REPORT OF THE ADVISORY COMMITTEE 

TO THE SURGEON GENERAL 

OF THE PUBLIC HEALTH SERVICE 

U-23 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 
Public Health Service Publication No. 1103 

For sale by the Suprrintendent of Documents, U.S. Government Printing Office 

U~ashingmn. D.C., 20402 - Price $1.25 
THE SURGEON GENERAL’S ADVISORY 

COMMITTEE ON SMOKING 

AND HEALTH 

Stanhope Bayne-Jones, M.D., LL.D. 

Walter J. Burdette, M.D., Ph. D. 

William G. Cochran, M.A. 

Emmanuel Farber, M.D., Ph. D. 

Louis F. Fieser, Ph. D. 

Jacob Furth, M.D. 

John B. Hickam, M.D. 

Charles LeMaistre, M.D. 

Leonard M. Schuman, M.D. 

Maurice H. Seevers, M.D., Ph. D. 

. . . 

111 
COMMITTEE STAFF 

Professional Staff 

Eugene H. Guthrie, M.D., M.P.H. Peter V. V. Hamill, M.D., M.P.H. 

Staff Director Medical Coordinator 

Alexander Stavrides, M.D. Jack Walden 

Special Assistant to the Director Information Officer 

Mort Gilbert Jane Stafford 

Editorial Consultant Editorial Consultant 

Helen A. Johnson Benjamin E. Carroll 

Administrative Oficer Biostatistical Consultant 

Secretarial and Technical Staff 

Helen Bednarek Alphonzo Jackson 

Mildred Bull Jennie Jennings 

Grace Cassidy Martha King 

Rose Comer Sue Myers 

Jacqueline Copp Irene Orkin 

Adele Rosen 

Margaret Shanley 

Don R. Shopland 

Elizabeth Welty 

Edith Waupoose 

iv 
Foreword 

Since the turn of the century, scientists have become increasingly interested in the effects of tobacco on health. Only within the past few decades, 

however, has a broad experimental and clinical approach to the subject been 

manifest; within this period the most extensive and definitive studies have 

been undertaken since 1950. 

Few medical questions have stirred such public interest or created more 

scientific debate than the tobacco-health controversy. The interrelationships 

of smoking and health undoubtedly are complex. The subject does not lend 

itself to easy answers. Nevertheless, it has been increasingly apparent that 

answers must be found. 

As the principal Federal agency concerned broadly with the health of the 

American people, the Public Health Service has been conscious of its deep 

responsibility for seeking these answers. As steps in that direction it has 

seemed necessary to determine, as precisely as possible, the direction of 

scientific evidence and to act in accordance with that evidence for the benefit 

of the people of the United States. In 1959, the Public Health Service 

assessed the then available evidence linking smoking with health and made 

its findings known to the professions and the public. The Service’s review 

of the evidence and its statement at that time was largely focussed on the 

relationship of cigarette smoking to lung cancer. Since 1959 much additional data has accumulated on the whole subject. 

Accordingly, I appointed a committee, drawn from all the pertinent 

scientific disciplines, to review and evaluate both -this new and older data 

and, if possible, to reach some definitive conclusions on the relationship between 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 complicated and the pressures of time on eminent men busy with many other 

duties has been great. I am aware of the difficulty in writing an involved 

technical report requiring evaluations and judgments from many different 

professional and technical points of view. The completion of the Committee’s task has required the exercise of great professional skill and dedication of the highest order. I acknowledge a profound debt of gratitude to the 

Committee, the many consultants who have given their assistance, and the 

members of the staff. In doing SO, I extend thanks not only for the Service 

hut for the Nation as a whole. 

SURGEON GENERAL 

” 
Table of Contents 

FOREWORD . . . . . . . . . . . . . . . . . . 

ACKNOWLEDGMENTS . . . . . . . . . . . . . 

PART I INTRODUCTION, SUMMARIES AND 

CONCLUSIONS 

Chapter 1 Introduction . . . . . . . . . . . . 

Chapter 2 Conduct of the Study . . . . . . . . 

Chapter 3 Criteria for Judgment . . . . . . . . 

Chapter 4 Summaries and Conclusions . . . . . 

PART II EVIDENCE OF THE RELATIONSHIP 

OF SMOKING TO HEALTH 

Chapter 5 

Chapter 6 

Chapter 7 

Chapter 8 

Chapter 9 

Chapter 10 

Consumption of Tobacco Products in the 

United States . . . . . . . . . . . . 

Chemical and Physical Characteristics 

of Tobacco and Tobacco Smoke . . . . 

Pharmacology and Toxicology of Nicotine . . . . . . . . . . . . . . . . 

Mortality . , . . . . . . . . . . . . 

Cancer . . . . . . . . . . . . . . . 

Non-Neoplastic Respiratory Diseases, 

Particularly Chronic Bronchitis and Pulmonary Emphysema . . . . . . . . . 

Cardiovascular Diseases . . . . . . . 

Other Conditions . . . . . . . . . . 

Characterization of the Tobacco Habit 

and Beneficial Effects of Tobacco . . . 

Psycho-Social Aspects of Smoking . . . 

Morphological Constitution of Smokers. 

Chapter 11 

Chapter 12 

Chapter 13 

Chapter 14 

Chapter 15 

Page 

V 

ix 

3 

11 

17 

23 

43 

47 

67 

77 

121 

259 

315 

335 

347 

359 

381 

vii 
ACKNOWLEDGMENTS 

During this study the -4dvisory Committee on Smoking and Health has 

had the constant support of individual s. groups and institutions throughout 

a broad range of professional and technical occupations. In many cases 

the contributions of these individuals involved considerable personal. professional or financial sacrifice. In every case the contributions lessened the 

burden of the Committee and increased the authorit>- and completeness of the 

Report. In this space it is impossible to assign priorities or special emphasis 

to individual contributions or contributors. The Committee. however, does 

acknowledge with gratitude and deep appreciation-and with sincere 

apologies to any individual inadvertently omitted--the substantial cooperation and assistance of the follo\ving: 

ACKERMAN, LAUREN, \I.D.-Professor of Pathology, Washington University 

School of Medicine, St. Louis, MO. 

ALBERT, ROY E., M.D.--Associate Professor, Department of Industrial Medicine, New York University Jledical Center, New York, N.Y. 

ALLEN, GEORGE V.-President and Executive Director, The Tobacco Institut3, Inc., Washington, D.C. 

ALLING, D. W., M.D.-Statistician, National InsGtute of Allergy and Infectious Diseases, U.S. Public Health Service, Bethesda, Md. 

AMERICAN CANCER SOCIETY, New York, N.Y. 

AMERICAN TOBACCO Co., lYew York,N.Y. 

AXDERSON, AUGUSTUS E., Jr., M.D.--Senior Attending Internist, Research 

Laboratory, Baptist Memorial Hospital, Jacksonville, Fla. 

ANDERVONT, HOWARD B., SC. D.-Chief, Laboratory of Biology, National 

Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

ARTHUR D. LITTLE, INC., Cambridge, Mass. 

ASCARI, WILLIAM, M.D.-Pathologist, Presbyterian Hospital, New York, N.Y. 

AsHFoRD, THOMAS-P., M.D.-Instructor in Surgery, College of Medicine, 

University of Utah. Salt Lake City, 1.tah. 

ASTIN, ALEXANDER W., Ph. D.-Research Associate, National Merit Scholarship Corporation, Evanston, Ill. 

?I~ERB.~CH, OSCAR, M.D.-Senior Medical Investigator, Veterans Administration Hospital, East Orange, N.J. 

ljAIL&R, JOHN C. III: &M.D.-Head, Demopraphv Section, Biometry Branch, 

National Cancer Institute, U.S. Public Healih Service. Bethesda, Md. 

NhTTIST~, S. P.-Pharmacologist, Arthur D. Little, Inc., Cambridge, Mass. 

AEARMAK, JACOB E., Ph. D.-Professor of BioFtatistics. L’nirersit! of >linnesota School of Public Health, Minneapolis, Mimi. 

REERE, GILBERT W., Ph. D.-Statistician, National Academv of S(+nres. Rjational Research Council. Washinpton, D.C. 

ix 
BELL, FRANK A., Jr.,-Program Director for the Engineer Career Development Committee, Office of the Chief Engineer, U.S. Public Health Service, 

Washington, D.C. 

BERKSON, JOSEPH, M.D.-Head, Division of Biometry and Medical Statistics, 

Mayo Clinic, Rochester, Minn. 

BEST, E. W. R., M.D., D.P.H.-Chief, Epidemiology Division, Department of 

National Health and Welfare, Ottawa, Canada. 

BLUMBERG, J., Brig. Gen.-Director, Armed Forces Institute of Pathology, 

Washington, D.C. 

BOCKER, DOROTHY, M.D.-Bibliographer, Reference Section, National Library of Medicine, U.S. Public Health Service, Bethesda, Md. 

BRAUNWALD, EUGENE, M.D.-Chief, Cardiology Branch, National Heart 

Institute, U.S. Public Health Service, Bethesda, Md. 

BRESLOW, LESTER, M.D.-Chief, Division of Preventive Medical Services, 

California Department of Public Health, Berkeley, Calif. 

BROWN AND WILLIAMSON TOBACCO CORP., Louisville, Ky. 

BROWN, BYRON WM., Jr., Ph. D.-Associate Professor, Biostatistiea Division, 

School of Public Health, University of Minnesota, Minneapolis, Minn. 

BUTLER, WILLIAM T., M.D.-Clinical Investigator, Laboratory of Clinical 

Investigations, National Institute of Allergy and Infectious Diseases, U.S. 

Public Health Service, Bethesda, Md. 

CANADIAN DEPARTMENT OF NATIONAL HEALTH AND WELFARE, Ottawa, 

Canada. 

CANADIAN DEPARTMENT OF VETERANS AFFAIRS, Ottawa, Canada. 

CARON, Herbert S., Ph. D.-Cleveland Veterans Administration Hospital. 

Cleveland, Ohio 

CARNES, W. H., M.D.-Professor and Head of Department of Pathology, 

College of Medicine, University of Utah, Salt Lake City, Utah. 

CARRESE, LOUIS M.-Program Planning Officer, National Cancer Institute, 

U.S. Public Health Service, Bethesda, Md. 

