronchitis show other morphologic signs of acute andi chronic inflammation, these are not as constant as are the glandular changes.. Provided further investigation of the pathologic anatomy of chronicc bronchitis in other countries indicates that the disease is essentially identical pathologically, the few British studies on goblet cell's and mucous glands in smokers offer the first anatomic support~ for the relat'~ionshipbet,~veen srnokina and chronic br~onchitis suggested by several epidcmiologic reports. Con- ceivably, one or more components of cigarette tobacco: smoke have the prop- 714-422 0-64-19 271

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 pathogenesis of chronic bronchitis (cf. 64i). This mucous cell activity, accompanied by excessive mucus production, may increase the susceptibility of the tracheobronchial tree to secondary infection wit'h various micro- organisms which in turn may lead to acute and chronic inflammation and their consequences. Although this hypothesis (64i) has many attractivee features, especially in reconciling the epidemiologic and anatomic findingss 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- chiectasis 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 ini animals therefore support a conclusion that cigarette smoke is irritating to the t'racheobronchial tree and' is capahle of inducing severe acute and chronic bronchitis. It must' be emphasized that the traeheobronchiall 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 certaint'yy 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 ofl 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 ofl the: rela- tionship of smoking, parenchymal pigment,, and emphysema (136)~. The causes of death included "diffuse obstructive bronchopulmonaryy disease." The quantity of "'d'epartitioning',' (Le., emphysema) and the amount of! black pigment were graded from zero to three. The pigment was not! analyzed but was considered to be anthracotic. A close correlat2on~ was observed between the quantity of snioking, 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 (Figurc 1). Histologie examination of peripheral lung sections has revealed changes in~ pulmonary parenchyma, the severity of which was proportional to the 272

BLACK PIGMENT AND EMPHYSEMA IN LUNGS OF 83 PATIENTS DEPARTITIONING BLACK PIGMENT I 1 1 ..•O •OOQ 0 AAA A00 • •• 0 • ~ •. 00 000 *00 00 AQ .O •O 0 • 000 00 ~ NON-SMOKERS ~ - 0 _ >15 CIGARETTES PER DAY < 15 CIGARETTES PER DAY FIGURE 1. Source: Mitchell, R. S. (136) 8v8Sme0

0 i intensity of cigarette smoking as well as to its duration (12)'. One section fromi 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 abnormalities, measured by arbitr~ary gradations, included the: following: (a)', fibrosis or tliiekening of albeolar septa,, (b)' rupture of alveolar septa; (e)' thickening of the walls of small arteries and of arterioles, and (d) pad-like attachments to alveolar septa. The association of increased pulmonary fibrosis an& cigarette smoking was apparent in all age groups (less than 45, 45-49, 60-64, 65-69, 70-74, 75+ ), eveniin, 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 (160+ ) 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 t'lrickening of walls of arterioles and small arrteries. 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 ('pulmonaryy fibrosis,,rupture of alveolar septa, thickening of the walls of small arteries and arterioles) for the following groups: (111) The older cigarette smoker greater than the younger cigarette smoker;, (2) The one-two pack cigarette smoker greater than "never smoked";. (13) The one-half pack a d'ay cigarette smoker greater thani "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 whoo had stopped 20 years. In addition, the degree of fibrosis (but not the otherthree 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 thani one-two pack a day cigarette smokers; (3)' In current cigarette smokers than in ex-cigarette smokers stopped 3-4 years. Degree of fibrosis, rupturing of alkeolar septa, and thickening ofl 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. All 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 wsmoking 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 cigarsand pipes. 274 4b

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-lfke attachments are puzzling and the possibility of'~ arti- fact has been discusse& repeatedly. The conclusions drawn~ from this study 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 al cause of human chronic bronchitis. Whereas definite pathologic changes in the lung parenchyma: of man also are clearly associated with cigarette smoking, the abnormalities observed in thee lung parenchyma: cannot be related with cert'ainty to recognized di'seasee entities at the present time. RELATION OF SMOKING TO DISEASES OF THE' RESPIRATORY SYSTEM EFFECTS OF SMOKING ON TI7IE NOSE, MOUTH, AND THROAT Edema, vascular engorgement', dryness, excess mucus production and epithelial changes have been attributed to cigarette smoking on the basis of clinieal' observation. Rhinitis, angina, and! laryngitis, also observed fre- quently in cigarette smokers, are reversible on cessation of smoking. Aggravation and prolongation of' sinusitis are also attributed to smoking. These observations have become clinical tradition, yet surprisingly little documentationi of predictable changes in these tissues as a conseqpence of smoking is available(129). Changes in the palatal mueosa("stomatitis nicotina") and in the laryngeal epit'helium(45)elosely associated with tobacco smoking have been cono 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 epit'heliall changes in the larynx has there been adequate pathological substantiation of the clinical opinion that~ alterations are induced by smoking. SbIOKING AND ASTHMA The definition of asthma of the American Thoracic Societyy will be used for the purposes of this report (4) : "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. 275 I

"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'y 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). 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)1. Apart fromi 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 ofl the physiologic alterations induced in the tracheobronchial tree by tobacco smoke. Nonetheless, substantiation of worsening from cigarette smoking im asthmatics has not been reported'frequently. A cause-and,effect relation- ship between cigarette smoking and asthma; as defined above, is not support'ed by evidence available. RELATION OF SMOKING AND INFECTIOUS DISEASES The category, influenza and pneumonia (ISC 480-493), contributed to the excess mortalityof'~ smokers observed in six of seven prospective st'udies (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 epidemiologi- cal researchL Studies adequate for examination of this association are available for only two categories of infectious diseases, upper respiratory viral illness and tuberculosis (301. Experiments on transmission of common cold's f'ailed to demonstrate increasedy susceptibility in volunteers with a; history of ciga- rette smoking (50). Moreover, common colds were detected among, 5,500 employees over a 2-year period! with approximately the same frequency, in smokers and non,smokers (110). In a study of illness ima 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 cold's in a group of college graduates followed over a 20-year period (85). 276

A number of studies have suggested a substantial relationship between smoking and puhnonary tubercul'osis (55, 124,,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 (i29): in~ which both cigarette an& aleohol consumption were found to be in excess in tuberculosis patients as compared to the matched controls. The number of cigarettes consumed in the two ;roups was the same, however, at each Ievel of alcoholl intake. Matching by cigarette consumption failed to weakenithe 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 aleohol 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 observationi 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 experiment'ally induced upper respir- atory viral infections. CHRONtC BRONCHOPULMONARY DISEASES .Mbrtality for certain respiratory diseases (bronchitis, bronchiectasis, chronic pulmonary fibrosis, chronic interstitial pneumonia, and' emphysema) increased in the decade 1949-1959 (48)and'eontinues to show an upward trend (132, 1411). In 1955, cancer of the lung was certified as the under- lying cause of death in 27;133 persons and chronic bronchopulhnonary dis- eases in 11,480 persons. A tabulation of all diagnoses, both contributing as well as underlyi'ng causes of death, however, showed that cancer of the lung was entered upon a total of 28,123 death certificat'es, whereas the chronic bronchopulmonary diseases were certified as cont'ributing, t'o 32,041 deaths 147). The possibility that mortality data, as presently recorded, may under- estimate the role of chronic bronchopulnionary diseases through incorrect listing, by the physician as contributory rather tham 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''l to male workers 50 years of age or older in the United States (186). Chronic bronchitis and emphysema are the chronic lironchopulmonary diseases of greatest public health importance in the United States. They contribute to the excess mortalitryof cigarette smekers, 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 liI 27,7~ _.4 --47"~s-___... =V'

emphysema. Since descriptions of both~ were published long before ciga- rette smoking became commonplace (13, 14, 114)~„ it seems reasonable to suggest at the outset that cigarette smoking alone is not the only cause of chronic bronchitis and emphysema. Chronic Bronchitis and Emphysema DEFINITIONS Many definitions of chronic bronchitis and emphysema have been sug- gested. For the purposes of this report the definitions proposed' by the American Thoracic S'ociety (4) will beuse& "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 shoul& 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. Thus, the diagnosis of chronic bronchitis can be made only by excluding these other bronchopulmonary or cardiac disorders as the sole cause for the symptoms." This definition and classification of chronic bronchitis later considers complications, listing, three: infection, airway obstruction, an& pulmonary emphM1•sema:. "Emphysema is an anatomic alteration of the lung characterized by an abnormal enlargement of the air space distal to the terminal, nonr respiratory bronchiole, accompanied by destructive changes of the alveolar walls." DIAGNOSIS The diagnosis of chronic bronchitis isbase& essentiallyon~ descriptions of clinical manifestations and is achieved by exclusion. Recollection and int'erpretatiom on~ the pam of the subject are necessary. There is no simple sensitive pulmonary function test that will indicate which person has chronic bronchit'is. 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 pulmonary,functiontestingand nopulfnonary function test is specific for the detection of patholbgic lesions of'emphyserna: . (52). The clinieall detec. tion of emphysema is therefore not a simple matter, especially in the presence of' chronoc bronchitis. 278 Ow ~ ~ ~ 00 cn

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 om clinicall grounds with considerable accuracy. On the other hand, clinicallmanifestations identical with those of patients with emphysema may occur in persons who are not fbund' to have this disease at autopsy but who, have some other hing disease. Emphysema may exist without any clinical manifestations, and its elinicaland 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 clhnicall continuum appears to extend from bronchitis at' one end„through a mixture of the thvo 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- lbgical change. A close relationship is found between chronic lironchitis and emphysema on purely morphologic grounds. Although emphysema occurred more frequently in patients with chr~onic 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 aree found in association more often thani 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 eilia: and a mucous sheath, and the lower respiratory tract mechanisms involve macrophages, the lymphatic system, and possiblyy 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 hypotheticall 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 respiratory tracts simultaneously, perhaps with potentiation of the injury in the lbwer tract, by particles. Severall 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 hron« chitis preceded clinical evidence of emphysema in over 50 percent of cases in one continuing study (137). Others suggest that emphysema: may be a cause of chronic bronchitis (53). It seems likely that a common cause, eausat'ion of emphysema by chronic bronchitis, and causation of', chronic bronchitis byy emphysema are all operating mechanisms, with varying importance in dfifFerent populations an& different individlials (12.3). 279 O W ~ ~ CJ1 ~ C11 6A f

Evidence Relating Smoking to Chronic Bronchitis and Emphysema Experimental' and pathological' evidence bearing on the possible rela- tionship of smoking to chronic bronchitis andl emphysema has been pre- sented in an earlier section of this chapter. Epidemiological and clinical evidence relating smokina to these diseases will be considered here. EPIDEMIOLOGICAL EVIDENCE Chronic bronchitis and emphysema probably represent disorders of multi~ pie causality. Such problems are particularly suited for analysis by the epidemiological methods 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 STtrntes.-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 standardieed! diagnostic methods in chronic bron• chitis and the non-specificity of clinical diagnost!ic criteria for emphysema have resulted in the use of prevalence of symptoms and signs of! the respira~ torydiseases 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 andl 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 findfngs. (1.) Smoking and Respiratory Symptoms-(',a.) Chronic Cough`The common phrase "smoker's cough" suggests that this symptom is popularlh- be- lieved to be associated with smoking. Several workers have investigated the relationship betweeni 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 1,45&mi11 workers studied by Balchum et al. (116)' constituted the ran- dom sample of those who volunteered for chestl X-rays and pulmonary f'unc- tion tests. Of 1,198 smokers, 233 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 foundl for those reporting cough~ ranging from 1l1 percent': of those who smoked less tham one pack-year of cigarettes up to 50 percent of the subjects with 60' or more pack-years of smoking experience. 280

TasLE1.-Summary of' reports on the prevalence of cough in relation to smoking Refer- Number of subjects Percent with coueh Atithor Year ence Smokers ' I Non- 'smokers Smokers Non- smokers Ralchum -------------------------- 1962 (16) 1}798 253 23.a 10.2 I Roucot--------------------------------------- 1962 (25) 5,331 8os 31.5 13.0 i RoiCer________________________ ______ 1961 (26) 76 49. 27.6 4.1 i DenPn --------------------------------------- 1963 (44) 2,530 514', 21.2 7.8 Fletcher: Londnn Transport'------------------------- 19fi1 (67) 272 30. 20.0 0 Post Office---------------------------------- 1961 (67) 166 10 18. 7 0 I Flick----------------------------------------- 1959 (68) 157 51 54.8 9.8 i 0lsen: United Kingdom~-------------------------- 1960 (148) 162 11 32.1 0 Denmark° _________________ 196(1 (148) 132 241 19.9 8.3 Rhort----------------------------------------- 1938 (176) 1! 292 496 6.4 1.6 Liebesohuetz ________________ 1959 (120) 83 52 6.0 a Boucot and others (25) considered the relationship in older men of smok- ing andchronic cough in a self-selected population 45 years of age and older. Chronic cough was defined as cough, existing for months or years. Againa 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 adinitted to cough "more or less every day." Of the smokers, 27.6 percent adhnitted to daily coughi (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. Flet'cher and. Tinker (67) studied male workers agedl 30 to 59 in the British Generali Post Office and in the London Transport Executive. In the G.P.O., 118.7 percent of 166 smokers reported cough during the whole ofl the day in the winter, compared with none of 10 non.smokers. Among smokers ofl 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 Patoni (68) in a study of patients excluding those with cardiac and respiratory disorders,, found 55 percent of 157 smokers admitted to habitual cough compared withi 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 st'andardized'as in some of! the more recent surveys. Olsen and Gilson (148), in their study comparing findings in population samples in Biitain 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 J O W ~ C!1 aD CN1 M