CASTLEMAN, BENJ.4MIN, M.D.-Department of Pathology, Massachusetts 

General Hospital, Boston, Mass. 

CHADWICK, DONAI.D R., M.D.-Chief, Division of Radiological Health, U.S. 

Public Health Service, Washington, D.C. 

CLARK, KESNETH, Ph. D.-Consultant, Office of Science and Technology. 

Executive Office of the President, Washington, D.C. 

COBB, SIDNEY, M.D.-Program Director, Survey Research Center, Universityof Michigan, Ann Arbor. Mich. 

COMROE, JULIUS H., M.D.-Professor of Physiology and Director of the 

Cardiovascular Research Institute, University of California, San Francisco. 

Calif. 

COONS CARLETON S., Ph. D.-Curator of Ethnology, University of Pennsylvania Museum, Philadelphia, Pa. 

COOPER, W. CURK, M.D.-Professor, Occupational Medicine, School of 

Public Health, Berkeley, Calif. 

CORNFIELD: JEROME-Acting Chief, Biometrics Research Branch, National 

Heart Institute, U.S. Public Health Service, Bethesda, Md. 

DAMON, ALBERT, M.D.-Associate Professor, Department of Epidemiology, 

Harvard University School of Public Health, Cambridge, Mass. 

X 
DAWSON, JOHN M.-Statistician, National Cancer Institute, U.S. Public 

Health Service, Bethesda, Md. 

DIPAOLO, JOSEPH A., Ph. D.-Senior Cancer Research Scientist, Rowe11 

Park Memorial Institute, Buffalo, N.Y. 

DOBBS, GEORGE, M.D.-Associate Chief, Division of Scientific Opinions, 

Federal Trade Commission, Washington, D.C. 

DOLL, RICHARD, M.D.-Director, Medical Research Council’s Statistical 

Research Unit, University College Hospital Medical School, London, 

England 

l DORN, HAROLD F.-Chief, Biometrics Research Branch, National Heart 

Institute, U.S. Public Health Service, Bethesda, Md. 

DOYLE, JOSEPH T., M.D.-Direotor, Cardiovascular Health Center, AlbanyMedical College, Union University, Albany, N.Y. 

DUNHAM, LUCIA J., M.D.-Medical Officer, Laboratory of Pathology. National Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

EBERT, RICHARD V., M.D.-Professor and Head, Department of Medicine, 

University of ,irkansas Medical Center, Little Rock, Ark. 

EDDY, NATHAN B., M.D.-Executive Secretary, Committee on Drug Addiction and Narcotics, National Academy of Sciences, National Research 

Council, Washington, D.C. 

EISENBERG, HENRY, M.D.-Director of Chronic Diseases, Connecticut State 

Department of Health, Hartford, Conn. 

ELLIOTT, JAMES LLOYD, M.D.-Assistant Chief, Bureau of Medical Services, 

U.S. Public Health Service, Silver Spring, Md. 

ENDICOTT, KENNETH M., M.D.-Director, National Cancer Institute, U.S. 

Public Health Service, Bethesda, Md. 

FALK, HANS L., Ph. D.-Acting Chief, Carcinogenesis Studies Branch, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

FILLEY, GILES F., M.D.-Associate Professor of Medicine, University of 

Colorado Medical Center, Denver, Colo. 

FISHER, RUSSELL SYLVESTER, M.D.-Chief Medical Examiner, State of 

Maryland, Baltimore, Md. 

FORAKER, ALVAN G., M.D.-Pathologist, Baptist Memorial Hospital, Jacksonville, Fla. 

FOX, BERNARD H., Ph. D.-Research Psychologist, Division of Accident Prevention, U.S. Public Health Service, Washington, D.C. 

FRAZIER, TODD M., SC. M.-Director, Bureau of Biostatistics. Baltimore City 

Health Department, Baltimore, Md. 

GARFINKEL, LAWRENCE, M.A.-Chief, Field and Special Projects, Statistical 

Research Section, Medical Affairs Department, ijmerican Cancer Society, 

Inc., New York, N.Y. 

%LIAM, ALEXANDER, M.D.-Professor of Epidemiology. The Johns Hopkins University, Baltimore, Md. 

GOLDBERG, IRVING D., M.P.H.-Assistant Chief, Biometrics Branch. National 

Institute of Neurological Diseases and Blindness, U.S. Public Health 

Service, Bethesda, Md. 

GOLDSMITH, JOHI\‘. M.D.-Head. Air Pollution Medical Studies, California 

Department of Public Health, Berkeley, Calif. 

‘Deceased. 

xi 
~OI.DSTEIY, HYMEN, Ph. D.-Chief, Biometrics Branch, National Institute of 

Neurological Diseases and Blindness, U.S. Public Health Service, Bethesda, 

Md. 

GRAH.431, SAXON. M.D.-Associate Cancer Research Scientist, Roswell Park 

Memorial Institute, Buffalo, N.Y. 

GREENBERG, BERUARD G., Ph. D.-Professor of Biostatistics. School of Public 

Health. University of North Carolina, Chapel Hill, N.C. 

GROSS. PAUL, M.D.-Research Pathologist. Industrial Hygiene Foundation, 

Mellon Institute. Pittsburgh, Pa. 

HAENSZEL, WrLrr.AM-Chief, Biometrv Branch, National Cancer Institute, 

U.S. Public Health Service, Bethesda, Md. 

HAINER, RAYMOND M., Ph. D.-Research Physical Chemist, A. D. Little Inc.. 

Cambridge, Mass. 

HALL, ROBERT L.. Ph. D.-Program Director, Sociology and Social Psychology, National Science Foundation, Washington, D.C. 

HAIXSTAIL D.kvtD-Actuary, The National Center for Health Statistics, U.S. 

Public Health Service, Washington, D.C. 

HAMMOND, E. CUYLER, SC. D.-Director, Statistical Research Section, Medical Affairs Department, American Cancer Society, Inc., New York, N.Y. 

HAMPERL, H.. M.D.-Director of the Pathology Institute, University of 

Bonn, Bonn, Germany. 

HARTWELL, JON.4TH.4N L., Ph. D.-Chief, R esearch Communications Branch, 

National Cancer Institute, U.S. Public Health Service, Silver Spring, Md. 

HAYDEK. ROBERT G.. Ph. D.-Research Psychologist, Behavioral Sciences 

Section, Division of Community Health Services, U.S. Public Health 

Service, Washington, D.C. 

HEIMANN. HARRY, M.D.-Chief, Division of Occupational Health, U.S. 

Public Health Service, Washington, D.C. 

HEINZELMJNN, FRED. Ph. D.-Assistant Chief, Behavioral Sciences Section, 

Division of Community Health Services, U.S. Public Health Service, 

Washington, D.C. 

HELLER, JOHN R., Jr.. M.D.-President and Chief Executive Officer, SloanKettering Institute for Cancer Research, New York, N.Y. 

HERMAN, DORIS L., M.D.-Pathologist, Tumor Tissue Registry, Cancer Commission, California Medical Association, Los Angeles, Calif. 

HERROLD: K.~THERISE, M.D.-Medical Director, Laboratory of Pathology. 

National Cancer Institute. I.S. Public Health Service, Bethesda, Md. 

HESTON, WALTER E.: M.D.. Ph. D.-Chief, Laboratory of Biology, National 

Cancer Institute, T7.S. Public Health Service, Bethesda, Md. 

HIGGINS, 1.t~ T. T.. M.D.-Professor of Epidemiology and Microbiology, 

University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pa. 

HOCHRC->I> GODFREY, Ph. D.-Chief, Behavioral Sciences Section, Division 

of Community Health Services: U.S. Public Health Service, Washington. 

D.C. 

HOCKETT. ROBERT C.: Ph. D.--Associate Scientific Director, Tobacco Industry Research Committee: New York, N.Y. 

HORN, DASIEL: Ph. D.-Assistant Chief for Research, Cancer Control Program, Division of Chronic Diseases, U.S. Public Health Service, Washington, D.C. 

xii 
HORTON, ROBERT, J. M.: M.D.-Chief, Field Studie: Branch, Dix-ision of Air 

Pollution, U.S. Public Health Service, Cincinnati. Ohio. 

HUEPER, WILHELM C., M.D.-Chief, I? nvironmental Cancer Section. Sational Cancer Institute, U.S. Public Health Service, Bethesda, Told. 

IPSEN, JOHANI~ES, Ph. D.-Professor of Medical Statistics Henry Phipps lnstitute, University of Pennsylvania. Philadelphia, Pa. 

ISBELL, HARRIS, M.D.-Professor of Clinical PharmacoloF)-. I’niversity of 

Kentucky Medical School. Lexington, KY. 

ISKRANT, ALBERT P.-Chief, Developmental Research Yecticjrl. Division of 

Accident Prevention, U.S. Public Health Service, Washington. D.C. 

JANUS, ZELDA-Statistician, National Cancer Institute, 1..S. Public Health 

Service, Bethesda, Md. 

JOSIE, G. H., SC. D., M.P.H.-Chief, Epidemiolo=)- Divi.;iotr. Department of 

National Health and Welfare. Ottawa, Canada. 

KAHN, HAROLD A.-Statistician, Biometrics Research Branch. National Heart 

Institute, U.S. Public Health Service. Bethesda. Md. 

CANNEL, W. B., M.D.-Associate Director, Heart Disease Epidemiology 

Study, National Heart Institute. U.S. Public Health Service. Framingham. 

Mass. 

KELEMEN, GEORGE, M.D.-Research Associate, hlassachusetts Eye and Ear 

Infirmary, Harvard University Medical School. Boston, 3iass. 

KELLEY, HAROLD H., Ph. D.-Professor, Department of Psychology, University of California, Los Angeles, Calif. 

KENSLER, CHARLES J., Ph. D.-Senior Vice President, Life Sciences Division, 

Arthur D. Little, Inc., Cambridge, Mass. 

KESSELMAN, AvIva-Statistician, National Cancer Institute, U.S. Public 

Health Service, Bethesda, Md. 

KLEINERMAN, JEROME, M.D.-Associate Director, Medical Research Department, St. Luke’s Hospital, Cleveland, Ohio 

KNIGHT, VERNON, M.D.-Clinical Director, National Institute of Allergy and 

Infectious Diseases, U.S. Public Health Service, Bethesda, Md. 

KNUTTI, RALPH E., M.D.-Director, National Heart Institute. U.S. Public 

Health Service, Bethesda, Md. 

KOTIN, PAUL, M.D.-Associate Director of Field Studies, National Cancer 

Institute, U.S. Public Health Service, Bethesda, Md. 

KREYBERG, LEIV, M.D.-Director of Institute for General and Experimental 

Pathology, University of Oslo, Oslo, Norway 

KRUEGER, DEAN E.--Statistician, Biometrics Research Branch, National 

Heart Institute, U.S. Public Health Service, Bethesda, Md. 

KUSCHNER, MARVIN, M.D.-Professor of Pathology and Director of Laboratories, Bellevue Hospital Center. New York University Medical Center, 

New York, N.Y. 

LARSON, PAUL S., Ph. D.-Professor and Chairman of Department of Pharmacology, Medical College of Virginia, Richmond, Va. 

LEITER, JOSEPH, Ph. D.-Chief, Cancer Chemotherapy National Service 

Center, U.S. Public Health Service, Silver Spring, Md. 

rdEUCHTE~~~~~~~, CECILIE, M.D., Ph. D.-P ro f essor, EidgenGssische Technische Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland 

. . . 

XIII 
LEUCHTENBERGER, RUDOLF, M.D.-Professor Eidgeniissische Technische 

Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland 

LEVIN, MORTON L.. M.D.-Professor of Epidemiology, Roswell Park Memorial Institute, Buffalo, N.Y. 

LIEBOW, AVERILL A., M.D.-Professor of Pathology, Yale University School 

of Medicine, New Haven, Conn. 

LIGGETT & MYERS, INC., New York, N.Y. 

LILIENFELD, ABRAHAM, M.D.-Professor of Chronic Diseases, The Johns 

Hopkins School of Hygiene and Public Health, Baltimore, Md. 

LISCO, HERMAN, M.D.-Cancer Research Institute, New England Deaconess 

Hospital, Boston, Mass. 

LITTLE, CLARENCE COOK, M.D.-Scientific Director, Tobacco Institute Research Committee, New York, N.Y. 

LOUDON, R. G., M.B.-Assistant Professor of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. 

MAR’OS, NICHOLAS E.-Statistician, Division of Occupational Health, U.S. 

Public Health Service, Washington, DC. 

MARDER, MARTIN, Ph. D.-Research Psychologist, Behavioral Sciences Section, Division of Community Health Services, U.S. Public Health Service, 

Washington, D.C. 

MATARAZZO, J. D., Ph. D.-Professor of Medical Psychology, Department of 

Medical Psychology, University of Oregon Medical School, Portland, 

Oreg. 

MCFARLAND, JAMES J., M.D.-Professor of Otolaryngology, School of Medicine, George Washington University Hospital, Washington, D.C. 

MCGILL, HENRY C., M.D.-Professor of Pathology, Louisiana State Uni: 

versity School of Medicine, New Orleans, La. 

MCHUGH, RICHARD B., Ph. D.-Associate Professor of Biostatistics, School 

of Public Health, University of Minnesota, Minneapolis, Minn. 

MCKENNIS, HERBERT, Jr.-Professor of Pharmacology, Medical College of 

Virginia, Richmond, Va. 

MEDALIA, NAHUM Z., Ph. D.-Executive Secretary, Mental Health Small 

Grants Committee, National Institute of Mental Health, U.S. Public Health 

Service, Bethesda, Md. 

MEHLER, MRS. ANN-Research Assistant, National Cancer Institute, U.S. 

Public Health Service, Bethesda, Md. 

MILLER, JACK, M.D.-Research Fellow in Medicine, The University of Texas 

Southwestern Medical School, Dallas, Tex. 

MILLER, ROBERT W., M.D.-Chief, Epidemiology Section, National Cancer 

Institute, U.S. Public Health Service, Bethesda, Md. 

MILLER, WILLIAM F., M.D.-Associate Professor of Internal Medicine, The 

University of Texas Southwestern Medical School, Dallas, Tex. 

MITCHELL, ROGER S., M.D.-Associate Professor, University of Colorado 

School of Medicine, Denver, Colo. 

MURPHY, EDMOND A., M.D.-Attending Physician, The Moore Clinic, The 

Johns Hopkins University Hospital, Baltimore, Md. 

NASH, HARVEY. Ph. D.-Illinois State Psychiatric Institute, Northwestern 

University Medical School, Chicago, Ill. 

xiv 
NELSON, NORTON, Ph. D.-Professor and Chairman, Department of Industrial Medicine, New York University Medical Center, New York, N.Y. 

ORCHIN, MILTON, Ph. D.-Professor of Chemistry, University of Cincinnati, 

Cincinnati, Ohio. 

P. LORILLARD Co., New York, N.Y. 

PAFFENBARGER, RALPH S., Jr., M.D.-Medical Director, Field Epidemiology 

Research Section, National Heart Institute, U.S. Public Health Service, 

Framingham, Mass. 

PAUL, OGLESBY, M.D.-Chairman, Committee on Epidemiological Studies, 

Passavant Memorial Hospital, Chicago, Ill. 

PFAELZER, ANNE I.-Concord, Mass. 

PHILLIP MORRIS, INC., New York, N.Y. 

PICKREN, JOHN W., M.D.-Chief, Department of Pathology, Roswell Park 

Memorial Institute, Buffalo, N.Y. 

PIERCE, JOHN -4., M.D.-Associate Professor, Department of Medicine, University of Arkansas Medical Center, Little Rock, Ark. 

POTTS, ALBERT M., M.D.-Professor of Ophthalmology, University of Chicago School of Medicine, Chicago, Ill. 

PRINDLE, RICHARD A., M.D.--Chief, Division of Public Health Methods, 

U.S. Public Health Service, Washington, D.C. 

R. J. REYNOLDS TOBACCO Co., Winston-Salem, N.C. 

REED, SHELDON C., Ph. D.-Professor of Zoology, Department of Zoology, 

University of Minnesota, Minneapolis, Minn. 

REMINGTON RAND, LTD. (Ottawa) 

ROOS, CHARLES A.-Head, Reference Services Section, National Library of 

Medicine, U.S. Public Health Service, Bethesda, Md. 

ROSEN, SAMUEL, M.D.-Chief, Pulmonary Mediastinal and ENT Pathology 

Branch, Armed Forces Institute of Pathology, Washington, D.C. 

ROSENBLATT, MILTON B., M.D.-Associate Clinical Professor of Medicine, 

New York Medical C o 11 e g e, and Visiting Physician, Metropolitan Hospital, 

New York, N.Y. 

Ross, JOSEPH, M.D.-Associate Professor of Medicine, University of Indiana 

School of Medicine and Head of Chest Division, Robert Long Hospital, 

Indianapolis, Ind. 

SANFORD, J. P., M.D.-Associate Professor of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Tex. 

SAVAGE, I. RICHARD, Ph. D.-Professor of Statistics, Florida State University. 

Tallahassee, Fla. 

SCHIFFMAN, ZELDA-$Ckd Assistant to Executive Officer, National Cancer 

Institute, U.S. Public Health Service, Bethesda, Md. 

SCHNEIDERMAN, MARVIN. A-Associate Chief, Biometry Branch, National 

Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

SCHWARTZ, JOHN THEODORE, M.D.-Head, Ophthalmology Project, National Institute of Neurological Diseases and Blindness, U.S. Public Health 

Service, Bethesda, Md. 

SCOTT, OWEN-Executive Officer, National Institute of General Medical Sciences, U.S. Public Health Service, Bethesda, Md. 

SELICMAN, ARNOLD M., M.D.-Chairman, Department of Surgery, Sinai Hospital, Baltimore, Md. 
SELTSER, RAYMOND, M.D.-The Johns Hopkins IJniversity School of Public 

Health, Baltimore, Md. 

SELTZER, C~RI. C., Ph. D.-Research Associate in Physical Anthropology, 

Peabody Museum, Harvard University, Cambridge, Mass. 

SHAPIRO, HARRY, M.D.-Curator of Anthropology, American Museum of 

Natural History, New York: N.Y. 

SHUBIK, PHILLIPE, M.D.-Professor of Oncology, Chicago Medical School, 

Chicago, Ill. 

SILVETTE, HERBERT, Ph. D.-Visiting Professor of Pharmacology, Medical 

College of Virginia, Richmond, Va. 

SIRKEN, MONROE, Ph. D.-Acting Chief, Division of Health Records, The 

National Center for Health Statistics, U.S. Public Health Service, Washington, D.C. 

SLOAN, &RGARET H.. M.D.-Special Assistant to Director, National Cancer 

Institute, IT.S. Public Health Service, Bethesda, Md. 

SPIEGELMAN, MoR’rrMER-Associate Statistician, Metropolitan Life Insurance 

Company, New York, N.Y. 

STALLOKES, REUEL, M.D.-University of California School of Public Health, 

Berkeley, Calif. 

STEINBERG, ARTHUR, Ph. D.-Biologist, Professor in Department of Biology, 

Western Reserve University, Cleveland, Ohio 

STEWART, HAROLD L.: M.D.-Chief, Laboratory of Pathology, National Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

STOCKS, PERCY, M.D.-World Health Organization Consultant, Former Chief 

Medical Statistician in the Office of the General Registrar (1933-50), 

London, England 

STOUT, ARTHUR P., M.D.-Professor Emeritus of Surgery, Laboratory of Surgical Pathology, College of Physicians and Surgeons, Columbia University. 

New York, N.Y. 

STOWELL, ROBERT, M.D., Ph. D.-Scientific Director, Armed Forces Institute 

of Pathology, Washington, D.C. 

SYME: SHERM.~N LEOYARD-SOciOIOgiSt, San Francisco Field and Training 

Station, I’.S. Public Health Service Hospital, San Francisco, Calif. 

TAEUBER, K. E.-Research Associate, Population Research and Training 

Center, University of Chicago, Chicago, Ill. 

TOBACCO IXSTITI-TE, INC.. Washington, D.C. 

TOB.~CCO INSTITUTE RESEARCH COMMITTEE, New York, N.Y. 