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, 4.3.9 percent of 2,153 subjects had cough whereas 18.0 percent of 718 who had smoked' less than 10 years lia& cough. In the population samples quoted thus far, the percentage of smokers admitting to cough ranged f'rom, 17.3 percent to 55 percent, whereas the range for non-smokers was 0 percea 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 (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 an& none of 52 non-smokers admitted to cough. The study of members ofl 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 st'ate 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 reporte& 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 iniboth sexes and in all four age groups. Except for ex-sinokers, the relationship betweeni "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 was almost three times as great as might have been, expected on the basis of coughi prevalence among, non-smokers. For women, the ratio of observed-to-expected smokers with the complaint of cough was 2.5 to~ 1. The ratio of observed-to-expected numbers complaining of' coughi "more severe than slight" was 4.09 for males an&2.74:for females. The difference in frequency ofl the complaint 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 populat2on; but~ it' provides information about the relationship~ between smoking and various complaints for larger numbers of subjeetsthan d'oes any other study. The results again make it' clear that! a larger proportion of cigarette smokers are aware of cough than are non-smokers. I!n~ each of the surveys, smoking, wasfbunds to be associated with the symptom of cough defined in a variety of way,s: The studied populationss 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 ini regard 282

to~cough. In each of the surveys, a larger propo rtion of the subjects ad- mitt2ng 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- lenee 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-smokerss report sputum production more frequently thamcough. j TABLE 2.-Summary of' rePorts on the prevalence of sputum in relation to j ~ smoking' Author Year Reer- Number of subjects Percent with sputum ence Smokers Non- smokers~. Smokers Non- smokers Balchum ------------------------------------- 1982 (16) 1,198 ' 253 30.4 11.1 Bower---------------------------------------- 1981 76 49 I 3'4. 2 20. 4 Densen-------- ------------------------------- 1963 (44) 2,530 514 21i9 13.8 rris: Males------ --------------- ----------------- 1962 (61) 340 125 I 140.3 I 1 13.8 ~ Females------------------------------------ 1962' (61) 209 379 1 19.8 I I 119.4 F1Ptcher: London Tr,3nsport.------------------------- 1961 (67) 272 30. 18. 9 7.01 Post Office-- ------------------------------- 1961 (67) 166 10 18.7 10.01 Flick --------------------- 1959 (M) 156 49. ('rl. 7 24.5 O1sen: United BinFdom-----------__-_---_--_ 1960 (14R) 162 11 27.2 0 Denmark----------------------------------- 1960 (14s') 132 24 11. 4 R:Z I Percentages standardized for age. Ferris and' Anderson (61)i studied a sample of the populationi of a town, their results are presented as percentages, standardized for age. The sample sizes were 542 males and 695 females. Among males -10:3 percent of smokers and 13:8' percent of non-smokers admitted to sputum production with the corresponding' figures for females being, 119.8' percent for smokers and 9.4 percent for non-smokers. Thus, sputum product'iom in each of the diverse populations was found associated with smoking and ai consistent difference between smokers and non-smokers was present in regard to sputum production. ('c:)Cougk, andSputum.-The clbseiy , associated symptoms of cough and, sputum have been combined in:the results of a number of epidemiologic sur- veys. Table 3 showsthe prevalence of cough and sputumi in smokers and ini non-smokers among samples studiedL Of partlicular interest is the series of comparisonsmade byHig;ins 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 im the collection of informa- tion. In the disparategroupsstudied-incl'uding male and flemalesubjeets,, older and younger, and varying, in degree of dust exposure andl 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 between smoking andl productive cough in a variety of different situations, and the predominance of smoking as a determinant of these symptoms. 283

i TABLE 3.-Summary of reports on the prevalence o f cough and sputum in relation to srnokzng Author Year , Refer- Numbeno[ subjects PercenVwith cough and sputum ence Smokers, i Non- smokers Smokers Non- smokers Higgins: Males.-------------------------------------- 1957 (88), 222 28 23.9 7:1' Femalcs------------------------------------ 1957 (88)' 93 176 17:2 4.5 Higgins: Male~~s.-------------------------------------- 1958 (93) 75 6 24.0 0 Females ------------------------------------ 1958 (93) 20 64 30:0 3:1'1 Higgins: Males--------------------------------------- 1959 (90) 315 33 29:8 6.1 Hieeins: '-5-34-------------------------------- Males, 1959 (92) 282. 56 29.1 8.9 . Males,.55-64-------------------------------- 1959 (92) 293 29 44.7 3:4' Payne: Males--------------------------------------- 1962 (153) 1, 400 304 11.0 1.9 Females------------------------------------ 1962 (iS3) 888 1,468 6:0 1.9 Pliillips--------------------------------------- 1956 (156) 823 451, 51.0 2.0 Read: Malhs--------------------------------------- 1 1961 (159) 91 46 23.1 4.4 Females--- -------------------------------- ' 1961 (159) 43 81, 18.6 4.9 - Liebeseiiuetz---------------------------------- I 1959 (120) R3 52 7.2 0. The percentages of symptoms noted by Oswald' and Medvei (150) are unusually high because occasional cough~ or sputum is includ'ed; 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 Medveis study had cough or sputum: Among females, 63.2 percent of 970 smokers and 47.7 percent of 1,27'2' non-smokers admitted to either or both of these symptoms. Payne and Kj elsberg (153 )' presente& 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 1'or Grade II, the latter being, defined as both cough and phlegms of whi& at least one was present throughout': the day for three months in the year or longer. The prevalence of Grade II symptoms is notedl in Table 3. Dur- ing an interview period continued for 18 months, authors were able to show that the prevalence ofl symptbms did! not vary significantly with thee season of the year. Cough and sputum at~ the Grade II level were admitted to by 111 percent of 1,400 cigarette-smoking males, and 2 percent of 364 non- smoking males. The corresponding, figures for, females were 6 percent of 888'smokers and Zpercent of 1,468 non-smokers. These Grade II symptoms increased in prevalence with advancing, age in men, and in women up to 49 years. It is interesting, to note that, lesser degrees of cough and sputum, classed as Gr~adeIsymptoms, showed little ehangein frequency after 19 years of age in either sex. In both sexes, Grade I symptoms of cough and sputum were 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, an& 29 percent of! 888 smokers and 17 percent of 1,468 non- srnokers among the females. 284

4 Phillips and' his associates (156) studied two' groups: one of male em- plovees 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 30D 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. Im a tabulation of chronic: cough by age in decades, for cigarette smokers and nomsmokers, it was shown that the increasing prevalence of chronic cough with age was much greater in the cigarette-smoking group. Read an& 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 rton-smokers. and to cough and sputum five times as often. In their femalee 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 may he taken to be a general one. TABLE 4.-Summary of,reports on the prevalence of'breathlessness in relation to smoking Refe'r- ence Author I Year Number of subjects Smokers Non- smokers Percent elth breathlessness Smokers Non- smokers Balchum - 1962 (16) 1 198 253 14!.5 9.8 - ----------------------------------- Dpnsem -------------`------------------------- 1963: (44) , 0 2,530 514 25.3 16.9 Fletchen: London TransRort-____-_-__________________ 1961 (67), 272 30 8.5 0 Post Oirice------------------ --------------- 1981 (67) 166 10 9.0 10.0 HigRins: Dtales -- ----------------------------------- 1957 (88) 222 I 28 19:8 7:1i Females------------------------------------ 1957 (88) 93' 176 9.7 19.9 HSKvins: bfales.-------------------------------------- 1958 (03) 75 6 29:3 33.3 Females------------------------------------ 1958 (93) 20 1 64 20.0 45.3 Higeins: Sfales -------------------------------------- 1959 (90) 315 33 31. 7' l 19:2 HiR¢ins: Males, 25-34-------------------------------- 1959 (02) 282' 56 9:.9~.. 5:4~, Males, 55-54------------------------------- 1959 (92) 293 29 42.7 7 ~ 17.2 . Pa5•ne: Males-- --------- - ------------------------- 1962 (153) 1,400 364 24. W I 12.1 Females------------------------------------ 1962 (153) 888. 1,468 29.1 29,0 ~. Short----------------------------------------- 1938 (176) 1,292 496 11.51 4.8'. 285 99 IMENUMM f 1

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 surveys quoted are open tocritacism in thisregard„ but in others considerable pains have beeni taken to avoid! any possibility of suggesting a relationship, which may not truly exist. It would be wrong to extrapolate from; say, a hospital population to the general public, but the groups surveyed vary enough that the evidence demonstrates clearlk- that cigarette smokers more often report symptoms of cough, sputum, or both, tban do non-smokers. (d.) Breathlessness.-Table 4 summarizes the prevalence of breathlessness 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 byy pack-years of smoking experience showed a less smooth gradient than for prevalence ofl cough~ and sputum. Densen and others (44), who studied respiratory svmptoms in transit workers and postmen in New York City, foundi that 253 percent of 2,530 smokers and 16.9 percent ofl 514 non-smokers admitted to breathlessness of Grade II or worse (indicated 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 breat'blessness, and 38' smokers out of 438. These figures are for workers complaining of dyspnea (a positive answer to the question, "Do you have t'o 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 (88) in the agricultural district of the Vale of Glamorgan, the author presents 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 amona the non-smokers, but the difference is not statistically significant. Female smokers ini the over 45 age groups have rather more cough and sput'umi and wheeze than the non-smokers;, but apparently have less breathlessness. In his study in Annandale (93) the prevalence of breathlessness among all men and all women studied was greater in the non-smokers than in the smokers, although the numbers of non-smoking men and! of smoking womeni were small. Wheni males aged 55 to 64 are considered, from the three surveys 190Y, breathlessness is more prevalent among the smokers; and the same thing applies t'o flie two~ different, age ~groups of~~ males stud ied' in Staveley~ (92). ~ Payne and Kjel?;berg (15U, in their survey of a totali community, have stated that among, t'he men, cigarette smokers were affected more often with breathlessness at alUages. Among the wornen,,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

I I compared torion-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 among smokers than among non-smokers. Hammond (82) also presents figures for the frequency with which breath- lessness was noted in answer to a questionnaire by' 18,697 meni and 24,371 women. The relationship between breathlessness and smoking, is less clear than the relationship between cough and smoking. A sigpificantlyy greater proportion of complaints of breathlossness 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 ofl breathlessness more severe than slight. The ratios for females were 1.36 and 1.49. A considerationi of the frequency of complaints of shortness of breath in smokers and ini non•smokers, by age group andl by sex,, shows that'.the excess ofl 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- ness 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 associationi 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 ini 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 Illhess.-The percentage of smokers and non- smokers who reported chest illness in the three years prior to the interview TABLE 5-Summary of reports on history of chest illness in the past 3 years in relation to smoking Author 'Year Refer- Number oGsubjeats Percent with chesti illness ence Smokers Non- smokers Smokers Non- smokers ~~. Fletcher: London Transport---_--------------------- 19fi1 (67) 272~ 30 9.2~ 4.3 . Yost Offiloe --------------------------------- 1961 (67) , 166~. 10 I 33:7~ 211.0~. llivgins: Sfales'--------------------------------------- 1957 (88) 222' 28 17.1 ~ 3:fi Females------------------------------------ 1957 (St3) I 93 176 15. 1 I 13: l Iiigcins: Siales.-------------------------------------- 19:iF (93) 75 6 FemalOs------------ ------------------------ 1958 (93) 20 6.1 10!0'.~ 10:9~. IliReins. Males------------- ------------------------- 1959 (4M)) 315 33 23. 8 s: 0 ~. HiReins;. Males, 25-34-------------------------------- 19.59 (y2). 282 56 72.~5~~ - .1 Males, 55-fi4'-------------------------------- 19:i9 (92) 293 29 27.3 I G.:9 ~~ P.rcne: h4ales.-- --------- -------------------------- 1962 (153). 1„400. 364 . 11.0 I 9'1 Femssles'------------------------------------ 196'2 (153). 888 . 1,468 16.0 i 13.0: 714-422 0-64-20 287, s

date is presented'in Table 5. For men, the prevalence was consistently higher among smokers, and in one study (',93'), the associatiom of smoking and chest illness was apparent for the younger (25-34), as well as theold'er males (55- 64). For female smokers and non-smokers, the prevalence of chest illness was about the same. (If.)~ Combinations of Symptoms.-A number ofprevalencestudies. (7; 54, 61, 62, 77, 150) have reported results, either totally or in part,, under diag, nostic headings which cannot be translated into sing]e 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. Summary of reports on the prevalence of combinations of certain symptoms in relation to smoking Number of subjects Percent wit symptoms h Author Year ft efer- ence Sm okers Non- smokers Smo kers No smo n- kers Ashford ------------------------ ------------- 1961 (7)'~ 3,214 677 21.7 ' 10J3'. F.d«ard4s.-------------------------------------- Ferris: I 1959~ (54), 779! 524 29.4 19: 5 bfales~---------- ----------------- 1962 (61) 340 125 24. 9 1 7.3 Females------------------------------------ 112 ~i (61) 209 379 17.5 ~ 9.4 Ferris: tifales -------------------------------------- 1962~ I (6'2). 54 20 42.6 15:0 Females------------------------------- ----- 196'2 (62)~. 10 60 20.0 10.0 (]oldsmith ------------------------------- --- 1962 ~ (~7 1,2311 744 43.0 31.4 Osw'ald: Males - ------------------------------------ 195':5 ' ( SW)~, 2,617 9S5 16.1 9.7 Females ------------------------------------ 195.5. ~ ( i150)~, 970 1, 272 15.4 9.1 'Percentages standardized for age. Ashford and his colleagues (7) found twice the proportion of "respir~a. tory symptoms"' among Scottish coal mine workers who smoked than among those who did rlot smoke. "Respiratoryy symptoms" were regarded as pres, ent in those who have cough or sputum all da}-y for more than three monthsper 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 an& who claimed the weather affected their chest were also classed under "respiratory symptoms." Edtvards and others (54) presented the percentage of smokers and non- smokers with bronchitis, according to clinical assessment by one of 11 general practitioners coouerating in the survey. No attempt to standardize the diagnosiswas reported. Of 779 smokers, 29.-1i percent had "'bronchitis" comparedl with 19!5 percent of 524 non~smokers. Ferris and Anderson (61) presented the prevalence of "irreversible ob- structive Iting disease," which was defined as the report that wheezing or whistling in the chest occurred most daysand nig)lts, that the subject had to stop for breath when walking at his owm pace on the level; or had a forced expiratory volume in the first second of expiration (F.E.V. 11.0) of less than 60 percent of the total fbreedl expiTat'ory voltime. According to this d'efi• nit'iorn 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. In a study conducted in a flax mill, Ferris, et all.(62) presented the prev- alenee of "chronic respiratory disease," defined as productive cough on f,,urdays of the week, for three months of the year, forthreesuceessive vears;, 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 t'iie time of the survey; or F.E.V. 1.0 less than 60 percent of forced vital ,I,pacity. Under this definition, 42.6 percent of 54 male smokers and 15.0 percent of 20~ male non-smokers had! "chronic respiratory disease." Forfemalesr the figures were 10.0 percent of 10 smokers and 10.0 percent of 60 wn-smokers. Goldsmith andi others (77), in their study of longshoremen, classified the lubject as having a "respiratory condit'ion" if he had ever had asthma or hrionchiti's, or currently was "troubled by constant coughing." Withi this ciefinitioni 43.0 percent of 1,238 moderate or heavy smokers had a respira- tory condition, compared with 31.44 percent of 744 non-smokers. Oswald! and Medvei (150)!, defining"bronchi'tis" as disability f'romi acute t,xacerbations of chest symptoms, or breathlessness,, or both, found a prev- alence of 16.1 percent, among2,617' male smokers, and of 9.7 percent among ')35 non-smokers. In their female subjects, 15.4 percent of 970 smokers compared' withi 9.1 percent of 1,272 non.smokers had "bronchitis." Although t'hese various combinations of symptoms are not comparable, the consistency an& extent of the differences between, prevalence of symp- tom combinations in smokers and non-smokers are striking. (g.) 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 cigarett'es of high nicotine con- tent. Other symptoms and measurements of pulmonary function show a less clear relationship between prevalence and amount smoked. (hL)Relationsh'ip betw•eenSymptoms andSignSandRleth;od of Smoking.- The numbers ofl pipe and cigar smokers in many prevalence 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.) VentiltrtoryFunction.-Pulmonary test's and the method of! presenting results, though varying widely, are important features of the prevalence surveys. In the study by Ashford and others (7) of 4,014 coal miners, the forced expiratory volume in the first second ofl expiration (F.E.V. 1.0') of non. smokers wasslightlyhigher thani that of the smokers, and! a smalli but sta- tistically significant difference was fbund 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 14:3 percent of 1,194 smokers and 7.8 percent of 243 non-smokers had' an "abnormal" test, an F.E.V. 1.0 of less t'han70percent. When the "abnormal" test' was compared with the number, of pack-years of cigarettes smoked, a steady increase in the proportion of, men with decreased F.E.V. 1.0~ was found with increasing, pack-years. Ferris an& Anderson (61) showed a progressive decrease in the mean F.E;V. 1.0 in successive age groups for male smokers, male non-smokers;, and' female non-smokers. Im, males, there was also a regular decrease in F.E.V. 1.0 within each age group with increase in the number of cigarettes age group over 45, the peak flow was lower in smokers than in, non-smokers, but the numbers were small. These differences are not explained byy differ- ences in age, social class, or occupation. The difference between smokers and non~smokers in peak flow measurement was not seen in tests of women. Higgins• (00=); summarized the dif£'erencein F.E.V. 0.7,5in a variety of different samples of the populat9onL Tabulations for 16 different groups included miners and ex-miners in varying pneumoconiosis categories and non-miners in the same district, and agricult'ural.' workers in two different areas in Britain. In the 13 groups in which comparisons weree 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 smokers, and also between ~ non -smokers and light smokers. In each 10-year 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 no significant difference; between non-smokers and, the lighter smoking, gGoup: Peak flow measurements indicated a difference between heavy and light Higgins (88) showed a decrease, in F.E:V. 0.75 among smokers of 15 w.orkers; foun& the; mean expiratory flow rated'uring the third quarter of maximal forced expiration to be approximately 20 percent less in "heavy smokers" than in "light smokers." "Heavy smokers" were defined as those who had, smoked 30 pack-years or more, and "light smokers" less than 10 pack-years: Franklimand Lowell (73), in a study of 1,000 apparentlyy healthy factory expiratory flow rate showed a decrease with age and a decrease within the age groups with cigarette smoking. Chiv.ers (36)' showed that smoking, age: an& height werecorrelat'ed sig- nificantlv with the expiratory flow rate: The older and, shorter meni had 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 apparent change among non-smokers until 70 years of, age. Fletcher and, Tinker (67), measuring expiratory flow rates liy the Peak Flow Meter„ found one group, of smokers, but not another, had lower values than the non-smokers. In a later paper (58)'., Fairbairn, Fletcher an& Tinker reported that the Peak Flow Meter appeared to be a less satisfactory sereen- ingtest than the forced expiratory volume. currently smokedi In females, there was little difference in the F.E,V. 11.0 between smokers and non.smokers except in one age group. The peak 290 -L- t