TOICL-HATA: GEORGE, Ph. D., D.P.H.-Chief of Epidemiology, St. Jude Research Hospital, Institute of Biology and Pediatrics, Memphis, Term., and 

Assistant Professor of Preventive Medicine, University of Tennessee, College of Rledicine. Memphis, Tenn. 

TOMPSETT, RALPH, M.D.-Professor of Internal Medicine, The University of 

Texas Southwestern Medical School, Dallas, Tex., and Director of Medical 

Education. Baylor University Medical Center, Dallas, Tex. 

TOTTEN, ROBERT S.. M.D.-Associate Professor of Pathology, University of 

Pittsburgh School of Medicine, Pittsburgh, Pa. 

TURNER, CI.ACDE G.-Director, Tobacco Policy Staff, Agriculture Stabilization and Conservation Service. United States Department of Agriculture. 

Washington. D.C. 

xvi 
VINCENT, WILLIAM J.-Student, University of California, Los Angeles, Calif. 

VON SALLMANN, LUDWIG, M.D.-Chief, Ophthalmology Branch, National Institute of Neurological Diseases and Blindness, U.S. Public Health Service, 

Bethesda, Md. 

VORWALD, ARTHUR, M.D.-Chairman, Department of Industrial Medicine 

and Hygiene, Wayne University College of Medicine, Detroit, Mich. 

WALKER, C. B., B.h.-Biostatistics Section, Research and Statistics Division, 

Department of National Health and Welfare, Ottawa, Canada 

WALLENSTEIN, MERRILL, Ph. D.-Chief, Physical Chemistry Division, National Bureau of Standards, Washington, D.C. 

WEBB, BLAIR M.: M.D.-Otolaryngologist and ENT Consultant at the 

National Institutes of Health, U.S. Public Health Service, Bethesda, Md. 

WEINSTEIN, HOWARD I., M.D.-Director, Division of Medical Review, Food 

and Drug Administration, Washington. D.C. 

WOOLSEY, THEODORE D.-Assistant Director, National Center for Health 

Statistics, U.S. Public Health Service, Washington, D.C. 

WYATT, JOHN P.: M.D.-Professor of Pathology, St. Louis University School 

of Medicine, St. Louis, MO. 

ZERZm4\‘Y, FRED M., M.D.-Department of Maternal and Child Health. The 

Johns Hopkins School of Public Health, Baltimore, Md. 

ZUKEL, WILLIAM, M.D.-Associate Director, Collaborative Studies, National 

Cancer Institute. U.S. Public Health Service, Bethesda, Md. 

114-422 o-64-2 xvii 
PART I 

Introduction, 

Summaries, and 

Conclusions 
Chapter 1 

Introduction 
Chapter 1 

Realizing that for the convenience of all types of serious readers it would 

he desirable to simplify language. condense chapters and bring opinions 

to the forefront. the Committee offers Part I as’surh a presentation. This 

Part includes: (a) an introduction comprising. amon? other items. a chronology especiallv pertinent to the subject of this study and to the establishment and activities of the Committee. (b ) a short account of how the study 

was conducted, cc) the chief criteria used in making judgments. and td t 

a brief overview of the entire Report. 

HISTORICAL NOTES AND CHRONOLOGY 

In the early part of the 16th century. soon after the introduction of 

tobacco into Spain and England by explorers returning from the New World. 

controversy developed from differin g opinions as to the effects of the human 

use of the leaf and products derived from it by combustion or other means. 

Pipe-smoking, chewing, and snuffing of tobacco were praised for pleasurable and reputed medicinal actions. At the same time, smoking was condemned as a foul-smelling, loathsome custom. harmful to the brain and 

lungs. The chief question was then as it is now: is the use of tobacco bad 

or good for health, or devoid of effects on health? Parallel with the increasing production and use of tobacco, especially with the constantly increasing 

smoking of cigarettes, the controversy has become more and more intense. 

Scientific attack upon the problems has increased proportionatelv. The 

design, scope and penetration of studies have improved, and the yield of 

significant results has been abundant. 

The modern period of investigation of smoking and health is included 

within the past sixtv-three years. In 1900 an increase in cancer of the 

lung was noted particularly by vital statisticians. and their data are usually 

taken as the starting point for studies on the possible relationship of smoking 

and other uses of tobacco to cancer of the lung and of certain other organs. 

to diseases of the heart and blood vessels I cardiovascular diseases in peneral; coronary artery disease in particular) ~ and to the non-cancerous 1 nonneoplasticl diseases of the lower respiratory tract ( especially chronic 

bronchitis and emphysema 1, The next important basic date for starting 

comparisons is 1930. when the definite trends in mortality and disease-incidence considered in this Report became more conspicuous. Since then a 

great variety of investigations have heen carried out. Many of the chemical compounds in tobacco and in tobacco smoke have been isolated and 

tested. Numerous experimental studies in lower animals have been made 

by exposing them to smoke and to tars. gases and various constituents in 

tobacco and tobacco smoke. It is not feasible to submit human beings to 

5 
experiments that might produce ranters or other serious damage, or to 

expose them to possibly noxious agents over the prolonged periods under 

strictly controlled conditions that \vould be necessary for a valid test. 

Therefore. the main evidence of the effects of smoking and other uses of 

tobacco upon the health of human beings has been secured through clinical 

and pathological observations of conditions occurring in men, women and 

children in the course of their lives. and by the application of epidemiological and statistical methods by which a vast array of information has been 

assembled and analyzed. 

Amon? the epidemiological methods which have been used in attempts to 

determine whether smoking and other uses of tobacco affect the health of 

man: two types have been particularly useful and have furnished information 

of the greatest \-alue for the work of this Committee. These are (1 i retrospective studies which deal with data from the personal histories and medical 

and mortality records of human individuals in groups: and I 2) prospective 

studies, in which men and w-omen are chosen randomly or from some 

special group. such as a profession, and are follo\ced from the time of their 

entrv into the study for an indefinite period. or until thev die or are lost 

on account of other events. 

Since 1939 there ha\-e been 29 retrospective studies of lung cancer alone 

which ha1.e varying degrees of completeness and validity. Following the 

publication of several notable retrospective studies in the years 1952-1956. 

the medical evidence tending to link cigarette smoking to cancer of the lung 

received particularly widespread attention. .4t this time, also. the critical 

counterattack upon retrospective studies and upon conclusions drawn from 

tllem was launched by unconvinced individuals and groups. The same types 

of criticism and skepticism have been. and are. marshalled against the methods. findings, and conclusions of the later prospective studies. They will he 

discussed further in Chapter 3. Criteria for Judgment. and in other chapters, 

especially Chapter Z. Mortality. and Chapter 9. Cancer. 

During the decade 1950-1960. at various dates. statements based upon the 

accumulated evidence were issued by a number of organizations. These 

included the Rritish I\ledical Research Council: the cancer societies of Denmark. Norwal. Sweden. Finland. and the Netherlands: the American Cancer 

Society: the .4merican Heart Association: the Joint Tuberculosis Council of 

Great Rritain : and the Canadian Yational Department of Health and Welfare. 

Th e consensus. publici!- declared. \$-a< that smoking is an important health 

hazard. particularlv I\ ith respect to lunc cancer and cardiovascular disease. 

Early in 195-l. the Tnl)acco lndustrv Research Committee rT.1.R.C.i was 

established br representatives of tobacco manufacturers. growers. and srarehousemen to sponsor a program of research into questions of tobacco use 

and health. Since then. under a Scientific Director and a Scientific .4d\-isory 

Board composed of nine scientists \vho maintain their respective institutional 

affiliations. the Tobacco Industry Research Committee has conducted a 

grants-in-aid program. collected information. and issued reports. 

The I!.S. Public Health Service first became officially engaged in an 

appraisal of the available data on smoking and health in June. 19.36. when. 

under the instigation of the Surgeon General. a scientific Study Group on 

6 
the subject was established joint]\- hv the Sational Cancer Institute. the 

National Heart Institute. the American Cancer Societ!-. and the American 

Heart Association. .4fter appraising 16 independent itudies carried on in 

five countries over a period of 18 l-ears. this group concluded that there is 

a causal relationship between excessive smokin, CT of cirrarettrs I and lung cancer. 

Impressed b!- the report of the Study Committee and h\- other new evidence. Surgeon General Leroy E. Rurnev issued a statement on Jul\ 12. 1937. 

reviewing the matter and declaring that: “The Public Health service feels 

the weight of the e\-idenw is incwasin=l!- pointing in one dirrction: that 

excessive smoking is one of the ,rausative factors in lung cancer.” ‘AFain. 

in a special article entitled “Smoking and I,ung Cancer--\ Statement of the 

Public Health Service.” publi~hrd in the Jourrlal of the dnwrican Medical 

Association on IVovemher 2:;. 19.50. Surgeon General Rurne\- referred to 

his statement issued in 19.7; and reitrrated the brlief of the Public Health 

Service that: “The weight of e\-idence at l)resrtlt iml)lic,ates smoking as the 

principal factor in the increased incidence of lung ranwr.” and that: “Cigarette smoking particular]\ is associated w-ith an irlcreasrd chance of developing lung cancer.” These quotations state the position of the Public 

Health Service taken in 19.57 and 19.59 on the qur>tion of fmokinp and 

health. That position has not chanFed in the succeeding years. during 

which several units of thr Serlire conducted rstensiw investigations on 

smoking and air pollution. and the Sewice maintairlrd a constant scrutinv 

of reports and ljuhlications in this field. 

ESTABLISHMENT OF THE CO~IMITTEE 

The immediate antecedents of the establichmrnt of the Surgeon General’s Advisory Committee on Smoking and Health began in mid-1901. 

On June 1 of that year. a letter was sent to the President of the I’nited States, 

signed by the presidents of the American Cancer Societv. the American 

public Health Association. the American Heart Association. and the National Tuberculosis Association. It urged the formation of a Presidential 

commission to study the “widespread implications of the tobacco problem.” 

On January 4. 1962. representatives of the various organizations met 

with Surgeon. General Luther L. Terra-. \+ho short]\ thereafter proposed to 

the Secretary of Health. Education. and Welfare the formation of an advisory committee composed of “outstanding experts who would assess available knowledge in this area [smokin g 1s. health] and make al)propriate recommendations . . .” 

On April 16. the Surgeon General sent a more detailed proposal to the 

Secretary for the formation of the ad{-isor\- _ group. calling for re-evaluation 

of the Public Health Service position taken I~\- Dr. Rurnr! in the Journal 

of the American Medical Association. 

IId at the Se 

Dr. Tkrry felt the nerd for a new 

r\ice’s position in the light of a number of si=nifirant dr\-elol)- 

‘nents since 1939 which emphasized the need for further actiorl. He listed 

he as: 
1. New studies indicating that smoking has maior adverse health effects. 

2. Representations from national voluntary health agencies for action on 

the part of the Service. 

3. The recent study and report of the Royal College of Physicians of 

London. 

4. Action of the Italian Government to forbid cigarette and tobacco advertising: 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 commission to investigate the health effects of smoking. 

6. A request for technical guidance by the Service from the Federal Trade 

Commission on labeling and advertising of tobacco products. 

7. Evidence that medical opinion has shifted significantly against smoking. 

The recent study and report cited by Surgeon General Terry was the highly 

important volume: “Smoking and Health-Summary and Report of the Royal 

College of Physicians of London on Smoking in Relation to Cancer of the 

Lung and Other Diseases.” The Committee of the Royal College of Physicians 

dealing with these matters had been at its work of appraisal of data since 

April 1959. Its main conclusions, issued early in 1962, were: “Cigarette 

smoking is a cause of lung cancer and bronchitis, and probably contributes to 

the development of coronary heart disease and various other less common 

diseases. It delays healing of gastric and duodenal ulcers.” 

On June 7, 1962, the Surgeon General announced that he was establishing 

an expert committee to undertake a comprehensive review of all data on smoking and health. The President later in the same day at his press conference 

acknowledged the Surgeon General’s action and approved it. 

On July 24. 1962. the Surgeon General met with representatives of the 

American Cancer Society. the American College of Chest Physicians, the 

.imerican Heart Association, the American Medical Association, the Tobacco 

Institute. Inc.. the Food and Drug Administration. the National Tuberculosis 

Association. the Federal Trade Commission, and the President’s Office of 

Science and Technology. At this meeting, it was agreed that the proposed 

work should be undertaken in two consecutive phases, as follows: 

Phase I-An objective assessment of the nature and magnitude of the health 

hazard. to be made by an expert scientific advisory committee which would 

review critically all available data but would not conduct new research. This 

committee would produce and submit to the Surgeon General a technical 

report containing evaluations and conclusions. 

Phase II-Recommendations for actions were not to be a part of the 

Phase I committee’s responsibility. No decisions on how Phase II would 

be conducted were to be made until the Phase I report was available. It 

was recognized that different competencies would be needed in the second 

phase and that many possible recommendations for action would extend 

beyond the health field and into the purview and competence of other 

Federal agencies. 

The participants in the meeting of July 27 compiled a list of more than 

150 scientists and physicians workin, 0 in the fields of biology and medicine. 

8 
rvith interests and competence in the broad range of medical sciences and 

with capacity to evaluate the element. = and factors in the complex relationship between tobacco smoking and health. During the next month. these 

lists were screened by the representatil-es of organizations present at the 

July 27 meetin?. Any organization could \-et0 any of the names on the 

list. no reasons being required. Particular care was taken to eliminate 

the names of any persons \vho had taken a public position on the questions 

at issue. From the final list of names the Surgeon General selected ten men 

who agreed to serve on the Phase I committee. which was named Tlrc 

Surgeon General’s Advisory Committee on Smoking and Health. The committee members. their positions. and their fields of competence are: 

Stanhope Bayne-Jones. M.D.. LL.d.. I Retired 1. Former Dean. Yale School 

of Medicine i 193.5-40 I _ former President. Joint Administrative Board. Corrlell University. New York Hospital Medical Center (1947-52 I : former 

president. Socjetv of Ameriran Bacteriologi$ts I 1929 \. and American Societ! 

of Pathologv and Bacteriolog! I 19401. Field: Nature and Causation of 

N-ease in Human Populations. 

Dr. Bayne-Jones served also as a special consultant to the Committee 

staff. 

Walter J. Burdette. M.D.. Ph. D.. Head of Deljartment of Surgery. Uni- 

\rrsitv of Itah School of Medicine. Salt Lake Cit\-. Fields: Clinical 8 

f:uperimental Surgery; Genetics. 

William G. Cochran. M.A.. Professor of Statistics. Harvard University. 

Field: Mathematical Statistics. lcith Special .4pplication to Biological 

I’rohlems. 

Emmanuel Farber. M.D.. Ph. D.. Chairman. Department of Pathology. 

t-rliversity of Pittsburgh. Field: E. Y p el . imental and Clinical Pathology. 

Louis F. Fieser. Ph. D.. Sheldon Emory. Professor of Organic Chemistry. 

II arvard University. Field: Ch emistry of Carcinogenic Hydrocarbons. 

Jacob Furth, M.D.. Professor of Pathology. Columbia University. and 

ljirector of Pathology Laboratories, Francis Delafield Hospital, skew York. 

u.Y. Field: Cancer Biology. 

John B. Hickam, M.D.. Chairman, Deljartment of Internal Medicine. Uni- 

‘c’rsity of Indiana, Indianapolis. Fields: Internal Medicine. Physiology of 

“ardiopulmonary Disease. 

Charles LeMaistre. M.D.. Professor of Internal Medicine, The IIniversit) 

“I Texas Southwestern Medical School. and Medical Director. Woodla\l n HosVital. Dallas, Texas. Fields: Internal Medicine. Pulmonary Diseases, 

I’rt.\.entive Medicine. 

Leonard M. Schuman, M.D.. Professor of Epidemiology. I-niversity of 

“ilsnesota School of Public Health. Minneapolis. Field: Health and its 

ti ’ d Ionship to the Total Environment. 1. t’ 

\hrice H. Seevers. M.D., Ph. D.. Ch 

‘.lliversity of Michigan, Ann Arbor. 

airman. Department of Pharmacology. 

Field: PharmacoloFy of Anesthesia 

“11(1 Habit-Forming Drugs. 

(‘hairman: Luther L. Terry, 1,f.D.. Surgeon General of the United States 

Public Health Service. 

9 
Vice-Chairman : James M. Hundley. X’I.D.. Assistant Surgeon General for 

Operations, United States Public Health Service. 

Staff Director Medical Coordinator 

Eugene H. Guthrie. M.D., M.P.H. Peter V. V. Hamill, M.D., M.P.H. 

Public Health Service Public Health Service 

10 
Chapter 2 

Conduct of the Study 
Chapter 2 

CONDUCT OF THE STUDY 

The work of the Surgeon General’s Advisory Committee on Smoking and 

Health was undertaken. organized. and pursued with independence. a deep 

sense of responsibilitv. and with full appreciation of the national importance 

of the task. The Committee’s constant desire was to carrl. out in its own 

way. with the best obtainable advice and cooperation from experts outside 

its membership. a thorough and objectit-e review and evaluation of available 

information about the effects of the use of various forms of tobacco upon the 

health of human beings. It d esired that the Report of its studies and judpments should be unquestionably the product of its labors and its authorship. 

With an enormous amount of assistance from 155 consultants. from members 

and associates of the supportin, c staff. and from several organizations and 

institutions. the Committee feels that a document of adequate scope. integrity. 

and individuality has been produced. It is emphasized. however. that the 

content and judgments of the Report are the sole responsibility of the 

Committee. 

At the outset, the Surgeon General emphasized his respect for the freedom 

of the Committee to proceed with the study and to report as it saw fit, and he 

pledged all support possible from the United States Public Health Service. 

The Service, represented chiefly by his office. the National Institutes of Health, 

the National Library of Medicine. the Bureau of State Services, and the National Center for Health Statistics, furnished the able and devoted personnel 

that constituted the staff at the Committee’s headquarters in Washington, and 

provided an extraordinary variety and volume of supplies, facilities and resources. In addition, the necessary financial support was made available by 

the Service. 

It is the purpose of this section to present an outline of the important 

features of the manner in which the Committee conducted its study and composed this Report. A retrospective outline of procedures and events tends to 

convey an appearance of orderliness that did not pertain at all times. A plan 

was adopted at the first meeting of the Committee on November g-10, 1962, 

but this had to b e modified from time to time as new lines of inquiry led 

into unanticipated explorations. At first an encyclopedic approach was considered to deal with all aspects of the use of tobacco and the resulting effects, 

with all relevant aspects of air pollution, and all pertinent characteristics of 

the external and internal environments and make-up of human beings. It 

was soon found to be impracticable to attempt to do all of this in any reasonable length of time, and certainly not under the urgencies of the existing 

situation. The final plan was to give particular attention to the cores of problems of the relationship of uses of tobacco, especially the smoking of cigarettes, to the health of men and women, primarily in the United States, and 

13 
to deal with the material from both a general viewpoint and on the basis of 

d’ isease categories. 

As may be seen in a glance at the Table of Contents of this Report, the main 

topical divisions of the study were: 

l Tobacco and tobacco smoke, chemical and physical characteristics 

(Chapter 6 ) . 

l Nicotine: pharmacology and toxicology (.Chapter 7). 

l Mortality, general and specific, according to age, sex, disease, and smok. 

ing habits. and other factors (Chapter 8). 

l Cancer of the lungs and other organs; carcinogenesis; pathology, aud 

epidemiology (Chapter 9). 

l Non-neoplastic diseases of the respiratory tract, particularly chronic 

bronchitis and emphysema. with some consideration of the effects of 

air pollution (Chapter 10). 

l Cardiovascular diseases. particularlv coronary artery diseases iChapter 

11 I. 

l Other conditions. a miscellany including gastric and duodenal ulcer, 

perinatal disorders. tobacco amblyopia, accidents (Chapter 12). 

l Characterization of the tobacco habit and beneficial effects of tobacco 

i Chapter 13’1. 

l Psy-cho-social aspects of smoking i Chapter 14‘). 

l Morphological constitution of smokers (Chapter 15). 