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 om a strong trendl 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 t'heirstudy of miners and foundry workers in Staveley (92), ;, Higgins andUs colleagues showed a decrease in the F-E-V. 0:75 in smokers. Non- smokers, light smokers, and heavy smokers (15 grams per day and over)~ ranked in that order for decreasing F.E.V. 0:75, both in men aged 25 to 34 andl in those aged 55 to 64. The difference between the non-smokers and the light smokers was smaller than the difference between the light and the heavv smokers in the younger age group; in~ the older age group the dif- fcrence was larger between non-smokers and light smokers. Olseni 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 ha& a lower mean F.E-V'. 0.75 than cigar smokers or pipee 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 groupe& 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 oflF.E-V. 1.0 for men and women by age group and by smoking category; found a lbwer mean value for cigarette smokers than for non-smokers in each age: group of men over 19. In the 16-to-119 age 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 years, 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 3 ' percent of! the meam values in non.smoking men and women respectively wheni values adjusted to the over-all mean age of 40 years were compared. Read! and! Selby (159) measured peak flow rates in smokers with coughk and in smokers with cough and sputum. Tn a statistically significant extent, male smokers without cough or sputum showed'a more rapid fall in peak flow rate with age than expectedl Male smokers with cough showedl a still more rapid fall with age, and tbosewibhi coughi and sputum, the most napi& fall. Amount smoked ha& no obvious effect. Result's were similar fbr women. Revotskie,and his colleagues (165)i, who grouped smokers in, Framingharn as never smoked, light smoker, medium smoker, and heavy, smoker, found that the F.E.V. 11.0 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 "Puff meter" ratios tended! in the same direction, but in less clear-cut fashioni thani the F.E.V. 1.0 measurements. 291

Goldsmith and others (77), showed that smokers, regardless of amount smoked, have a slight diminution in the pulmonary function test results, even in the absence of respiratory symptoms. The total vital capacity was much less sensitive in this regprd! than the F.E.V. 1.0 or the "Puffmeter" reading. Longshoremen with "respiratory conditions;" and particularly those with ~ shortness ofi 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 an& abnormal results of pul- ~ monary function tests is more difficult to evaluate from the published surveys than is the relationship between symptoms and cigarette smoking: Pul- <' monary function test results are influenced by severali 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 func- ' tioni between smokers and' non-smokers. ~ Inithe majority of prevalence surveys, the subjects were not forbidden to smoke prior to pulmonary funetion, testing. Since acute alterations due to smoking might be mis- interpretedias due to a permanent abnormality, it is important to examine the magnitude and significance of the acute effects of smoking on pulmonary function. Biakerman and Barach (20)' 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 of 16 young subjects after smoking, and the difference for the group was statistically sig- nificantL No significant change was found in the total eapacity. Severall authors have studied more sensitive tests of airway resistance and lung com- pliance. Eich, Gilbert and Aucltincloss (56) made compliance and' airway resistance measurements, using an esophageal balloon technique, onia group of nine healthy adults, five of whom had respiratory symptoms. No difference was detected after one:cigarette. Ih a group of emphysematous patients, a statistically significant increase in airflow re- _ sistanee was found, but withouV significant change in compliance. Attinger and others (8) reported no statistically significant difference in expiratory airflow resistance or compliance, but in a later study of subjects with~ pulmonary disease, 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 hing volumes, spirometry, blood gas exchange, and pulmonary compliance in 141 subjects, before and after smoking two cigarettes. Not all of these measurements,were made on all subject's: There was no,significant change in a the meam values of vital capacity performed after smoking, some subjects showing a: decrcase,, and others an increase. Six of the normal subjects showed a decreased com- '1 pliance after smoking. Ih 33 subjects with cardiac or respiratory di'sease, 17 had a sig• ` nificant decrease in compliance after smoking: The authors felU that' a decrease in pul- ,~ monary compliance was the only notable abnormality which followed smoking acutely: :' Forced expiratory volume and airflow resistance studies were not included. Miller (134aY, who constructed pressure-volume work loops, demonstrated increase& airflow resistance and uneven ventilationi resulting in increased' work of breathing, ` This author conclUded that inhalation of cigarette smoke gives rise to a significant ; degree of uneven ventilation, which is responsible for the observed decrease in dynamic .' compliance and increased elastic work of breathing.. Nadelland Comroe(Q46) showed a mean decrease of 31 percent in, the ratio of airwayconduetance to thoracic gas volume after inhalation of cigarette smoke, the changes being ' highly significant statistically, and similar for smokers and non-smokers. Repeated test- ~ ing,after smoking showed the response to last for from 10 tu 80 minutes. Without inhala- ' tion{ no significant uhange in the conductance to thoracic gas volume ratio occurred. Inhalation of Ikuprel aerosol before smoking preventedl the increase in airway resistance, ' and when givemafter cigarette smoking it counteracted the increase. 292

b Zamel, Youssef, and Prime (194) found thaUthe,smoking of one cigarette increased airway resistance in smokers and non-smokers, and that'the inhalation ofl Ikuprel reduced airway resistance in both groups. The authors comment that the difference in airway resistance between non-smokers and cigarette smokers is apparent only when the actual estimates of airway resistance are compared with predicted values based on lung volume, because of a reciprocal relationship between airway resistance and lung volume. They add that the experimental values for airway resistance in two groups of persons are not comparable unless allowance is made for the volume of the lungs in each. 'Do sum up this point, the acute effects of cigarette smoking, upon pulmonary function are expressed mainly through increase in airway resistance, which is not severe enough to produce clinically evident manifestations. The smoker is not immediately aware of any increased! difficulty in breathing nor are the pulmonary function tests used in surveys -uffioiently sensitive to detect the acute effects. The differences in results of pulmonary functiow tests between~ smokers and non-smokers, therefore, are greater than cam be accounted for by acute effects from a recently smoked cigarette. PROSPECTIVF. STIIDIES.-In six of seven prospective studies, chronic bron- chitis and emphysema contribute markedly to the excess mortality among cigarette smokers; in the remaining study the mortality ratio was increased but to a lesser extent. In aI11 these studies, mortality ratios for chronic bronchitis and emphysema have been calculated (see Tables 19, 23, 26 in Chapter 8, Mortality). Cigarette smokers in these studies died of chronic bronchitis and emphysema 6.1 times more frequently than non-smokers. In the large study of U.S. veterans (49) the observed number of deaths among smokers attributed to chronic bronchitis was 26 whereas,the expected number based on deaths among non-smokers was 5.6, or a mortality ratio of 4.6. For emphysema, the observed number of deaths among smokers was 1115„ whereas the expected! number was 8.8, or a mortality ratio of! 13.1. In a recent study (82), informatfioni is available on the first 22 months of follow-up of 447;831 menibetween the ages of 35 and 89, of whom 11,612 have died. The observed number of deaths attributed to emphysema in cigarette smokers was 1115 whereas the expected number was 15.4; the mortality ratio was 7.47. For other pulmonary diseases the mortality ratio was 1.65, with 1185 observedldeaths in smokers as compared with 112.7 expected deaths. The duration of follow-up is na yet sufficiently long to allow one to expect deaths from chronic bronchopulmonary disease in, persons who were not afflicted at entry. The paucity of published morbidity studies is striking. Very little iss known of the progression in population samples of symptoms or signs related to chronic bronchitis or emphysema, or found in smokers more frequently than in non-smokers. And very little is known of the incidence rates of such symptoms and'signs in the different categories of subjects constituting popu- lathion samples. This is unfortunate, as prospective studies of morbidity in population samples can best measure.the possible health hazard of smoking. Several studies are under way, but some of the important' informationi will concern changes oceurring, over a period of five years or more. The only study of this type reported! so far is by Higgins and Oldham (94), who measured the F.E.V. 0.75 in a five-year follbw-up study on ventilatory capacity in a population sample in, a mining dlstrict, in Wales. In non- miners this measurement fell more over the five years in smokers than in non~smokers, and within the smoking group there was an increasing fall with amount of smoking. When the miners and ex-miners were considered, 293

the pattern was less clear. In~ three of the four groups, t'he F.E:V. 0.75 of the smokers fell more than that of the: non-smokers or ex-smokers; but the fall was usually greater in the light than in the heavy smoking, group. The authors pointed out that when the original sample was selected, no follow-up was intended, and that! the sample was not very suitable for this purpose: Thus, morbidity data are insufficient at present to be of value in the estimation of the possible health hazard of smoking. Prospective studies in populations followed over long periods offer the best opportunity for filling the major gaps in knowledge about the relationships of smoking,and chronic bronchopulmonary diseases. CLINICAL EVIDENCE Several' studies concerned with individual patients rather than defined populations form the basis for the clinical evidence. A current and continuing study of an "emphysema registry" with entry based on clinical and physiolbgical evidence, has been~ reported(',138) . Of 131 patients with diffuse pulmonary emphysema, 20 had findings at necropsy of widespread alveolar destruction. Clinical differentiationi was made into three groups : a"bronchitic" group in whom a history of cough was present years before onset of d'yspnea on exertion, a "dyspneic" group in whom cough and! dyspnea occurred at about the same time or in whom dyspnea occurred first, and an "asthmatic" group who gave a history of episodic dyspnea or asthma for years before the onset of uninterrupted dyspnea. When the sample of patients was adjusted for age and sex, 95 percent were smokers as compared with an expected 80 percent based on smokina, habits of Americans. In a later reportl (137)', the number of patients had in- creased to 150; 99 percent of the "bronchitic" group, 98 percent of the "dyspneic" group, and 79 percent of the "asthmatic" group were cigarette smokers. Improvement occurred' in 70 percent of the 60 patients who stopped smoking, as: compared! with 1 percent of the 84 patients who con- tinued smoking. Studies of series of patients by others (4, 125) have also notedl the fre- quent association of cigarette smoking with emphysema. A number of clinical studies indicate the frequent association of cigarette smoking, in chronic bronchitis (1:06;, 11,7; 149). Fewer non-smokers were among, the bronchitis patients than in~matched controls in two of the studies (117, 149). Of' interest is a comparison of 127 cases of chronic bronchitis with a similar number of eontrols (,7~5) ; no difference in smoking, habits was found in the men, an& very little difference in the women. On the basis of such studies, with varying diagnostic criteria,, several authors have concluded that cigarette smoking may be an etiologic factor in chronic bronchitis and emphysema; Most but not alll of! the studies have shown smoking to be a more common habit among the bronchitis or emphysema: patients than among the controll groups. Such evidence can~ do little more than provide a basis for hypothesis and indicate the effect of continued smoking on established disease; it does not, of course, establish~ or exclude a causal relationship. 294

t Relationship of Smoking, Environmental Factors, and Chronic Respiratory Disease ATMOSPHERIC POLLUTION BASIS FOR INTERRELATIONSHIP AND RELATIVE MAGNITUDE OF EXPOSURE- (1. ) Ezperimental, Evid'ence: The threshold level below which chronic ex- posure to a toxic:agent fails to produce damage to the respiratory system has not been established even for many of the known components of tobaeco smoke and atmospheric pollution. It is known, however, that the mechanism by which inhaled substances produce an irritant response in the lung, is not a simple one. Physical, chemical, and biologic interaction may result from multiple, simultaneous exposure to a wide variety of' the components. Poten- tiation of the irritative actiom of certain gases when inhaledl together with an aerosol of small particles has beem demonstrated (5, 113~ 152)~. A possible example of potentiatiom may be found by contrast of two natural atmospheric pollution disasters; the 1962 London smog episode had lbw-er particulate levels, approximately equivalent sulfur dioxide levels, and fewer deaths than the 1952 London smog. Innumerable components with potential biologic effects are present in tobacco smoke and as atmopheric.pollution, some components are common to both. At present, information concerning the effects on the respiratory system is available for relatively few of these components. In an earlier chapter ofthfls report (Chapter 6)~„ the toxic actions of the particulate phase and major gas constituents ofcigarette.smoke are discussed; nitrogen dioxide, and to a much lesser extent, formaldehyde, are the gas components capable of producing, pulmonary lesions related to respiratory disease of man. The components which constitute pollutants in ambient air vary wid'ely, largely because of differences in source, meteorologic variables, and photochemical interactions. The effects of some of the majpr gas const'ituents in air pollu- tion uponAhe respiratory system are knowni and willl be presented briefly. Sulfur dioxide is rapidly absorbed into the lung butl removed slowl~-, peri- sisting for one week after a single exposure (115). Interference with the clearance mechanismi is produced through effects upon the mucus, rather than by inhibition of ciliary motility as seen withi cigarette smoke. Sulphur dioxide usually, exerts: its effects uponithe upper bronchial tree but intensive, protracted exposure may result in damage to the more distal air- ways. In animals, short4erm, high-level exposures result in increased air- flow resistance, and hypersecretion of mucus has been suggested' by changes in, the mucosa after moderately high, intermittent! exposure of guinea pigs for six weeks (162). Chronic 1bw,level sulfur dioxide exposures have pro- duced'fibrotie bronchitis (86). Experimental human exposures confirm the increased airflow resistance which may occur without symptoms; augmenta- tion of the effects of sulfur dioxide ini the presence of particulates also has been observe& in humans but it was less evident than in guinea pigs (72, 76, 193). Ozone produces irritant actions on the respiratory tract much deeper in the lung than sulfur dioxide. Repeated ir.halationi of 1' ppm. produces chronic bronchitis and bronchiolitis in rodents, especially rats, but no detectable ef- 295