As the primary duty of the Committee was to assess information about 

smoking and health. a major general requirement was that of making the 

information available. That requirement was met in three ways. The first 

and most important was the bibliographic service provided by the National 

Library- of Medicine. .\s th e annotated monograph by Larson, Haag, and 

Silvette-compiled from more than 6.000 articles published in some 1,200 

journals up to and largely into 1959-was available as a basic reference 

source. the National Library of Medicine was requested to compile a bibliog 

raphy thy author and by subject) covering the world literature from 1958 

to the present. In compliance with this request, the National Library of 

Medicine furnished the Committee bibliographies containing approximately 

1100 titles. Fortunately. the Committee staff was housed in the National 

Library of Medicine on the grounds of the National Institutes of Health, 

and through this location had ready access to books and periodicals, as 

well as to scientists working in its field of interests. Modern apparatus for 

photo-reproduction of articles was used constantly to provide copies needed 

for studv by members of the Committee. In addition, the members drew 

upon the libraries and bibliographic services of those institutions in which 

thev held academir positions. A considerable volume of copies of reports 

and a number of special articles were received from a variety of additional 

sources. 

All of the major companies manufacturin, u cigarettes and other tobacco 

products were invited to submit statements and any- information pertinent to 

the inquiry. The replies vvhich were received were taken into consideration 

by the Committee. 

Through a system of contracts with individuals competent in certain fields, 

special reports were prepared for the use of the Committee. Through these 

14 
sources much valuable information was obtained: some of it new and hitherto 

unpublished. 

In addition to the special reports prepared under rontracts. many conferences, seminar-like meetings. consultations, visits and correst,ondence 

made available to the Committee a large amount of material and a considerable amount of well-informed and well-reasoned opinion and advice. 

To deal in depth and discrimination with the topics listed aho\-e. the Committee at its first meeting formed subcommittees with much overlapping in 

membership. These subcommittees were the main forces engaged in collection. analysis. and evaluation of data from published reports. contractual 

reports. discussions at conferences. and from some new prospective studies 

reprogrammed and carried out generousll- at the request of the Committee. 

These will be acknowledged more fullv elsewhere in this Report. The first 

formulations of conclusions \qere made by these subcommittees. and these 

were submitted to the full Committee for revision and adoption after debate. 

At the beginning. and until the Committee began to meet routinely- in 

Pxesutive session, it had the advantage of attendance at its meetings of observers from other Federal agencies. There were representatives from the 

following agencies: Executive Office of the President of the United States. 

Federal Trade Commission, Department of Commerce. Department of Agriculture. and the Food and Drug Administration. Ser\-ing as more than observers and reporters to their agencies. \$hen they were present or by 

written communication, the)- supplied the Committee with much useful 

information. 

There were an uncounted number of meetings of subcommittees and other 

lesser gatherings. Between November 1962 and December 1063. the full 

Committee held nine sessions each lasting from two to four days in Washington or Bethesda. The main matters considered at the meetings in October, 

November, and December 1963 were the review and revision of chapters. 

critical scrutiny of conclusions, and the innumerable details of the composition and editing of this comprehensive Report. 

714-422 O-64-3 15 
Chapter 3 

Criteria for Judgment 
Chapter 3 

CRITERIA FOR JUDGMENT 

In making critical appraisals of data and interpretations and in formulating its own conclusions, the Surgeon General’s Advisory Committee on 

Smoking and Health-its individual members and its subcommittees and the 

Committee as a whole-made decisions or judgments at three levels. These 

levels were: 

I. Judgment as to the validity of a publication or report. Entering into 

the making of this judgment were such elements as estimates of the competence and training of the investigator, the degree of freedom from 

bias, design and scope of the investigation, adequacy of facilities and 

resources, adequacy of controls. 

II. Judgment as to the validity of the interpretations placed by investigators 

upon their observations and data, and as to the logic and justification of 

their conclusions. 

III. Judgments necessary for the formulation of conclusions within the 

Committee. 

The primary reviews, analyses and evaluations Of publications and unpublished reports containing data, interpretations and conclusions of authors 

were made by individual members of the Committee and, in some instances, 

by consultants. Their statements were next reviewed and evaluated by a 

subcommittee. This was followed at an appropriate time by the Committee’s 

critical consideration of a subcommittee’s report, and by decisions as to the 

selection of material for inclusion in the drafts of the Report, together with 

drafts of the conclusions submitted by subcommittees. Finally, after repeated critical reviews of drafts of chapters, conclusions were formulated and 

adopted by the whole Committee, settin g forth the considered judgment of the 

Committee. 

It is not the intention of this section to present an essay on decision-making. 

Nor does it seem necessary to describe in detail the criteria used for making 

scientific judgments at each of the three levels mentioned above. All members Of the Committee were schooled in the high standards and criteria imIllicit in making scientific assessments; if any member lacked even a small 

Part of such schooling he received it in good measure from the strenuous 

debates that took place at consultations and at meetings of the subcommittees 

and the whole Committee. 

CRITERIA OF THE EPIDEMIOLOGIC METHOD 

It is advisable, however, to discuss briefly certain criteria which. although 

applicable to all judgments involved in this Report. were especially significant 

for judgments based upon the epidemiologic method. In this inquiry the 

19 
epidemiologic method was used extensively in the assessment of causal factors in the relationship of smoking to health among human beings upon whom 

direct experimentation could not be imposed. Clinical, pathological and experimental evidence was thoroughly considered and often served to suggest 

an hypothesis or confirm or contradict other findings. When coupled with 

the other data. results from the epidemiologic studies can provide the basis 

upon which judgments of causality may be made. 

In carrying out studies through the use of this epidemiologic method, many 

factors, variables, and results of investigations must be considered to determine 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 association exists, then the question is asked: “Does the association have a causal 

significance?” 

Statistical methods cannot establish proof of a causal relationship in an 

association. The causal significance of an association is a matter of judgment 

which goes beyond any statement of statistical probability. To judge or 

evaluate the causal significance of the association between the attribute or 

agent and the disease, or effect upon health, a number of criteria must be 

utilized. no one of which is an all-sufficient basis for judgment. These criteria 

include : 

a) The consistency of the association 

b) The strength of the association 

c) The specificity of the association 

d) The temporal relationship of the association 

e) The coherence of the association 

These criteria were utilized in various sections of this Report. The most 

extensive and illuminating account of their utilization is to be found in 

Chapter 9 in the section entitled “Evaluation of the Association Between 

Smoking and Lung Cancer”. 

CAUSALITY 

Various meanings and conceptions of the term cause were discussed 

vigorously at a number of meetings of the Committee and its subcommittees. 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 addition, thoughts about causality in the realm of this inquiry were constantly 

and inevitably aroused in the minds of the members because they were 

preoccupied with the subject of their investigation-“Smoking and Health.” 

Without summarizing the more important concepts of causality that have 

determined human attitudes and actions from the days even before t2ristotle, 

through the continuing era of observation and experiment. to the statistical 

certainties of the present atomic age. the point of view of the Committee with 

regard to causality and to the language used in this respect in this report 

may be stated briefly as follows: 

1. The situation of smoking in relation to the health of mankind includes 

a host ( v-ariable man) and a complex agent (tobacco and its products, partic20 
ularly those formed by combustion in smoking). The prohe of this inquirv 

is into the effect. or non-effect. of components of the agent upon the tissues. 

organs. and various qualities of the host which might: a\ improve his wellbeing. b I let him proceed normally. or c I injure his health in one way or 

another. To obtain information on these points the Committee did its best. 

with extensive aid. to examine all available sources of information in puhlications and reports and through consultation w-ith well informed persons. 

2. When a relationship or an association between smoking. or other uses 

of tobacco, and some condition in the host was noted. the significance of the 

association was assessed. 

3. The characterization of the assessment called for a specific term. The 

chief terms considered were “factor.” “determinant.” and “cause.” The 

Committee agreed that Mhile a factor could he a source of variation. not all 

sources of variation are causes. It is recognized that often the coexistence of 

several factors is required for the occurrence of a disease. and that one of 

the factors may plav a determinant role. i.e.. without it the other factors I as 

genetic susceptibility 1 are impotent. Hormones in breast cancer can play 

such a determinant role. The word cause is the one in general usage in 

connection with matters considered in this study. and it is capable of conveying the notion of a significant, effectual. relationship between an agent and 

an associated disorder or disease in the host. 

4. It should be said at once, however, that no member of this Committee 

used the word “cause” in an absolute sense in the area of this study. 

Although various disciplines and fields of scientific knowledge were represented among the membership, all members shared a common conception 

of the multiple etiology of biological processes. No member was so naive 

as to insist upon mono-etiology in pathological processes or in vital phenomena. All were thoroughly aware of the fact that there are series of events 

in occurrences and developments in these fields. and that the end results are 

the net effect of many actions and counteractions. 

5. Granted that these complexities were recognized, it is to he noted clearly 

that the Committee’s considered decision to use the words “a cause,” or “a 

major cause,” or “a significant cause,” or “a causal association” in certain 

conclusions about smoking and health affirms their conviction. 

21 
Chapter 4 

Summaries and 

Conclusions 
Contents 

A. BACKGROUND _4ND HIGHLIGHTS .......... 

Kinds of Evidence .................. 

Evidence From the Combined Results of Prospective Studies . 

Other Findings of the Prospective Studies ...... 

Excess Mortality ................. 

Associations and Causality ............... 

The Effects of Smoking: Principal Findings 

Lung Cancer ... .... ..... : : : : : . . 

Chronic Bronchitis and Emphysema ......... 

Cardiovascular Diseases .............. 

Other Cancer Sites ................ 

The Tobacco Habit and Nicotine ........... 

The Committee’s Judgment in Brief .......... 

B. COMMENTS AND DETAILED CONCLUSIONS .... 

(A Guide to Part II of the Report) 

Chemistry and Carcinogenicity of Tobacco and Tobacco 

Smoke . 

Characteriza&t bf.th.e ,Tdbacco Habit : : : : : : : : : : 

Pathology and Morphology ............... 

Mortality. ...................... 

Cancer by Site .................... 

Lung Cancer ................... 

Oral Cancer. ................... 

Cancer of the Larynx ............... 

Cancer of the Esophagus .............. 

Cancer of the Urinary Bladder ........... 

Stomach Cancer .................. 

Non-Neoplastic Res iratory Diseases, Particularly Chronic 

Bronchitis and Pu P monary Emphysema ........ 

Cardiovascular Disease ................. 

Other Conditions ................... 

Peptic Ulcer ................... 

Tobacco Amblyopia ................ 

Cirrhosis of the Liver ........... 

Maternal Smoking and infant Birth Weight ..... 

Smoking and Accidents .............. 

Morphological Constitution of Smokers ......... 

Psycho-Social Aspects of Smoking ............ 

List of Tables 

1. Deaths from selected disease categories, United States, 1962 . 

2. Expected and observed deaths for smokers of cigarettes only 

and mortality ratios in seven prospective studies . . . . . 

24 

Page 

25 

26 

28 

2 

30 

33: 

31 

E 

;“3 

33 

33 

34 

34 

;; 

37 

37 

37 

i; 

38 

26 

29 
Chapter 4 

This chapter is presented in two sections. Section A contains background 

information, the gist of the Committee’s findings and conclusions on tobacco 

and health, and an assessment of the nature and magnitude of the health 

hazard. Section B presents all formal conclusions adopted by the Committee 

and selected comments abridged from the detailed Summaries that appear 

in each chapter of Part II of the Report. The full scope and depth of the 

Committee’s inquiry may be comprehended only by study of the complete 

Report. 

A. BACKGROUND AND HIGHLIGHTS 

In previous studies, the use of tobacco. especially cigarette smoking, has 

been causally linked to several diseases. Such use has been associated with 

increased deaths from lung cancer and other diseases, notably coronary 

artery disease, chronic bronchitis, and emphysema. These widely reported 

findings, which have been the cause of much public concern over the 

past decade, have been accepted in many countries by official health agencies, 

medical associations, and voluntary health organizations. 

The potential hazard is great because these diseases are major causes 

of death and disability. In 1962, over 500,000 people in the United States 

died of arteriosclerotic heart disease (principally coronary artery disease), 

41,000 died of lung cancer, and 15,000 died of bronchitis and emphysema. 

The numbers of deaths in some important disease categories that have been 

reported to have a relationship with tobacco use are shown in Table 1. This 

table presents one aspect of the size of the potential hazard; the degree of 

association with the use of tobacco will be discussed later. 

Another cause for concern is that deaths from some of these diseases have 

been increasing with great rapidity over the past few decades. 

Lung cancer deaths, less than 3,000 in 1930, increased to 18,000 in 1950. 

In the short period since 1955, deaths from lung cancer rose from less 

than 27,OOO to the 1962 total of 41,000. This extraordinary rise has not 

been recorded for cancer of any other site. While part of the rising trend 

for lung cancer is attributable to improvements in diagnosis and the changing 

age-composition and size of the population, the evidence leaves little doubt 

that a true increase in lung cancer has taken place. 

Deaths from arteriosclerotic, coronary, and degenerative heart disease 

rose from 273,000 in 194.0, to 3%,000 in 1950, and to 578,000 in 1962. 

Reported deaths from chronic bronchitis and emphysema rose from 2,300 

in 1945 to 15,000 in 1962. 

The changing patterns and extent of tobacco use are a pertinent aspect of 

the tobacco-health problem. 

25 
TABLE l.-Deaths from selected disease cattgories, United States, 1962 

Cause of death* ( Total ( Males ( Fcmales 

Depcnerative nnd arteriosclerotir heart disease, including cwona~y 

dkease (420, 422)~~..~.....~........~.~~~.....~~~~..~.~~-~~~~~- . ..- 

Hypertensive heart disuse (44~33) ..... .._ .... ..__.__..._____ .. ..__. 

cnnccr ofllmn (163.3)~ .......... _. ... .._ ..... ..__. ...... . ... .._ .... 

rirrIwis of liver (581) ......... .._ ... _....._ ..... .._ .. .._.__ ....... . Qronchitis andcmphysrma (502, 527.1). .._ .... _......._._. .......... 

Stomach and duoilcnal nlcrrs (510-1)~~- .__ .._ .._ ............. .._ ... Csnrrr ofhladdrr (lS1)..~..............................~ ........... 

CancProforal carity (140-8). .. .._. _...._ .......................... 

Canrerofrso~ham (150) ..... .._ ......... ................ .._ ..... 

CanrPr or IarynY (161) ........ _......._ .._ ............. .._ ....... 

5i7 9tR 

62: 176 

41.376 

21.824 

15. 104 

12.278 

R. OR1 

Ii, 481 

5. OPR 

34R, Ml4 22% 

26.6,54 

35,312 

14.323 

12.93i 

8, RX 

5. 575 

4.920 

3.973 

2, Ii? 

All Pause.5 . . . . . ..-..... ~~ _......._.. -.- . . . . . . . . . . . . . . . . .._.. /1,p3i+Gq- 

‘International Statistical Classifkation numbers in parentheses. 

761. 

Nearly 70 million people in the United States consume tobacco regularly. 

Cigarette consumption in the United States has increased markedly since 

turn of the Century, when per capita consumption was less than 50 cigarettes 

a year. Since 1910, when cigarette consumption per person (15 years 

older) was 138, it rose to 1,365 in 1930, to 1,828 in 1940, to 3,322 in 1950, 

and to a peak of 3,986 in l%l. The 1955 Current Population Survey 

showed that 68 percent of the male population and 32.4 percent of the female 

population 18 years of age and over were regular smokers of cigarettes. 

In contrast with this sharp increase in cigarette smoking, per capita 

of tobacco in other forms has gone down. Per capita consumption of cigars 

declined from 117 in 1920 to 55 in 1962. Consumption of pipe tobacco, 

which reached a peak of 2\/, lbs. per person in 1910, fell to a little more 

than half a pound per person in 1962. Use of chewing tobacco has declined 

from about four pounds per person in 1900 to half a pound in 1962. 

The background for the Committee’s study thus included much general 

information and findings from previous investigations which associated 

increase in cigarette smoking with increased deaths in a number of major 

disease categories. It was in this setting that the Committee began its work 

to assess the nature and magnitude of the health hazard attributable 

smoking. 

KINDS OF EVIDENCE 

In order to judge whether smoking and other tobacco uses are injurious 

to health or related to specific diseases. the Committee evaluated three main 

kinds of scientific evidence: 

1. Animal experiments.-In numerous studies, animals have been exposed 

to tobacco smoke and tars, and to the various chemical compounds they 

tain. Seven of these compounds (polycyclic aromatic compounds) have 

established as cancer-producing (carginogenic), Other substances in tobacco 

and smoke, though not carcinogenic themselves, promote cancer production 

or lower the threshold to a known carcinogen. Several toxic or irritant gases 

contained in tobacco smoke produce experimentally the kinds of non-cancerous damage seen in the tissues and cells of heavy smokers. This includes 

26 
suppression of ciliary action that normally cleanses the trachea and bronchi, 

damage to the lung air sacs, and to mucous glands and goblet cells which 

produce mucus. 

2. Clinical and autopsy studies.-Observations of thousands of patients 

and autopsy studies of smokers and non-smokers show that many kinds of 

damage to body functions and to organs, cells, and tissues occur more frequently and severely in smokers. Three kinds of cellular changes-loss of 

ciliated cells, thickening (more than two layers of basal cells), and presence 

of atypical cells--are much more common in the lining layer (epithelium) 

of the trachea and bronchi of cigarette smokers than of non-smokers. Some 

of the advanced lesions seen in the bronchi of cigarette smokers are probably 

premalignant. Cellular changes regularly found at autopsy in patients with 

chronic bronchitis are more often present in the bronchi of smokers than 

non-smokers. Pathological changes in the air sacs and other functional tissue 

of the lung (parenchyma) have a remarkably close association with past 

history of cigarette smoking. 

3. Population studies.-Another kind of evidence regarding an association 

between smoking and disease comes from epidemiological studies. 

In retrospective studies, the smoking histories of persons with a specified 

disease (for example, lung cancer) are compared with those of appropriate 

control groups without the disease. For lung cancer alone, 29 such retrospec 

tive studies have been made in recent years. Despite many variations in design and method, all but one (which dealt with females) showed that proportionately more cigarette smokers are found among the lung cancer patients 

than in the control populations without lung cancer. 

Extensive retrospective studies of the prevalence of specific symptoms and 

signs--chronic cough, sputum production, breathlessness, chest illness, and 

decreased lung function-consistently show that these occur more often in 

cigarette smokers than in non-smokers. Some of these signs and symptoms 

are the clinical expressions of chronic bronchitis, and some are associated 

more with emphysema; in general, they increase with amount of smoking and 

decrease after cessation of smoking. 

Another type of epidemiological evidence on the relation of smoking and 

mortality comes from seven prospective studies which have been conducted 

since 1951. In these studies, large numbers of men answered questions 

about their smoking or non-smoking habits. Death certificates have been 

obtained for those who died since entering the studies, permitting total death 

rates and death rates by cause to be computed for smokers of various types 

as well as for non-smokers. The prospective studies thus add several important dimensions to information on the smoking-health problem. Their 

data permit direct comparisons of the death rates of smokers and nonsmokers, both overall and for individual causes of death, and indicate the 

strength of the association between smoking and specific diseases. 

Each of these three lines of evidence was evaluated and then considered together in drawing conclusions. The Committee was aware that 

the mere establishment of a statistical association between the use of tobacco 

and a disease is not enough. The causal significance of the use of tobacco 

in relation to the disease is the crucial question. For such judgments all three 

27 
lines of evidence are essential, as discussed in more detail on pages 26-27 

of this Chapter, and in Chapter 3. 

The experimental, clinical, and pathological evidence, as well as data 

from population studies, is highlighted in Section I3 of this Chapter, which 

in turn refers the reader to specific places in Part II of the Report where 

this evidence is presented in detail. 

In the paragraphs which follow, the Committee has chosen to summarize 

the results of the seven prospective population studies which, as noted above, 

constitute only one type of evidence. They illustrate the nature and potential 

magnitude of the smoking-health problem, and bring out a number of factors 

which are involved. 

EVIDENCE FROM THE COMBINED RESIJLTS OF PROSPECTIVE 

STUDIES 

The Committee examined the seven prospective studies separately as well 

as their combined results. Considerable weight was attached to the consistency of findings among the several studies. However, to simplify presentation, only the combined results are highlighted here. 

Of the 1,123,OOO men who entered the seven prospective studies and who 

provided usable histories of smoking habits (and other characteristics such 

as age), 37,391 men died during the s&sequent months or years of the 

studies. No analyses of data for females from prospective studies are 

presently available. 