c fects are produced in dogs (179). Under conditions of acute exposure, somewhat more than 1 ppm. of ozone produced increased airway resistance and decreased diffusing capacity in mani (76). It is not known whether chronic low-levell exposure to ozone produces lung damage in man. The ingredients of motor vehicle exhausts most' likely to have biologic effects are aldehydes, hydrocarbons, oxides of nitrogen, and carbon monox- ide. Guinea pigs exposed to ultra-violet irradiated exhaust gases have enhanced susceptibility to infection and bronchospasm (2, 144)'. No d'ata are available on the long-term inhalation of low concentrations of irradiated exhaust gases or photochemical smog and its effects on human pulmonary tissues. At present, it has not been demonstrated that other components common in air pollution are associated with pulmonary lesions similar to those found in the chronic respiratory diseases of man. (2.) Relative Magnitude of the Exposure.-Estimates of the relative mag- nitude of exposure to constituents common to bot'h, cigarette smoke and atmospheric polltrtion are made diffcult by the complex nature of the char- acteristics of the exposure, such as the relationship between concentration and' durationi and! by the paucity of studies specifically designed to evaluatee this aspect. In general, levels are likely to be high, brief, and frequently repeated! in the discontinuous exposure to: cigarette smoke; air pollutant exposure may be considered to be relatively continuous but with~ wide varia- tion in concentration and composition, particularly in the United' States. The relative magnitude of each type of exposure cannot be accurately calculated at present. Ibsi€ht may be gained, however, into the relative magnitude of exposure to two components, carbon~ monoxide and the oxides of nitrogen, common to cigarette smoke and atmospheric pollution. The smoking of 30 cigarettes per day is estimated to provide a 2(1- to 25-fold gFeater exposure to carbon monoxide than wouldl be experienced in the ambient air of Pasad'ena by non-smokers (76)'. The effect of smoking on carboxyhemo- globin levels in man has been determined in studies utilizing carbon monox- ide in air expired byy cigarette smokers and non-smokers with similar high level community atmospheric pollution exposure. The effect of cigarette smoking on carboxyhemoglobin levels in~ man was more than five timess greater than the effect of atmospheric pollution, even, when the studies were performedl in a relatively heavily polluted area (76)'. The relative magnitude of exposure to the oxides of nitrogen may also be estimated for cigarette smoking as compared with atmospheric pollution. The average concentration of nitrogen oxides in, ambient air is 0:3 ppm. in the Fall quarter in downtown Los Angeles. The oxides of nitrogen present ini cigarette smoke vary from, 145 to 665 ppm. ; moreover, virtually complete absorption occurs after inhalation (23). During periods of cigarette smok- ing, therefore, a substantially greater exposure to nitrogen oxides would be expected (76). Since cigarette smoking is likelyy to occur on every day of the year an& periodically throughout the dayy and evening, and community air pollution~ is likely to be relatively less common or persistent, therelatfive magnitudeof the effect of cigarette smokins, for the bulk of the United States population is certaini to be, greater than indicated above. The exact magnitude is per- 296

haps less important than the finding that it is substantially greater (76). Thus, using exposure either to oxides of nitrogen or carbon monoxide as an index, substantially gFeater exposure results from cigarette smoking than from atmospheric pollution, even when studies are conducted in a highly pallute& atmosphere in the United States. WAereas estimates of exposure to many other constituents of both types of pollution will be necessary before the relative hazard can be calculated more fully, the experimental evi- dence at present is consistent and' indicates that cigarette smoking affords the greater exposure for the bulk of: the population of the United States. EPIDEMIOLOGICAL EVIDENCE.-Most investigations of epidemiologic design have not been directed toward determination of the relative importance, or the combined effects, of cigarette smoking and atmospheric pollution in chronic respiratory disease. Discernible effects of cigarette smoking, such as cough and sputum production, have been observed and documented in the presence or absence of atmospherie pollution. A detailed considera- tion of the epidemiological data is available (76) ; onlyy selected studies wiR he considered here. The prevalence of cough and sputum in the United States appears to be determined much more by the amount and duration of cigarette smoking than by atmospheric pollution. Incomparable samples of cigarette smokerss in New York, Baltimore, Los Angeles, and' San Francisco: no major differ- ences were found in the prevalence of cough and sputum (76, 101) ; it is interesting that similar results were obtained' comparing cigarette smokers in; London, England and Bergen; Norway (139). Atmospheric pollution had little or no detectable effect on the prevalence of respiratory disease among residents of a New Hampshire town; a substantially greater preva- lcnae of! chronic nonspecific respiratory disease was present; however, in cigarette snlokers than, in non-smokers ofl similar age and! sex (6; 61). In veterans pairedl by age and smoking history; the frequency of respiratory symptoms and alterations in pulmonary function tests correlated well with past cigarette smoking history; in contrast, study of these men during the season in which~ Los Angeles atmospheric pollution was high did not result in detectable response attributable to the atmospheric pollution (173)1. In studies in areas withi varying severity of atmospheric pollution, the effects of cigarette smoking have been observed (16, 77; 165). Pulmonary em- physema is relatively rare in a population of non-smokers who live mostly in the areas of California with greatest atmospheric pollution (51). In the Uklited Kingdom, cigarette smoking and' atmospheric.pollution both contribute to the development and progression of chronic bronchopulmonary disease (28). Chronic bronchitis results in a mortality rate 30 to 40 times higher in both sexes and at! all ages than is seen in the United States. The excess mortality remains even, after removal of possible differences in clas- sification and misinterpreted! diagnosis (63). Moreover, differences in to- bacco consumption do not appear to be sufficiently large to account for the excess mortality due to bronchitis in the United Kingdom. In producing,simple, uncomplicated bronchitis, cigarette smoking appears to have the,same result in the two:countries (63). Although recurrent chest illness and evidence of airway obstruction are more frequent in cigarette smokers, the frequency of more advanced forms of chronic bronchitis does 297 >.,-, WA>: ~.:w !

not increase with increasingly heavy smoking (65). Atmospheric pollu- tion in~ the United Kingdom exerts its effects primarily among chronic bron- chitzcs ('117) almost a111 of whom are cigarette smokers (64) ; it also is a major factor in the urban-rural differences in prevalence and mortality (37, 65, 154, 160). Wheni those findings are considered together with other evidence documenting the:role of atmospheric pollution inichronic bronchitis (28;, 76, 161), it seems probable that atmospheric pollution and cigarettee smoking in the United Kingdomi are at least additive and possibly synergis- tic in their deleterious effect on the respiratory tract. Thus the epidemiological evidence oni the relationship of cigarette smok- ing, atmospheric pollution, and chronic respiratory disease clearly indicatess that the dominant association in the United States is between cigarettee smoking and chronic respiratory disease. In the United Kingdom, disabling respiratory conditions and' d'eath are more likely to occur among persons who smoke cigarettes and are exposed! frequently to atmospheric pollutants than in those exposed to either alone. 1' OCCUPATIONAL FACTORS Occupational exposures provide other possible etiologic factors in the production of chronic bronchitis and emphysema. There is little convincing evidence on specific relationships. Nevertheless, epidemiolbgical studies. (,reviewed in 123, 128) provide information on the relative import'ance of cigarette smoking and occupational exposures in selected groups. In a study of 4,014 Scottish coal miners (7), the prevalence of respiratory symptoms among non-smokers was appreciably lower than among smokers of the same age, and the ventilatory function of' non-smokers in all age groups was significantly higher than~ that of the smokers. Among, smokers of 50 years of age andl above, the prevalence of pneumoconiosis tended to be lowest among the men who smoked the most and highest among men who 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 eliminate some persons with symptomatic pneumoconiosis from study groups should also be considered in the evaluation of these studies. In a; sample of 1,317 men aged 40 t'o 65 who worked in a variety of non- dusty and~ dusty environments, a: greater prevalence of bronchitis (daily cough for at least the preceding six months; productive of! one teaspoon of sputum per day) was found in moderate and heavy smokers (27). Between~ the non-smokers an& the heavy smokers, a significant difference was foun& 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 smoking 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

i I ; In a stu4 of 1,274 steel workers, non-smokers had a comparatiieelq low incidence of chronic cough, regardless of their job classificatiom or condi- tions of work or residence. There was a direct relationship between chronic cough and the number of cigarettes smoked daily in each occupational category (1I56):. 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 "chronie non-specific respiratory disease." The prevalence of such a syndrome, based om a certain combination of symptoms or signs, was related to age;, sex, smoking habits, years of exposure to dust, and estimated inhaledl quantity of dtrstl 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) show that smoking and occupational exposure are bothi relatedl 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~ l'ations surveyed', were such that exposure to occupational dusts was more varied than in the general population, the importance of the effect of! smoking inithis group of studies on the production of respiratory symptoms is rather convincing (123)1. The authors comment in one of the papers in this series: "So important is the influence of tobacco smoking that it is essential to alloww 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 funetion, the impairment of pulmonary function by years worked under- ground is clear and separate from the effect of smoking." In a st'udy 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 d'ay)', there was an additional d'e- cline of 1!0 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 associated 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 im all 299

i studies of chronic bronchopulmonary disease. In most studies, but not all, the relative importance of cigarette smoking, is greater than occupational ex- posures in~ the production of symptoms and signs of chronic bronchitis or emphysema. SUMMARY I Tobaeco smoke is a heterogenous mixture of a vast number of compounds, several of which have the ability to produce d'amage to the tracheobronchiai tissues and lung parenchyma. Retention of inhaled cigarette smoke particles in the respiratory system of man is about 80-90'percent complcte with breath holding of two-to-five seconds. Particles penetrate deeply into the respira-- tory tract andl are deposited on~ the surface of the terminal bronchioles, respiratory bronchioles, and pulmonary parenchyma. Little information is available concerning the specific toxic properties of the particulate phase 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 portion is retained along, the upper bronchial tract'. Certain of the gases known to be present in cigarette smoke are capable of' producing pulmonary damage 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~ ciliary motility in experimental animals. Post,mortem 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 func- tional impairment would result. Cigarette smoke is also capable of interference with functions in the lower airways. Ini 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 st'ress of protracted high-level exposure to cigarette smoke and'tb- bacco smoke components accumulate in the pulmonary parenchyma of' experimental animals. The acute: effects of ci'garette: smoking result, in an increase in airway re- sistance but clinical expression of this change in pulmonary function is not common. The chronic effects of cigarette smoking upon pulknonary fune- tion are manifest'ed mainly by a reduction in ventilatory functioni as measured by the forced expiratory volume. Histopathologieal' alterations occur as a result of tobacco smoke exposure in the tracheobronchial tree and in! the lung, parenchyma of man. Changes regularly found in, chronic bronchitis-increase in the number of goblet cells, and hypertrophyy 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 an& fibrosis, have a remarkably close association with past his- tory of cigarette smoking. These changes cannot be related with certainty to emphysema or other recognized' diseases at the present time. Chronic bronchitis and pulmonary emphysema are the chronic broncho- Pultnonarydfiseasesofgreatesthealtlh, significance. Epidemiologicallevidence provides the most important information relat2ngcigzrettesmokina~ to chronic bronchitis and emphysema: All seven of the majpr prospective studies show a: higher mortality rate f'or chronic bronchitis and' emphysema among, -cigarette smokers than among, non-smokers.In the few studies that have examined mort'alfity rates separately for the two~ conditions, chronic bronchitis or emphysema, both rates are higher among, civarette: smokers than among non-smokers. In one of the studies, the risk of mortality from chronic bronchitis was four times greater among cigarette smokers than anlong non-smokers: Emphl sema was listed as a cause of death 13' times more frequentlvy among smokers in one study, and 71/~ times more frequently among smokers in another study. Extensive prevalence studies, based largely on prevalence of specific svrnptoms and signs rather than imprecise diagnostic labels, show a consis- tently more frequent occurrence of! cough, sputum, or the two symptoms aombined. in cigarette smokers than in non-smokers. These manifestations are theclinicale expressions found in, chronicbr~onahitis. The resultsofl 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, particularl}'y in the older age groups, but not females. Similarly, a:consistent association of cigarette smoking and chest illness is more evidenti for males. In the prevalence surveys ini which various combinations of respirat'ory manifestations have been studied, a greater prevalence of these conditions is found consistently among cigarette smokers. The majority of clinical studies have noted a: relationship betweeni ciga- rette smoking and chronic bronchitis and emphysema. Cigarette smoking is a more common habit in the United States among, patients with~ chronic bronchitis or emphysema than in the control groups studied. The clinical stodies also show a decrease in clinical manifestations of chronic broncho- pulmonary disease after cessation ofl smoking. Examination of' experimental evidence shows that the lung may he dam~ aged by noxious agents found in either tobacco smoke or atmospheric poh lution. In the United' States; the noxious agents from cigarette smoking are much rnore important't ini the causation of chronic bronchopuhnonary disease than are those present as community air pollutants. In the. United Kingdom, persons who smoke cigarettes and are exposed frequently to at- mospheric poll~tants are at greater risk of developing disabling respi'ratory disease and d'eatlhithan those exposed to either, alone. 301

The relative: importance of cigarette smoking, also appears to be much greater than occupationali exposure as an etiologic factor for the chronic bronchopulmonary diseases. Cigarette smoking does not, appear to cause asthma; in, rare instances, allergy to tobacco products has been ascribed a causative role in asthma, like syndromes. Evidence does not support' a direct association between smoking and in« fectious diseases ofl the respiratory system. The category, influenza and pneumonia, contributes moderately to the excess mortality of cigarette smokers but other data are not available to extend' this observation. The association of cigarette smoking and tuberculosis does not appear to be a direct one,,but both are associated with the use of alcohol. Only for "stomatitis nieotina" and the epithelial changes in the larynx is there sufficient documentation to substantiate the clinical opinion that non- malignant alterations in the mouth, nose, or throat are indticed by, smoking. The changes in the mouth are more often associated with pipe smoking but disappear after cessation of! smoking. CONCLti SIONS 1. Cigarette smoking is the most important of'~ the causes of chronic bronchitis in~ the t'nited: States, an& increases the risk of dying from chronic bronchitis. 2. A relationship exist's between pulmonary emphysema and cigarette smoking but it', lias not been~ estkblished! that the reldtionshipis causal: The smoking of cigarettes is associated with an increased risk of dying from pulmonary emphysema. 3. For the bulk of the population of the United States, the importance of cigarette smoking as a cause of' chronic bronchopulmonary disease is much greater than that of atmospheric pollution or occupational exposures. -1. Cough, sputum production, or the two combined ar~econsistently more frequent among cigarette smokers than among non-smokers. 5. Cigarette smoking is associated with a reduction in ventilatory func- tion. Among males, cigarette smokers have a greater prevalence of breath- lessness than non+smokers. 6. Cigarette smoking does not appeart6cause asthma. 7. Although death~ certification shows that cigarette smokers have a mod-erately increased risk of death from inHluenza and pneumonia, an association of'cigarettesmoking and infectious diseases is not otherwise substantiated. REFERENCES 1. Abbott, C. A., Hopkins, W. A., Van Fleit, W. E., Robinson,, J. S. A new approach to pulmonary emphysema. Thorax 8: 1ll(-32; 1953. 2. Albert, R. E.,, Nelson, N. Special report to t'he Surgeon General's Advisory Committee on Smoking and Health.. 302

i 3. A1t'schuler, B. L. Personal communication to the Surgeon General's Advisory Committee on Smoking and Health, 4. American Thoracic Society. Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Amer Rev Resp Dis 85: 762, 1962. 5. AmdUr„ M. 0. The effect of~ aerosols: on the response to irritant gases. In: Davies; C. N. ed. Proceedings of International Symposium oni Inhaledi Particles and Vapors. Oxford, England, April 1960! Lon- don. Pergamon Press, 1961. p. 281-92. 6. Anderson, D. 0., Ferris, B. G.,, Jr. Role of tobacco smoking in the causatiom of chronic respiratory disease. New Eng J Med 267: 787-94. 1962. 7. Ashford, J. R., Brown; S., Duffield, D. P., Smith, C. S., Fay; J. W. J. The retention between smoking habits and physique, respiratory symptoms, ventilat'ory function, and radiolbgical pneumoconiosis, amongst coal workers at three Scottish collieries. Brit J Prey Soc Med 15: 106-17; 1961. 8. Attinger, E. O!, Goldsteins M. M., Segal, M. S. Effects of smoking upon the mechanics of breathing: I. In normal subject's. II. In patients with cardiopulmonary disease. Amer Rev Tulberc 77: 1-16;, 1958. 9. Auerbach, 0., Stout, A. P., Hammond, E.C., Garfinkel, L. Bronchial, epithelium in former smokers. N Eng J Med 26:n: 119-25, 1962. 10. Auerbach, 0.,, Stout, A. P., Hammond, E. C., Garfinkel, L. Changes ini the bronchiall epithelium in relation to cigarette smoking and in relation to lung cancer. New Eng J Med 265: 253-67, 11961. 11. Auerbach, 0.. Stout,, A. P., Hammond. E. C:, Garfinkel, L. Changes ini bronchial epithelium in, relation to sex, age. residence, smoking and pneumonia. New Eng J Med 267: 111-9, 1962. 12. Auerbach, 0., Stout', A. P., Hammond. E. C., Garfinkel, L. Smoking' habits and age ini relation to pulmonary changes: rupt'ure of the alveolar septums, fibrosis and thickening of walls of small arteries and arterioles. New Eng, J Med 269: 1045-53, 1963. 13. Iladhams C. Observations on the inflammatory affections of' the mu• cous membranes of the bronchiae. London Callow, 1808. 14. Badham, C. Practical observations on the pneumonic diseases of the poor. Edinburgh Med Surg J 1: 166-70, 1805. 15. Balchum, C. J., Dybieki; J.,, Meneely, G. R. The dynamics of sulphur dioxide inhalation. AMA Arch lndustr Health. ('Chicago), 21: 564, 1960. 16. Balchum, 0. J., Felton, J. S., Jamison,, J. N.. Gaines, R. S., Clarke, D. R., Owan, T. A survey for chronic respiratory disease in an in- dustrial city. Amer Rev Resp Dis 86: 675-85, 1962. 17. Ballenger, J. J. Experimental effect of cigarette smoke on human respiratory cilfia'. New Eng J Med 263': 832-5. 1960. 18! Baumberger, J. P. The amount of smoke produced from tobacco and its absorption in smoking as determined by electrical precipitation. J Pharmacoli E'xp Then 21: 47-57, 1927. 744'-422' 0-64'-21 303

19. Becklake, M. R., Goldman, H. L, Bosman, A. R.,, Freed, C. C. Long- term effects of exposure to nitrous fumes. Amer Rev Tuberc and Pul Dis 76~: 398-409, 1957. 20. Bickerman, H. A., Barach, A. L. The effect of cigarette smoking on ventilatory function in patients with bronchial asthma and obstructive pulmonary emphy sema. J Lab Clin Med 43:' 455-62, 1954. 21. Boake, W. C: A study of illness in a group of' Cleveland families: New Eng J Med 259: 1245-9, 1958: 22. Boche,, R. D., Quilligan, J. J. The e$ects of air pollutants on tissue cultures. Fed' Proc Bull 18: 559, 1959. 23. Bokhaven„ C., Niessen, H. J. Amounts of oxides of nitrogen and carbon monoxide in cigarette smoke, with and without inhalation, Nature (London) 192: 458-9, 1961. 24. Boren, H. Carbon as a carrier mechanism for irritant gases. Pre- sented at California State Department of Public Health Sixth Air Pollution Medical Research Conference. San~ Francisco, 1963. 25. Roucot, K. R.,, Cooper, D. A.,, Weiss, W. Smoking and health of older men. 1. Smoking and chronic cough. Arch Environ~ Health~ ('Chi: cago) 4: 59=78,, 1962. 26. Bower, G. Respiratory symptoms andl ventilatory function in 172 adults employed in a bank. Amer Rev Resp Dis 83: 684-9, 1961. 27. Brinkmam G. L., Coates, E. 0., Jr. The prevalence of chronic bron- chitis in an industriali population: Amer Rev Resp Dis 86: 47-55, 1962. 28. Bronchitis. Report, of a Sub-Committee of'~ the Standing Medical Ad. visory Committee, Scottish Home and Health Department. Edin- burgh, H M Stationery Off, 1963. 59 p. A national survey. Brit Med J 2: 973-9, 1961. 37. College of GeneralPract'itioners: Chronic bronchitfisini Great Britain: alkaline dusts. Brit J Industr Med 16: 51-60, 1959. African gold miners. AMAArch Environ Health 1:335-42,,1960. 36. Chivers, C. P. Respiratory function and disease among, workers in 35. Chatgid'akis, C. B. A study of' bronchial mucous gland's in white South of hard palate. A1_1~1A ArcL Path 70: 133-40, 1960! in~human subject. Long-term effects of pipe smoking on epithelium 34. Chapman, I.,, Redish, C. H. Tobacco-induced epithelial proliferation 1958. and non-smokers. [Abstract] Proc Amer Ass Cancer Res 2: 286-7; 33. Chang, C. S. Studies of subepithelial tissue of bronchi from smokers smokers. [Abstract], Proc Amer Ass Cancer Res 2: 99-100, 1956. 32: Chang, S. C. Studies of bronchial epithelium from smokers and non- 10: 1246-61, 1957. human bronchial epithelium of smokers and' non-smokers: Cancer Bt•iti I Dis Chest 55: 150-8, 1961. 30! Butler, W. T., Alling, D. W., Knight, V. Special report to the Sur- geon General's Advisory Committee on Smoking and Health. 31. Chang., S: C. Microscopic properties of whole mounts and' sections of 29. Brown; K. E., Campbell, A. H. Tobacco, alcohol, and tuberculosis. 304

I 38. Cross, K. R., Walz, D. V., Palmer, G. K., Warner, E. D. A study of the tracheobronchial epithelium and changes related to smoking. J Iowa Med Soc 51: 137-40, 1961. 39. Dalhamn, T. The effect of cigarette smoke on ciliary activity in, the upper respiratory tract. AMA Arch Otolaryng 70: 166~-8, 1959. -10: Dalhamn, T:, Rhodin; J. Mucous flow and ciliaryactivity, in the trachea of rats exposed to pulmonary irritant gas. Brit J Industr 1;'Led 13 : 11i0-3, 1956. -11. Davies, C: M. The handling of particles by the, human lung. Brit. Medl Bull 19: 49, 1963. U Deichmann, W. B., Kitzmiller, M. D., Witherup, S. The effects upon experimental animals of the inhalation of phenol vapor. Amer J Clin Path 14: 273, 1944. 13. Deichmann, W. B., Witherup, S., Dierkeri, M. Phenol studies 12. J Pharmacol Exp Ther 105: 265, 1952. 14. Denseny P. ML, Breuer, J., Bass, H. E., Jones, E. W. New York City Health Department Chronic Respiratory Disease Survey, Interim Report. May 1963. 15. Devine, K. D. Pathologic effects of smoking on the larynx and oral cavity. Proc Mayo Clin 35: 349-52, 1960. -16. Djuric, D.,, Raicevic, P., Konstantinovic, l. Excretion of thiocyanate in the urine of smokers. Arch EnvironI Health 5: 1I2-5, 1962. 17. Dorn, H. F. Personal communication to the Surgeoni General's Ad- visory Committee on Smoking and Health. 18. Dorn, H. F. The increasing mortality from chronic respiratory dis- eases. Amer Stat Ass Proc Soo Stat Sec p, 148-53, 1961. 49. Dorn, H. F: The mort'alfity of smokers and non-smokers. Amer Stat Ass Proc Soc Stat Sec p. 34-71, 1958. 50. Dowling, H. F:, Jackson, G. G., Inouye, T. Transmission of the experi- mental common cold in volunteers. 2. The effect of certain host f'actors upon susceptibility. J Lab Clin Mcd 50!: 516-25, 1957,. 51. Dysinger. P. W., Lemon, F. R. Pulmonary emphysema in a non-sniok- ing population. Dis Chest 43: 17-25; 1963. 52. Ebert, R. V., Filley, G., Miller, W. F. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 53. Ebert, R. V., Pierce, J. A. Pathogenesis of pulmonary emphysema. Arch Intern Med 1!17 : 34, 1963'. 51. Ed'wards, F., McKeown; T., Whitfield, A. G. W'. Association between smoking and disease in men over sixty. Lancet 1: 196, 1959. 55. Edwards, J. H. Contribution of cigarette smoking to respiratory disease. Brit J Prev Soc Medl 11: 10-21, 1957. 56. Eich, R. H.,, Gilberts R., Auchincloss, J. H., Jr. The acuteeff'ect of smoking on the mechanics of respiration in chronic obstructive pulmonary emphysema. Amer Rev Tuberc 76: 22, 1957. 57. Ermala, P., Holsti, L. ll. Distribution and absorption of tobacco tars in organs of the respiratory tract. Cancer 8: 673, 1955. 58. Fairbairn. A. S., Fletcher., C. M., Tinker, C. M., Wood, C. H. A aom- parison of spirometric and peak expiratory flow measurements in men~ with and without chronic bronchitis. Thorax 17: 168-74, 1962. 305

59. Falk, H. L., Tremen; H. M.,, Kotin, P. Effects of cigarette smoke and its constituents on ciliated mucus-secreting epithelium. J Nat Cancer Inst 23: 999-1012, 1959. 60. Fassett. D. W. Cyanides and nitrites. In : Patty, F. A. ed. Industrial hygiene an& toxicology; Fassett, D. W. and Irish, D. D. eds. Toxi- cology. 2 rev ed. New Y ork, Interscience Pub.,,1962. Chapter 44, p. 1991-2036. 61. Ferris, B. G., Jr., Andersoni D. 0. The prevalence of chronic respira- tory disease in a Niew Hampshire town. Amer Rev Resp Dis 86: 165-77; 1962. 62. Ferris, B. G., Jr., Anderson,, D. 0., Burgess, W. A. Prevalence of res- piratory disease in a Aaxmill in, the United' States. Brit J Ind'ustr Med 19: 180-5,, 1962. 63. Fletcher, C. M. Chronic bronchitis in Great Britain and America. An account of chronic bronchitis in Great Britain with a compari, son between British an& American~ experience of the disease: Dis Chest 44: 1-10; 1963. 64'. Fletcher, C. M. Chronic bronchitis: Its prevalence, nature and path- ogenesis. Amer Rev Resp Dis 80: 4.83{-94;,1959. 65. Fletcher, C. M. Chronic Bronchitis, Smoking andi Aii- Pollution. To- bacco and' Health. Charles C: Thomas, Springfield, Illinois, 1962. p. 380-<101. 66. Fletcher, C. M~, Hugh,Jones, P., McNicol, N. W., Pride, N. B. The. diagnosis of pulmonary emph}-~•sema in the presence of chronic bronchitis. Quart J Me& 32=51, 1963. 67. F1otcher, C. M., Tinker, C. M. Chronic bronchitis; a further stud'y of simple diagnostic method'sin a working populat6on, Brit Med, J. 1: 1491-8, 1961. 68. Flick, A. L., Paton. R. R. Obstructive emphysemal in cigarette smok• ers. AMA Arch Intern Med 104,:518'-26, 1959. 69. Florey, H'., Carleton, H. M., Wells, A. Q. Mucous secretion in the trachea~ Brit J Exp Path 13: 269, 1932. 70. Forsey, R. R., Sullivan, T. J. Stomatitis nicotine. Arch Derm (Chi- cago )i 83 : 945-50, 1961. 71. Foster. D., Gassney. HL An investigation of the retention of smoke particulate matter by inhaling and' non-inhaling type of, cigarette smoker. Presented at the Tobacco Chemists Conference, Hoboken, N.J•,Oct. 1'958. 72. Frank,, N. R., _lmdur, M. 0., Worcester. J., Whittenberger, J. L. Effects of acute controlled exposure to,SO,, on respiratory mechanics in healthy adult males. J Appl Physiol 17: 252-8, 1962. 73. Franklin, W., Lowell, F. C: Unrecognized airway obstruction asso• ciated with smoking,,: A probable forerunner of' obstructivepul- monary emphysema., Ann Inter~n 11ed54: 379-86, 19611. 74.Fneeman. G., Hayd'on, G., Effects of continuous low-]evel exposure to nitrogen dioxide. Presented at California State Department of Public Health Sixth Annual Air Pollution Medical Research Con- ference. Sani Francisco, 1963. 306

75. Fry, J. Chronic bronchitis in general practice. Brit Med J 1: 190-4, 1954. 76. Gold'smith, J. R. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 77. Goldsmithy J. R., Hechter, H. H., Perkins, N. M., Borhani, N. 0. Pul- monary function and respiratory findings among longshoremen. Amer Rev Resp Dis 86: 867-74, 1962. 78. Gray, E. LeB. Oxides of nitrogen: Their occurrence toxicity,, hazardl AMA _krchIndustr Health (Chicago)19~: 479-86, 1959. 79: Gross, P., Hatch, T. Pulmonary clearance: Its mechanism and rela• tion to pulmonary disease. J Occup Med 5: 191-4; 1963. 80. Guillerm, R., Badre, R., Vignon, B. Inhibitory effects of tobacco smoke on the ciliary activity of the respiratory epithelium and nature Bull Acad Nat Med (Paris) 145: 81. Haagen-Sinit, A.J.,, Brunelle;, '.1L F.,, Hara. Ji. Nitrogen oxide content of! smokes from different types of tobacco. AMA Arch Industr Health, (Chicago) 201: 399-100i,1959. 82: Hammond, E. C: Special report to the Surgeon General's Advisory Committee on Smoking and Health. 83. Hatch, T. Respiratory dust retention and eliminatiom Proc Pneumo- coniosis Conf Johannesburg, 1959. p. 133. 84. Hausknecht, R. Experiences of a respiratory disease, panel' selected! from a representative sample of the adult population. Amer Rev Resp Dis 86: 858-66, 1962. 85. Heath, C. W. Differences between smokers and nonsmokers. AMA Arch Intern Med 101: 377-88, 1958: 86. Heimann, H. Effects of air pollution on human health. WH0. Monogr Ser No 46: 159-220„ 1961. 87. Higgins,l. T. T. An approach to~the problem of bronchitis in industry: Studles in agricultural, mining and foundry communities. In: King, E. J., Fletcher, C. M., eds. Symposium on Industrial PulMonary Diseases. London, Churchill; 1960. p. 195-207. 88. Higgins, I. T: T. Respiratory symptoms,, bronchitis, and ventilatoryy capacity in~ random sample of an agricultural population. Brit Med J 2: 1198-1203, 1957. 89: Higgins, I. T. T. The role of irritation in~ chronic bronchitis. In: Orie, N. G. M., Sluiter, H. J. eds. Bronchitis. Springfield, Ill'., Thomas, 1961. p. 31-42. 90: Higgins, I. T. T. Tobacco smoking, respiratory symptoms, and venti- latory capacity. Studies in random samples of the populbtion, Brit Medl J 1!: 325-9, 1959: 91. Higgins, 1. T. T., Cochrane, A. L. Chronic respiratory diseases in a random sample of men and women in the Rhondda Fach in 1958. Brit' J Industr Med 18: 93-102, 1961. 92. Higgins, I. T. T., Cochrane, A. L., Gilson, J. C., Wood, C. H. Popula- tion studies of chronic respiratory disease: A comparison of miners, foundry workers and others in Staveley, Derbyshire. Brit J. Industr Med 16: 255-68, 1959: of the responsible constituents. 416-23, 1961. 307 4,

93: Higgins, I. T. T., Cochran, J. B. Respiratory symptoms, bronchitis and~ disability in a random sample of an agricultural community in Dum- friesshire. Tubercle 39: 296-3011, 1958. 94. Higgins, I. T. T., Oldham, P. D. Ventilatory capacity in miners. A five year follow-up study. Brit J Industr Med 19: 65-76, 1962. 95. Higgins, I. T. T., Oldham, P. D., Cochrane, A. L., Gilson, J. C. Respira- tory symptoms and pulmonary disability in an industrial towm Sur- vey of a random sample of the population. Brit Med J 2: 904-9, 1956. 96. Hilding; A. C. On cigarette smoking, bronchial carcinoma and ciliary action. 2. Experimental study on the filtering action of cow's lung, the deposition of tar in the bronchiall tree and removal by ciliary action. Now Eng J Med 254: 1154r-60, 11956. 97. Hilding, A. C. On cigaTette smoking, bronchial carcinoma and ciliary action. 3. Accumulation of cigarette tar upon artificially produced deciliated islands in the respiratory epithelium. Ann Otol 65: 116-30; 1956. 98. Hill, L. The ciliary movement of the trachea studie& in vitro. Lancet 2: 802-5, 1928. 99: Hogner, R. Tobacco poisoning without using, tobacco. Amer Med 26: 111-2, 1920. 1100: Holland, R. H.,, Wilson, R. H., Morris, D., McCall, M. S., Lanz, H. The effect of cigarette smoke on the respiratory system of the rabbit. Cancer 11: 709 12, 1953. 101. Holland, W. W. A respiratory disease study of industrial groups. Ar&Environi Health (Chicagp)6: 15-22, 1963. 102. Horton, A. W:, Tye, R., Stemmer, K. L. Experimental carcinogenesis of the lung. Inhalation of gaseous formaldehyde or an aerosol of coal tar by C3H mice. J1 Nat Cancer Inst 30: 31--43,1963, ]03, Hyatt, R. E., Kistiny A. D., Mahaw, T. K. Respiratory disease ini southern West Virginia coal workers. Amer Rev Resp Dis (In, Press),. 104. Ide, G., Suntzeff, V., Cowdry; E. V. :k comparisoni of the histo- pathology of the tracheal and bronchial epithelium ofl smokers and non-smokers. Cancer 12: 473-8-1, 1959'.. 105. Jimenez-Diaz, C., Sanchez Cuenca, B. Asthma produced by suseepti} bility to unusual' allergies. Linseed, insects, tobacco, and chicory. J Allerg, 6: 397-403, 1935. 106. Joules; H. A preventive approach to common diseases ofithe lung. Brit' Med J 2: 1259-63, 1954. 107. Keith, C. H., Newsome, J. R. Quantitative studies on cigarette smoke. 1. An automatic smoking machine. Tobacco~ 144: (13) 26r32,. Mar 29'. 1957. 108. Kensler, C. J., Battista, S. P. Components of cigarette smoke with ciliary-depressant activity. Their selective removal by filters con, taining activated charcoali granules. New Eng J Med 269: 1161-66, 1963. 308

ii 109. Kleinerman, J., Wright, G. W. The reparative: capacity of animal lungs after exposure to various single and multiple doses of nitrite. Amer Rev Resp Dis 83: 423-24; 1961. 110. Kler, J. H. An analysis of colds in industry. Tr Amer Acad Opthal Otol 49: 201-7, 1945. 111. Kordik, P., Biilbring, E., Bum, J. H. Ciliary movement and acetyl- choline. Brit J Pharmacol 7: 67-79, 1952. 112. Krueger, A. P., Smith, R. F. Effects of gaseous ions on tracheal ciliary rate. Proc Soc Exp Biol Med 98: 412-4, 1958. 1!l3. LaBelle, C: W., Long, J. E., Christofano, E. E. Synergistic effects of aerosols. Particulates as carriers of toxic vapors. Arch Industr Health (Chicago) 1l1: 297-304, 1955. 11'4. Laennec, R. T. H. A treatise : on the disease of the chest. Translated by J. Forbes. Published under the auspices of the Library of the New York Academy of! Medicine by H'afner, NY 81-97, 1962. 11 5~ Landau, E., Mort'on,, J. An epidemiologic view of! chronic pulmonary insufficiency in~ the United States. Amer Rev Resp Dis83': 405-7, 1961. 16. . Langer, G., Fisher, M. A. Concentration and particle size of cigarette- smoke particles. AMA Arch Industr Health (Chicago) 13: 372-S, 1956, 17. Leese, W. L B. An investigation into bronchitis. Lancet 2: 762-5. 1956. 1J18. Leuchtenberger, C., Leuchtenberger, R., Dooliny P. F. A correlated his- tological( cytologicall and cytochemical study of! the tracheobronchial tree and lungs of mice exposed to cigarette smoke. Cancer 11: 490- 506; 1958. 119. Leuchtenherger, C., Leuchtenberger, R., Zebrun, W., Shaffer, P. A correlated histological, cytological, and cytochemieal' study of the tracheobronchial tree andl lungs of mice exposed to cigarette smoke. 2. Varying responses of major bronchi. Cancer 1'3: 721-32, 1960. 120. Liebeschuetz, H. J. Respiratory signs and symptoms in young, soldiers and their relationship to smoking. J Roy Army Med Corps 105: 76~-81, 1959. 121. Liggett & Myers Tobacco Co., Arthur D. Little, Inc. Special report too the Surgeon General's Advisory Committee on Smoking and Health. 122: Lindsey, A. J. Some observations om the chemistry of tobacco smoke. In : James, G., Rosenthal, T., eds. Tobacco and' Health. Sprinbfield; Ill., Thomas, 1962: p. 21. 123. Loudon, R. G. Special report to the Surgeon General's Advisory Com, mittee on Smoking and Health. 12'F. Lowe, C. R. An association between smoking and respiratory tubercu- losis. Brit Med J 2: 1081-6, 1956: 125. Lowell, F: C., Franklin, W., Michelson, A. L., Schiller, I. W. Chronic obstructive pulmonary emphysema: A disease of smokers. Ann Intern: Medl 45 : 268-74, 1956: 1126, Lowry, T.,,Schuman, L. M. Silo-filler's disease-a syndrome caused by nitrogen dioxide. JAMA 162: 153-60, 1956. I! ~ 309

127: Malfiszewski, T. F., Bass, D. E. True and~ apparent thiocyanate in, body fluids of smokers and nonsmokers. J Appl Physiol 8: 289=91,,195S. 128. Manos, N. E., Cooper, W. C. Special report, to the Surgeoni General's Advisory Committee on Smoking and Health. 129. McFarland, J. J., Webb, B. M. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 130. Mellors, R. C. Microscopic localization of tobacco smoke products in the respiratory tracts of'~ animals exposed to eigarette smoke. [Ab• straet]' Proc Amer Ass Cancer Res 2: 325,1958. 1.31. Mend'enhall, W. L., Shreeve, K. Effect of tobacco smoke on ciliary action. J Pharmacol Exp Ther 69: 295, 1940. The effect of! cig- arette smoke on the tracheal'cilia, Ibid. 60: 111-2, 1937. 132. Merrill, M. H. Public health responsibilities and program possibilities in chronic respiratory diseases. Amer J Public Health 53: (3): (supp)~,25-33; 1963. 133. Mills, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio Med J 46: 1165-70 ; 1950. 134. Miller, D., Bondurant, S. Effects of cigarette smoke in the surface characteristics of lhng extracts: Amer Rev Resp Dis 85 : 692-6, 1962. 134a. Miller, J. M. Special Report to the Surgeon General's Advisory Committee on Smoking,and! Health. 135. Mitchell, R. I. Controlled measurement of smoke-particle retent'ioni in the respiratory tract. Amer Rev Resp Dis 85: 526}33, 1962. 136. Mitchell, R. S. Personal communication to the Surgeon General's Ad- visory Committee on Smoking, and Health. 137. Mitchell, R. S., Filley, G. F. Personal communication to tihe Surgeon General's Advisory Committee on Smoking and Health. 138. Mitcheli, R. S.,Toll, G.,Fill'ey„ G. The earlly lesions in pulmonary emphysema. Amer J'_1led Sci 243I: 4i09-118, 1962. 139. Mork, T. A comparative study of respiratory diseascs in England'and Wales and lorway. Norwegian Universities Press., 1962. Also: ACTA Med!Scand 172(Suppl1384)~: 1-100, 1962: 140! Morris, J. N. Uses of epidemiology. Edinburgh, Livingstone, 1957. 135 p: 141. Moriyama, I. M. Chronic respiratory disease morta]ity in the United States. Public Health Rep 78: 743-8s 1963. 142. Motley, H. L., Kuzman, W. J. Cigarette smoke. Its effect on pulmo- nary function measurements. Calif Med 88!: 211-21, 1958; 143. Murphy, S. D., Klingshirn, D. A., Ulrich, C. E: Respiratory response of guinea pigs during acrolein inhalation and its modification by drugs. J Pharmacol Exp Ther 141: 79-83; 1963. 144. Murphy, S. D., Leng, J. K., Udrich, C. E., Davis, H'. V. Effects on ex- perimental animals on brief exposure to diluted automobile exhaust. Presented at Air Pollution Research Conference, December 9, 1961. California. 146. Nadel, J. A., Coniroe, J. H. Acute effects of inhalation of cigarette smoke on airnvay conductance. J Appl Physiol 16: 713-6, 1961. 310 ~.~_... .. __.

147. Nakashima, T. Pharmacological studies on ciliary movement. Naga- saki Igasakkai Zassi 14: 2219-37, 1936. [Abstract in English] Jap J Med Sci, Sect pharmacoll 11: 42, 1938. 148. Olsen, H. C.,, Gilson,, J. C. Respiratory symptoms, bronchitis and ventilatory capacity in men. An~ Anglb-Danish comparison„ with special reference to differences in smoking habits. Brit Med J 1: 450-6, 19601 149. Oswald, N. C., Harold, J. T:, Martin, W. J. Clinical pattern of chronic bronchitis: Lancet 2: 539-43, 1953. 150. Oswald, N''. C., Medvei, V. C. Chronic bronchitis; the effect of cigarette smoking. Lancet 2: 843~7, 1955. 151. Pattle, R. E: Properties, function, and origin of the alveolar lining layer. Proc Royall Soc Bioli 148: 217-4,0i 1958. 152. Pattle, R. E., Burgess, F. Toxic effects of mixtures of sulfur dioxidee and smoke with air. J Path Bact 73': 411-9, 11957. 153. Payne, M., Kjelsberg, M. Respiratory symptoms, lung function and smoking, habits in a total community-Tecumseh, Michigan. Paper presented before: the Epidemiology Section of the American Public Health Associationi in Miami Beach, October 17, 1962. 154. Pemberton, J., Goldberg, C. Air pollution and bronchitis. Brit Med J 2 : 567-700 , 1954. 155. Phelps, H. W:, Koike, S. Tokyo•Yokohama asthma. Amer Rev Resp Dis 86: 55-63, 1962. 156. Phillips, A. M., Phillips, R. W., Thompson, J. L. Chronic cough: analysis of' etiologic factors in a survey of 1,274 men. Ann Intern Med 45: 216-31, 1956. 157. Proetz, A. Some preliminary experiments in the study of cigarette smoke and its effect upon the respiratory tract. Ann Otol 48: 17Cr 94, 1939. 158. Rakiet'en, N'., Rakieten, M. L., Feldman,, D., Boykin, M. J., Jr. Mam- malian ciliated! respiratory epithelium. Studies with particular ref- erence to the effects of menthol, nieotine,, and smoke of mentholated and nonmentholated cigarettes. Arch, Otolaryng (Chicago) 56:: 494-503, 1942. 159: Read, J., Selby, T. Tobacco smoking and ventilatory function; of the lungs. Brit Med J 2: 1104-8, 1961. 160. Reid, D., Fairbairn, A. S. Air pollution and other local factors in res- piratory disease. Brit J Prey Soc Med 12: 9A-103', 11958. 161. Reid, D. D. Generall epidemiology of chronic bronchitis. Proc Roy Soc 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'y L. Measurement of the bronchial mucous gland layer: A diag- nostic yardstick in chronic bronchitis. Thorax 15: 132111i, 1960. 164~. Reid, L. M. Pathology of chronic bronchitis. Lancet 1: 275-8, 1954. 165. Revotskie;, N., Kannell, W., Goldsmith, J. R., Dawber, T. R. Pulmo- nary function in a community sample. Amer Rev Resp Dis 86: 907=11, 1962. 311

166. Rigdon, R. H. Effect of tobacco condensate on the respiratory tract of the white Pekin~ duek. AMA Arch Path ( Chicago ) 69: 55-63, 1960. 167,Rivera,J. A. Cilia, ciliated epithelium~ and, ciliary activit'y.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 ani 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. Sand'erud„K. Squamous metaplasia of the respiratory tract epithelium. 2. Relation to tobaeco smoking; occupat'ioni and residence. Acta Path Microbiol Scand 43: 47-61, 1958. 172. Saunders; W. H. Nicotina stomatitis of the palate. Ann Otol 67: 618-27, 1958. 173. Schoettlini C: E. The health effect of air pollution on elderly males. Amer Rev Resp Dis $6: 878-97, 1962. 1.75. Shah; J. R., Warawad'ekar, M. S., Deshumkhs P. A.,,Phutane, P. N. In- stitutional survey of pulmonary tuberculbsis with~special reference to smoking habits. Indian J 141ed 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 smokina, on the forced expiratory flow rate. Amer Rev Resp Dis 85: 53-1-9; 1962. 178. Sollmann, T., Gilbert, A. J. Microscopic observations of bronchiolar reactions. J Pharmacoll Exp Ther 61: 272-85, 1962. 179. Stokinger,, H. E., Wagner. W. D., Dobrogorski, 0. J. Ozone toxicity studies. 3. Chronic injury to lungs of animals following exposure at low levels. ANIAArch Industr Health 16: 514-22, 1957. 1'80. Sweet, H. C., Wyatt, J. P., Fritsch, A. J., Kinsella, P. W. Panlobular and centrilobular emphysemasCorrelation of clinical findings with pathologicpatterns. Ann Intern 1VIed 55 : 565-81, 1961. 181. Thoma, K. H. Stomatitis nicotina andi its effects on the palate. Amer J Orthodont 27: 38-47. 194'1. 182: Thuribeck, W. M. A clinsco-pathological study of emphysema in an American hospital. Thorax 18: 59-67, 1963. 1183. Thurlbeck, W. M.. Angus, G. E. The relationship between emphysema and chronic bronchitis as assessed morphologically. Amer Rev Resp Dis 87: 815-9, 1963. 184. Thurlbeck, W. M., Angus, G. E., Pare, J. A. P. Mucous g)and' hyper- trophy in chronic bronchitis, and its occurrence in smokers. Brit~ J DisChest 57: 73-78, 1963:185: Truhart„ H. Ein beitrag zur nicotinwirkung. Dorpat, 1869. Thesis, 70 p.. 186. U.S. Departmentl of Health, Education, and Welfare. Disability ap- plicants under the old-age survivors and disability program. 1960' selected' data; January 1962:

i 137. Von Oettingen, W. F: Toxicity and potential dangers of nitrous fumes. Public Health Bull 2 72: 1-34, 1941. 1f„°,. Vassar, P. S.,, Culling, C:, Saunders; A. M. Flourescent histiocytesin sputum related to smoking. AMA Arch Path (Chicagp) 70': 649-52, 1960. i 9. 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. Westerimark, T. Gaseous ions an& their possible role in the etiology of lung cancer and some observations on free charges in cigarette smoke. Acta Nled Scand 170:: (Suppl 369)1 119-20, 11961. )l. Wolff, W. A., Tuttle, J. G'., Godfrey, JI. M. Radioautographic method for studying deposition of cigarette smoke in the dog,lung. Abstract Fed Prioc 13: 32-1„ 1954. !'-'?. Wolff. W. A., Purd'om, E. G'., Isenhower, J. A. The use of radio- isotopes as tracers in cigarette smoke. NI Carolina Med J 15: ] 59- 63. 1954. '1i3. Wri,htL G. W., Lloyd, T. The pulmonary reaction of normal and emph5-seruatous persons to inhalatroni ofl S0;>, fly ash, and moisture. 3d Air Pollution Research Seminar. ULS. Public HealthService. -~'II. ZameL N'., Youssef, H. H., Prime, F. J. Airway resistance and peak expiratory- flow-rate ini smokers and non~smokers. New Orleans, 1960: Lancet 1: 11237-8. 1961 313' IM

Chapter 11 Cardiovascular Diseases f. ,

Contents r Page INTRODUCTION .................... 317 PERTINEN T PHARMACOLOGY . . . . .. . . . . . . . . 317 GENERAL OBSERVATIONS ON' CORONARY HEART DIS- EASE . . . . . . .. . . . . . . . . . . . . . . . . . . 320. SMOKING AND CORONARY HEART DISEASE ..... 322 SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE. . . . . . . . . . . . . . . . . . . . . . . 325 CHARACTERISTICS OF CIGARETTE SMOKERS . . . . 326 PSYCIIO-SOCIAL FACTORS OF' S11iOKING IN RELATION TO CARDIOVASCULAR DISEASE' . . . . . . . . . . . 327 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . 327 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . 327 REFERENCES . . . . . . . . . . . . . . . . . . . . . . 328 List of Tables TABLE 1. Death rates per 100,000 from arteriosclerotic and degenerative heart disease by sex and age, United States, 1958-60 . . . . . . . . . . . . . . . . 321 TABLE 2. Ratios of mortality rates for coronary heart disease, male smokers to non-smokers, by age and amount smoked, in selected' studies . . . . . . . . . . . 324 316

Chapter 11 INTRODUCTION 0 It has been suggested repeatedly that smoking may have adverse effects on thc eardiovascularsystem. Recently, studies of large groups of people have ,hown that cigarette smokers in particular are more prone to die early of' (.,rtain cardiovascular disorders than non-smokers. Chief among these dis- ''rd'ers is coronary artery disease, and the present chapter deals mostly with subject. The chapter begins with a summary of information about the .wute effects of smoking on the cardiovascular system. This is followed by a ;,; ief account of coronary disease, its frequency in different, kinds of people, :rnd the many factors known or thought to aff'ect the likelihood of its develop: ; mt. The aim here is not to: review critically our knowledge of coronary ~ii~,ease buti only to give baekground'for what follows. Next! is summarized information currently available fromi studw ofl large population groups the association of cigarette smoking with an increased tendency to have ,>ronary disease. There follows a; brief discussion of smoking and non« ~oronarv cardiovascular disease. Finally, there is a short, review of evidence rolatinl- to the questioni of whether cigarette smokers may; as a group, differ 'rom non-smokers in ways not caused by smoking itself. Mortality ratios -howing the associationi between cigarette smoking and deaths from cardio- ascular disease, especially coronary disease, do not indicate the magnitude ,41 t'he burden. This can, be better appreciated from considerationi of the foiloicing, facts: cardiovascular disease deaths now, total more than 700,000 .urnrually in the United States. Of these more than 660,000 were due to heart di'sease;, with more than 500,000 due to arteriosclerotic heart't disease inelud- ingcoronarydisease. The remaining approximately 40,000 were ascribed to disease of other parts of the cardiovascular system. Deaths from lung rancer 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 thee much higher lung cancer mortality ratio of 10:8 from the same studies repre- sents only 1I3'.5 percent to 24.0 percent of total excess deaths (Chapterr 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 1-2 mg of nicotine from a cigarette (5f, 57). Low concentrations of nicotine stimulate sympathetic ganglia„ and high concentrations paralyze them: Parasympathetic ganglia respond in the same way but are less sensitive. Nicotine 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 andi aortic bodies. When nicotine is given intravenously in in- creasing doses to dogs or cats the first effects, at about 1 mierogram,/kg body Weight, are increased' breathing an& sympathetic stimulation, with predomi- nant vasoconstriction, cardiac acceleration, and rise im 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 produces an increased urinary excretion of catechol6mines (84, 99). Smoking 1~--2 cigarettes causes in most persons, both smokers and non- smokers, am increase in resting heart rate of 15-25 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 1/min/sq~m (75). There is a decrease im digital blood flow and a consequent dFop in finger and toe temperature (31, 78, 103)~. The decrease in peripheral blood flow which normally follows smoking does not occur in a sympatliectomized lfmb, in- dicating that the effect is mediated primarily by the sympathetic nervous svstem rather than through the release of catecholamines fromi 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 prodtice 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)!. Relatuvelylittle 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 2). 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 gatherect 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 adininist'ration of! nicotine, but demonstrates less of a: . subsequent increase above the resthng, levell 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 produeedl by smoking or br the intravenous injiection, of an equivalent dose of! nicotine (82, 98). In sorne persons there:is a slight depression of the S-T segment and a flattening of 1-2 mm in the T wave of the limb leads. These changes are not like those associated with myocardial ischemia. Rarely in persons with true angina. an attack of paim 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, whodo not have organic heart disease, but it is rarely diagnosed today(73, 82)~. Extras?;stolesand other cardiac arrhythmias have been reported to be caused hv smoking, but! such cases appear to be unusual. The ballistocardiogram obtained from a high-frequency table is some- times,changed by smoking a cigarette from a normal patterm t'o; one said too he typical of coronary disease (78, 91)1.. This phenomenon is rare inihealthy persons belbw 50,, becomes increasingly common with advancing years ini apparentll° healthy persons, but is particularly proneto, occur ati any age inuersons with actual coronary disease. The effect has been used as a "stress roat" to help uncover coronary disease; but false positive and negative results a--e commom The ballistocardiographic changes on smoking have been ariously interpreted as resulting from impaired myocardial contractility 781, from changes in the peripheral circulatfion (82), or from uncertain au~ .es related to the physicall properties of the high-frequency table as well aS changes in the circulation. Cigarette smoking causes an increase in the concentration of! serum-free fatty 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 rholcsterol, phospholfipids,, 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 stimulationi of' the sympathetic nervous system or by administration ofepinephrine(1I2, 13, 14), but att'emptsto demonstrate that ci=arette smoking alters the clotting,properties of the blbod in man have been unsuccessful (5, 68). A decrease in platelet! survivaU in viwo has been found after smoking (68). Cigarette smokers have been reported.to show substan- tial decreases in hematocrit, hemoglbbin, and platelet counts after abstinence of 1I-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 success (93). Tobacco has antigenic properties (29, 93'). Rats can be sensitized to to- bacco extracts by intraperitoneal injection. Over a third of smokers demon~ strate a positive "immediate" skinireaction to such extracts while only about 1V'r 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 319

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 excitationi of the sympathetic nervous system. No additional or unique cardiovascular effects have been demonstrated whieh. in, the light, of our present understanding, seemilikelyto account for the observed association of eigarettesmoking with ani increased incidence of coronary disease. GENERAL OBSERVATIONS ON CORONARY HEART DISEASE Hearrt' disease is the most common cause of death in our population, and coronary disease is the commonest variety of fatal heart disease (59)i. In 1961 there were 1,701,522 deaths from all causes in the Unite&States.Heartdisease 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, redtrcingtheblood supply to the.heart muscle. The underlying cause of the obstruction is coronary atherosclerosis, but an acute coronary artery occlu, sion is often eaused! by theformat~ionof a~ blood clbti in a dfisease& artery. The common manifestations of coronary disease are angina pectoris, recur- rent brief attacks of chest pain caused by inadequate blood supply to the heart' muscle; my,ocardiali infarction, or necrosis of a portion of the heart muscle due to acute loss of blood supply; congestive heart failure,,a chronic state caused! by inability of the heart to pump enough blbod to satisfy the demands of the body;, and sudden death resulting from cardiac standstilll or ventricular fibrillation. There are considerable differences in the prevalence of coronary heart disease in different countries, and'ofteni in different ethnic and socio-economic: groups within a particular country (4fi; 62). The reported death rate of arteriosclerotic heart disease, which is primarily coronary disease, is hiaher in the Unite& States thani in other countries. It is also quite high in New Zealand, Australia, South Africa; Canada, and Finland; and moderately high, in Great B'ritain. The death rate in Norway,,Sweden, and Denmark is roughly half that in the high death ratecountries115/., The death rate in Japan appears to be about one-sixth that in the United States, although persons of Japanese origini living in the United! States are said to have a-death rate similar to that' of the general population of this country (52). Because ofl changing diagnostic skills and revisions in nomenclature of disease, it is difficult tobe certain, of the change in incidence of coronary disease inithe United States over the past few decades, but there is a general opinion that the incidence is increasing in this country and in England, 320

part'icularly in the younger male group (59, 62, 65, 83). In 1955 the nnortalitv rate from arteriosclerotic heart disease was reported to be about 240 19e r 100.000: Although this is an increase of more than 50% over the rate in 1940, it has been estimated that less than, 15% of the increase represented a real change in incidence of the disease, the remainder depending upon Ohan=es in diagnosis, in nomenclature and in the age ot the population (59). ince 1955 the death rate from coronary disease (ISC 420) and from :!rteriosclerotic and degenerative heart disease (ISG420 and 422) has con- ±inued to increase gradually. In~ 1960 the age-adjusted death rate from 420 ird 422 was 330 per 1'00;000 for white males and'150 for white females (55). Although the basic cause or causes of coronary heart disease are obscure,, ertain f'actors other than smoking,are known or thought to predispose to the ~()ndition or tobeassociat'ed with an increased incidence. The incidence of coronary heart disease in men under 45 is about 5 times sgreat as that in wonien (Table 1) (15„20, 59, 62). In both sexesthe inci- dence increases with advancing years. After the menopause the incidencee increases rapidly in women, and at age 80 the death rates from coronary ,'isease are about the same for the two sexes. Coronary thrombosis plays a relatively more important role in precipitating myocardial infarct2on in young ,cen than it does in old men (105t.In studies of large population groups :~ronary disease has been associetedl with elevation of the serum~ cholesterol„ n}lertension„and marked overweight (19, 20; 24, 36, 46, 59, 62). ~ome individual characteristics have been said'to be associated with coro- ~.rrv disease. There is a: significant familial tendencytbdeveiopit (36, 69, '1~1. ')6). Persons with a mesomorphic constitution are said to be more vul- erahlethan endomorphs and! ectomorphs (136, 62, 88). A coronary-prone; ier onality has been described as the aggressive, competitive person who takes ,-n too many jobs, fights deadlines, and is obsessed by the lack of adequate tirne for the perfbrrnance of his work (33, 34, 35)~. r%a:I,F 1. Deatli rates per 100,000 f,rom arterioseleroticand' d'egenerative, heart~ dis~ease* by sex and', age, L/nited~ States, 1'958--W e,~Group Malfs FemalesBoth Sexes Under 35------------------------------ 3.3 1.2 2.2 3'-44, --------------------------------- 90.2 18.3 53.3 -1'5-54 --------------------------------- 353.7 79.3 213.5 55-64 --------------------------------- 928.5 314.5 610.2 6.5-74 --------------------------------- 2129.2 1082.0 1569.5 75 or over------------------------------ 4765.1 3738.4 4179.7 k tnclhdes ISC numbers, 420 and 422. ~ource: W'HOO.I Epidemiologioal and Vital Statistics~ Report, Vol. 16, No. 2, 1963. Certain occupations have been said particularly to favor the development! of corouary disease, notablly those which feature responsibility and stress 1 3 )4, 81, 871~, and' w•hichare sedentary in nature (7). Others (58, 7~2, 90) 1iave not found that executives are more prone to coronary disease than non- executivepersonnel. Physicians have been said to have 3 or 4 times as much coronary disease as farmers or laborers (87), and generall practitioners 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 menwho drove more than 12,000 miles a year seemed, in one study, moree prone to the disease than those who drove less ('64)1. 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)1. A correlation between the national incidence of coronary disease and the percentage of food calories available as saturated f'at~ has been re- ported'among those countries for which adequate data exist (46) . The serum cholesteroli 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'environment'al factors can markedly affect the incidence of coronary disease. SMOKING AND CORONARY HEART DISEASE Over thelhst two decades a considerable number of' epidemiologie studies om diflerent populations, employing different techniques, have shown with remarkable consistency a sigpificant 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: (26), found the incidence of coronary disease: in male patients at the Mayo Clinic about 3 tirnesgreaterincigarette smokers than in non-smokers in the 40-59 year age range, but found little relation to smoking above 60. Russek (81)~ reporte& a similar relationship; but less striking, in young men~~ with coronary disease. Mill's (64)iii a study of reported mortalit'yy in a Cincinnati population foun& that heavy smokerss in the30a-59year 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 Wynder and Lemon (104)~ in a stlidy based on hospital admissions to have significantly less coronary disease and! to de• velop it later in life thani the general male hospitali population. Haag and Hanmer ('37) reported that employees in the tobacco industry, who tend to smoke heavily, hadi a lower death rate for cardiovascular disease than the generali population in 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 thisand otherrrounds (16). Large-scaleprospect'ive studies of mortality in British physicians (Doll arid Hilly 21), Unit'ed States males 50-69 recruited by volunteer workers

li (Hammond andl Horn, 3$; 39; 40;,42) and V.A. Life Insurance policyholders Dorn, 22) have confirmed the association of death froml coronary disease ~sithl cigarette smoking, In the British study, a step-wise association was found between the amount of tobacco consumed (not entirely,cigarettes) and the mortality from coronaryy disease. The association occurred in the : .,)-54 year age range, but not in older men. Hammond and Horm found a similar grad'ed' relationship between coronary deaths and cigarette smok- in,,,: the death rate being more than twice as great in men who smoked ,ver a pack a day as in non-smokers. Men who: had stopped smoking for nore than a year at the start of the study had a coronary d'eathl rate lower tlian those who continued. Studies on special groups of men, suchl as longshoremen (Buechley et al. t; i members ofl a fraternal order (Spain and Nathan, 89;)l andl industrial employees(Paull et al. 71)whieh, in the latter two instances: incorporated clinical coronary disease, as well as coronary deaths, also have shown a relationship between coronary disease andl smoking. The relationship was cl'oser forr menl under 51 than for older mens and closer for myocardlal 'nfarcts anddeath than for angina pectoris (70, 89). The long-term, prospective studies of cardiovascular disease in Framing- i.anr(19) andl in Albany (24)! which have: featured a painstaking searchl at regularintervals for clinieall manifestations of disease: have, on pooling the. ,11{ta (Dor1e et al. 23) shown a threefold increase in the incidence of myocardial infarction and coronary deaths in men who are heavy ciga- rette smokers as comparedl to non-smokers, pipe and ciaar smokers, andl former cigarette smokers. In the pooled data the incidence of angina liec- toris did not show a significant association with cigarette smoking. The lack of this particular relationship hadl beeni suggested on the basis ofl clinicallexperience (White and Sharber, 102). r1ni apparent intcrplar-y of factors relat'~ingto smoking and occupation turned up in al short-term studv of' the development of coronary heart dis- easein a general North Dakota populationi (Zukel et alL, 107)i. Farmersharl about half the incidence of myocardial infarction experienced by others. ln farmers. smoking had no appreciable effect on the incidence of infarc- tion. but' ini others the incidence of' infarctioni was twice as high among smokers as among the non-smokers. The farmers who smoked cigarettes smoked less heavilv than males in other occupational groups. In Chapter 8, Mortality, there is summarized the: most recent infbr- mation av.ailablefrom 7 large completed or current prospective smok~ingand death rate studies (Doll and Hill; Hammond arid Horn; Dorn; Dunny Linden and Breslow; Dunn; Buell and Breslow; Best, Josie, and'W'alker; and Hammond ). The median mortality ratfio for coronary disease of current cigarette smokers to non-smokers is 1.7 (range 1.5-2.0~). Table 2 presentsdatai from some of the large prospective studies onl the ratio of mortality rates due to coronary heart disease of male smokers to nonl-smokers, by age and amount smoked. The ratios tend in general to increase with amount smoked and to, decrease with advancing a,e: The data froin the first 22 months of Hammond's (41)cur~rent studyhell> to~ show the size of the eoronar~yproblem. For this purpose, actual numhersof deaths may,he more informative than mortality ratios. Of nearly 32:; . .r 1 I

TABLE 2: Ratios o f, mortality rates /,or coronary heart disease, male smokers to'non-smokers, by age and amount smoked, in sel'ectedstudies HAMAfO>ID~AND HORN-1958 (42) Cigarettes smoked per day Age ~. Group Less than 10~~ 10-19' 50-54----------------------------------- li 4 2:0 55-59---------------------------------------- 1.4 2.0 60-Fr1~..--------------------------------------- 1.2 1.9 65-69.- ------------------------------------- 1.3 1.6 Total (age adjusted) ----------------_----- 1.29 1.89 20 and over BUECHLEY, DRAKE, BRESLOW-1958'(8)' I 35-d4---------------------------------------- 45-54---------------------------------------- 55-84---------------------------------------- 65-7C --------------------------------------- L ------------------------------- --------------------------------- --------------------------------- --------------------------------- 2.0. 2.8' 1!8'. 0.9 FRAMINGHAM STUDY-19fi4 (47) 30a-62---------------------------------------- (less than 20) 1.5 (20 and!over)3.2 D ORV-1959 (22) Total (age adjusted)------------------------ ~ 1.321 1.76 1 1.75 DOLL AND HILI-1956 (21) Age Group Grams of tobacco smoked per day 1-1i Grams 15-24 Grams~~ 25.or more Grams 35-54---------------------------------------- 2.2 ' 3.3 4.2 55-fr1------------------'-------------------- 0.9 0.6 1.0 65-74---------------------------------------- 1.0 0: 9 1.3 75+F _ ---------'--------'--------------- 113 115 1.6 Total (age adjusted).- ---------------_-----_ 11 l i 1:1' 1.4'. ' Persons smoking 1 pack per day or more compared with those smoking less than t Ipack per day (including non-smokers). 10;000 deaths of men aged 45--79, 46 percent were ascribed to coronary. disease. 51.7 percent of the 2,630 "excess deaths" associated with cigarette smoking were caused by coronary disease: In approximate terms, nearly half of middle-aged and elderly males in the Uhited States die of coronary disease. About half of these males smol:e cigarettes. Cigarette smokers hacebeenfounJ in several studies~to have1.7 times as high a: coronary death rate as non-smokers. If cigarettes actually caused the additional coronary deaths of smokers, they would account for many deaths of middle-aged' and elderly males ill this country. Like other studies (19; 21, 22,, 23, 42), this one shows that the ratio of snlokers' coronary deathrat'es to those of non~ smokers inc.reases progre_,siAclyw•ith the daily cigarette consumption. In add2t'ions at each level of consunlptionvthcratioihcreases with theanlount of'inhalation reported by the smokers. Others (21„23; 26, 89) , have indicated 324

that the risk of'~ death from coronary disease:in male cigarette smokers relative tn that in non-smokers is greater in~middle age than old'age, and Hammond's rurrent study supports this. The mortality ratio was 3,09 in the age range h)---19, and in successive decades was 2.20, 1.58; and 1.38. Mien who stop smoking, have a lower d'eath rate from coronary disease t}lanthose who continue (23, 42, 47). In the study of Hammond and Horn 1 -1'l) the decrease in death appeared only 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 over-all relationship with smoking,. snd the association has not been strong in other studies (71, 89)i. In surmnar}: a significant association has been established between cigarette -Wc~king and the incidence of myocardial! infarction and sudden death in ;ale~. especially in middle life, in population groups whose members appear far to be similar except for smohinghabits. The question of whether they re. in fact, similar except for smoking is, of course, basic to.the problem of' ~.%-hethercigarettesmoking, actually promotes thedevelopment~ of coronary ,iisea~e or whether it is closely associated witLsome other factor or factors -., hich promote the development of eoronarydfisease. It has been pointed out .hat angina pectoris, which indicates advanced coronary atherosclerosis, is. ~ closely associated with cigarette smoking than is myocardial infarction, .:::d that this suggeststhat any etiologic role of~smoking inmyocardialinfarc- ti,~n shoulde reiate more to~acute occlusive mechanisms, such as intravasculariirombosisor coronary spasm, than to the development of chronic art'erial I', <ea se. SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE In survevs of large groups cigarette: smoking has not been found to be a"ueiated with an increased prevalence of hypertension (,3, 4, 19,, 47, 49). The study of Hammond and Horn (140; 42) did not showani increased death rate f'sorn hypertension in smokers: However, Dorni {221f~ound that thecleath rate of cigarette smokers fromi hy,pertensionwith heart disease was 1.53' times that of non-smokers, and from hypert'ension without heart dis- ease. 1.41 times that of non-smokers. Harumond's current study shows:, -iinilar figures141 I~. Sinoking~ has not been found to be associated Ntiith an increased' mortalitiyrate flromchronic nheumaticheart disease (22, 41, 42). Ilammondl and Horn1-12)found a modierateincrease in the mortalityrate from: cerebral vascular disease in cigarette smokers as compared to: !iwn-mokens 1 ratio 1.301. Dorn (22)reported a ratio of 1.33, and Ham- nannd (41 i a ratio of 1.43. Although non.s.-philitie aorticaneurysm is arel<iti% ek infrequent causeofl death, the mortalfityy ratio, for smokers to non-sniokers inthi~diaf;nosticcategory is large in relation t'othe ratiosin, other cardiovasc.ular disorders, In, the study ofH'ammond and Horn (42~) ~ it was 2.72. and'in Hammond's-current study (41)l it, is 3.10. 3 2 J

It has been reported (100) that diabetic males who smoke: have a 50'r/ogreater incidence of clinically detectable arteriosclerosis obliterans in the legs than those who; do: not smoke. In general, however, there is little inflormationi 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 thromboangifitfis obliterans, has been traditionally associated with smoking, anJ the literatureI contains numerous clinicall re- port's 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- centlychallenged, (1©1), but welli defended! (61). It is apparent that! much more work will have to be done to determinee what relationship may exist between non~coronary occlusive vaseular dis- ease, aneurysmal disease, and smoking. CHARACTERISTICS OFCIGARETTE SMOKERS If it could be shown, that': cigarette smokers and non-smokers had signifi- cant constitutional differences apart from any differences that might be cause& by smoking itself, then a; possibilityv would exist', that some predisposition of smokers to a parrticular disease might also be of constitutional origini and not caused by smoking, Cigarette smokers have, ini fact, been foundl to differ as a group from non~smokers, but the differences, such as serum cholesteroU concentrationi 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 foundlto 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 thab serumi cholesterol was higher in smokers thani 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, 49). A few personality differences have been reported between cigarette smokers and non.smokers. Friedman's type A men (the coronary type) tended to be heavy smokers (33):. Smokers are said to be more easily angeredi and to eat more when under stress (i94)~. They havebeen reported to marry oftener, to change jobs more frequently, to be more often hospitalized, and tb~ par- ticipate more actively in sports than non-smokers (60). Thomas (94, 951 has reported that the parents of inedicat students who smoke have a significantly higher incidence of arteriosclerotic and hyper- tensive cardiovascular disease thani parents of non-smokers. Clearly, this findinn is open to more than one interpretation. Smokers tend to have a higher heart rate than non-smokers (3, 94) . The matter of constitutional predisposition tosmokinghas been inves- tigated' in twins. It has been found (27, 28. 321 that the smoking habits of monozygotic twins are significantly more alike than those of dizygotic twins, even when members of a twin 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 est'ablished. The constitutional hypothesis, which links smoking, and predis- position to disease, is discussed in,detaillin Chapter 9, Cancer. PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO CARDIOVASCULAR DISEASE' Even less conclusve information is available on the rolo of psycho-social factors of smoking in relatfiomto cardiovascular disease. Studies which have focussed onithis are limitediin number according to Heinzelmann (44). Even fewer, he founds are those which have specifically examined the relative „•eight of, these variables or their interaction. Reviewing those available,, lie observes that the evidence is highly fragmentary and uncertain. The findings sungest that the relationship between smoking behavior an&coronary. !ieart di'sease may reflect the influence of stress factors and/or personality mechanisms. However, they permit no definitive statement's with respect to~ the relative role of pyscho-social factors and smoking in relation to etiolo~y of the disease. SUMMARY Smokinr and nicotine administration cause acute cardiovascular effects. ,irnilar to those induced by stimulation of the autonomic nervous syst'em, but these eff'ects do not account well for the observed association between cigarette smoking and coronary disease. It is established that male ciga- iette smokers have a higher death: rate f'rom~ coronary disease than non- smoking males. The association of smoking, with other cardiovascular disorders is less well established. If cigarette smoking actually caused the hiorher death rate from coronary disease, it would on this account be responsible for many deaths of middle-aged and elderly males in the Unite& States. Other factors such as high blood pressure, high serum cholesterol, andl excessive obesity are also knowm to be associatedl withi 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 reasoni for taking countermeasures against them. It is also more prudent to assume that the established association betweeni ciga• rette smoking and coronary disease has causative meaning than to suspend iudgment until, no uncert'ainty remains. CONCLUSION 1'Iale cigarette smokers have a hiaher deathi date from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance: 327 O W ~ ~ Cl1 CD O N

REFERENCES 1. Acheson, R. M., Jessop, W. J. E. Tobacco 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 myocardial met'abolism: Circulation 15: 2511-257, 1957. 3. Blackburn, H., Brozek, J., Taylor, H. L. Common circulatory meas- urements ini smokers and nonsmokers. Circulation, 22: 1112-1124, 1960: 4. Blackburn, H. W:, Brozek, J., Taylor, H. L., Keys, A. Cardiovascular and relratedl 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: 448-451, 1959. 6. Bronte-Stewart, B. Cigarette smoking and ischaemic heart disease. Brit Med J 1: 379-385, 1961. 7. Brunner, D,, Manelis, G. Myocardial infarction among members of communal settlements in Israel. Lancet 2: 1049-1050, 1960. 8. Buechley, R. W., Drake, R. M., Breslow, L. Relationship of amount of cigarette: smoking to coronary heart disease mortallty rat'es in men. Circulation 18: 1085-1090, 1958. 9. Burn; J. H. Action of nicotine on the heart. Ann N Y Acad Sci 90: 70-73, 1960. 10. Burn; J. H., Leach, E. H., Rand, M. J., Thompson, J. W. Peripheral effects of nicotine and acetycholine resembling thoseofe 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!: 1!37-139, 1958. 12. Cannon, W: B.. Gray, H. Factors affecting the coagulation time of blood. II. The hastening, or retarding of coagulationi by adrenalin injections. Am J Physiol 31: 232-242, 19114. 13. Cannon, W. B., Mendenhall, W. L. Factors affecting the coagulation time of blood. III. The hastening of coagulation by stimulating the splanchnic nerves. Am J Physiol 34: 243-250, 1914. 14. Cannon, W. B., Mendenhall, W. L. Factors aff'ecting the coagulation time of blood. IV. The hastening of' coagulation in pain and ema tional excitement. Am J Phgsioll34: 251-261', 1914. 15. Cardiovascular diseases mortality, 1954-1956, 1'958-1!960. WHO. Epidemiolbgical Vital! Stat Rep16c 115-205, 1963. 16. Case, R. A. M. Smoking habits and mortality among, workers in ciga- rette factories. Nature (London I 1811: 84-86;, 1958. 17. Comroe, J. H., Jr. The pharmacological actions of nicotine. Ann N Y Acad Sci 90: 48-51, 1960. 18. Damon, A. Constitution and smoking. Science 134: 339-341, 1961. 328