To permit ready comparison of the mortality experience of smokers and 

non-smokers, two concepts are widely used in the studies-excess deaths 

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 

measures the relative death rates of smokers and non-smokers. If the ageadjusted 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 

100 percent increase.). 

Table 2 presents the accumulated and combined data on 14 disease categories for which the mortality ratio of cigarette smokers to non-smokers was 

1.5 or greater. 

The mortality ratio for male cigarette smokers compared with non-smokers, 

for all causes of death taken together, is 1.68, representing a total death rate 

nearly 70 percent higher than for non-smokers. (This ratio includes death 

rates for diseases not listed in the table as well as for the 14 disease categories 

shown.) 

In the combined results from the seven studies, the mortality ratio of cig 

arette smokers over non-smokers was particularly high for a number 

diseases: cancer of the lung (10.8), b ronchitis and emphysema (6.1), can28 
T.~BLE 2.l-Expected and observed deaths for smokers of cigarettes onty and 

mortality ra.tios in seven prospective studies 

Underlying cause of death 

rsnwr of 1~ (162-3) I._._.______________.------...-.---.---.... .=.- 170.3 

Icronchitis and emphysema (502, 521.1). __..._._.____.....__--...... 89. 5 

c’anr~roflarynx (161) .. ..____ -.-- __.. __-- _.__________ _.- ._______.... 14.0 

0181cRncw (140-8).~.....~~~....-~-..~----.~~~~~~~.~..-~-~.~~~-~.... 37.0 

rnncer or Psophaglls (Irn)~ __---.---.._......._.-.-.---..-....-.--... 33.7 

Plomnch and duodenal ulcers (540, 541) _ _ _ __ .._... _____ -.. . ..___ _ _ 105.1 

IQhu circulatory diseases (451~661._____ __...._._____.___...-----.- 254.0 

rwrhosis of liver (al) __-- _....._ ..____ _..._.......___._......-- 169.2 

(‘Rnw of bladder (181). __..__.._.__ .._.______ _ . . . .._____._......._ 111.6 

r‘oronary artery discaw (420). _ _________. __._______.. -- ______ _.... 6,430. 7 

Whrr heartdiseasPs (421-2.43~)......-.---.-..--....--.-.-------.. 526.0 

llrrwtwsise heart (440-3) . .._____________ -- __._______._._._________ 4(ro. 2 

(it nrrsl arteriosclerosk (GO) ______.___________._.-....----.......... 210. 7 

~nnwrofkidmy (lIM)-------......-------.-...-...-.-~---.........- 79.0 

AIIrause8~~.~ ____ ---- _______. -- . . . . ..____...._.. . .._~ _._. __... -.. 15,653 0 

Obwrved Mortality 

deaths ratio 

1,833 

546 

1:: 

113 

294 

E 

216 

Il. li7 

E 

310 

23,E 

10.8 

6.1 

5.4 

4.1 

3.4 

2.8 

2.6 

2. 2 

1.9 

1.7 

l.i 

1.5 

1. 5 

1.5 

1.68 

I .AbridePd Irom Tablp 26, Chapter 8: Mortality. 

’ lntwnational Statistical Classiflcatlon numkrs in parentheses 

1 Includes all other causes of death as well as those hstcd above. 

cer of the larynx (5.4), oral cancer (4.1), cancer of the esophagus (3.4), 

peptic ulcer (2.8), and the group of other circulatory diseases (2.6). For 

coronary artery disease the mortality ratio was 1.7. 

Expressed in percentage-form, this is equivalent to a statement that for 

coronary artery disease, the leading cause of death in this country, the death 

rate is 70 percent higher for cigarette smokers. For chronic bronchitis and 

rmphysema, which are among the leading causes of severe disability, the 

death rate for cigarette smokers is 500 percent higher than for non-smokers. 

For lung cancer, the most frequent site of cancer in men, the death rate is 

nearly 1,000 percent higher. 

Other Findings of the Prospective Studies 

In general, the greater the number of cigarettes smoked daily, the higher 

the death rate. For men who smoke fewer than 10 cigarettes a day, according to the seven prospective studies, the death rate from all causes is about 

40 percent higher than for non-smokers. For those who smoke from IO to 

19 cigarettes a day, it is about 70 percent higher than for non-smokers; for 

these who smoke 20 to 39 a day, 90 percent higher; and for those who smoke 

40 or more, it is 120 percent higher. 

Cigarette smokers who stopped smoking before enrolling in the seven studie.3 have a death rate about 40 percent higher than non-smokers, as against 

70 Percent higher for current cigarette smokers. 

bef 

Men who began smoking 

ore age 20 have a substantially higher death rate than those who began 

arter age 25. Compared with non-smokers, the mortality risk of cigarette 

Jmokers, after adjustments for differences in age, increases with duration of 

smoking (number of years), and is higher in those who stopped after age 55 

than for those who stopped at an earlier age. 

In ho studies which recorded the degree of inhalation. the mortality ratio 

for a given amount of smoking was greater for inhalers than for non-inhalers. 

fie ratio of the death rates of smokers to that of non-smokers is highest 

29 
at the earlier ages (40-50) re p resented in these studies, and declines with 

increasing age. 

Possible relationships of death rates and other forms of tobacco use were 

also investigated in the seven studies. The death rates for men smoking 

less than 5 cigars a day are about the same as for non-smokers. For men 

smoking more than 5 cigars daily, death rates are slightly higher. There 

is some indication that these higher death rates occur primarily in men 

who have been smoking more than 30 years and who inhale the smoke 

some degree. The death rates for pipe smokers are little if at all higher 

than for non-smokers, even for men who smoke 10 or more pipefuls a day 

and for men who have smoked pipes more than 30 years. 

Excess Mortality 

Several of the reports previously published on the prospective studies 

included a table showing the distribution of the excess number of deaths 

of cigarette smokers among the principal causes of death. The hazard must 

be measured not only by the mortality ratio of deaths in smokers and nonsmokers, but also by the importance of a particular disease as a cause 

death. 

In all seven studies, coronary artery disease is the chief contributor 

the excess number of deaths of cigarette smokers over non-smokers, with 

lung cancer uniformly in second place. For all seven studies combined, 

coronary artery disease (with a mortality ratio of 1.7) accounts for 45 percent of the excess deaths among cigarette smokers, whereas lung cancer 

(with a ratio of 10.8’) accounts for 16 percent. 

Some of the other categories of diseases that contribute to the higher death 

rates for cigarette smokers over non-smokers are diseases of the heart and 

blood vessels, other than coronary artery disease, 14 percent; cancer sites 

other than lung, 8 percent; and chronic bronchitis and emphysema, 4 percent. 

Since these diseases as a group are responsible for more than 85 percent 

of the higher death rate among cigarette smokers, they are of particular 

interest to public health authorities and the medical profession. 

ASSOCIATIOM AND CAUSALITY 

The array of information from the prospective and retrospective studies 

smokers and nonsmokers clearly establishes an association between cigarette 

smoking and substantially higher death rates. The mortality ratios in Table 

2 provide an approximate index of the relative strength of this association, 

for all causes of death and for 14 disease categories. 

In this inquiry the epidemiologic method was used extensively in the 

assessment of causal factors in the relationship of smoking to health among 

human beings upon whom direct experimentation could not be imposed. 

Clinical, pathological, and experimental evidence was thoroughly considered 

and often served to suggest an hypothesis or confirm or contradict other 

findings. When coupled with the other data, results from the epidemiologic 

30 
studies can provide the basis upon which judgments of causality may be 

made. 

It is recognized that no simple cause-and-effect relationship is likely to exist 

between a complex product like tobacco smoke and a specific disease in the 

variable human organism. It is also recognized that often the coexistence of 

several factors is required for the occurrence of a disease, and that one of the 

factors may play a determinant role; that is, without it, the other factors 

(such as genetic susceptibility) seldom lead to the occurrence of the disease. 

THE EFFECTS OF SMOKING: PRINCIPAL FINDINGS 

Cigarette smoking is associated with a 70 percent increase in the agespecific death rates of males, and to a lesser extent with increased death 

rates of females. The total number of excess deaths causally related to 

cigarette smoking in the U.S. population cannot be accurately estimated. 

In view of the continuing and mountinp evidence from many sources, it 

is the judgment of the Committee that cigarette smoking contributes substantially to mortality from certain specific diseases and to the overall death 

rate. 

Lung Cancer 

Cigarette smoking is causally related to lune cancer in men; the mapnitude of the effect of cigarette smoking far outweighs all other factors. The 

data for women. though less extensive, point in the same direction. 

The risk of developing lung cancer increases with duration of smoking 

and the number of cigarettes smoked per day, and is diminished by discontinuing smoking. ’ In comparison with non-smokers, average male 

smokers of cigarettes have approximately a 9- to lo-fold risk of developing 

hmg cancer and heavy smokers at least a fO-fold risk. 

The risk of developing cancer of the lung for the combined group of pipe 

smokers, cigar smokers, and pipe and cigar smokers is greater than for 

non-smokers, but much less than for cigarette smokers. 

Cigarette smoking is much more important than occupational exposures 

in the causation of lung cancer in the general population. 

Chronic Bronchitis and Emphysema 

Cigarette smoking is the most important of the causes of chronic bronchitis in the United States, and increases the risk of dying from chronic bronchitis and emphysema. A relationship exists between cigarette smoking and 

emphysema but it has not been established that the relationship is causal. 

Studies demonstrate that fatalities from this disease are infrequent among 

non-smokers. 

For the bulk of the population of the United States, the relative importance 

of cigarette smoking as a cause of chronic broncho-pulmonary disease is 

much greater than atmospheric pollution or occupational exposures. 

114-422 O-64-4 31 
Cardiovascular Diseases 

It is established that male cigarette smokers have a higher death rate 

from coronary artery disease than non-smoking males. Although the 

causative role of cigarette smoking in deaths from coronary disease is not 

proven, the Committee considers it more prudent from the public health 

viewpoint to assume that the established association has causative meaning 

than to suspend judgment until no uncertainty remains. 

Although a causal relationship has not been established, higher mortality 

of cigarette smokers is associated with many other cardiovascular diseases, 

including miscellaneous circulatory diseases, other heart diseases, hypertensive heart disease, and general arteriosclerosis. 

Other Cancer Sites 

Pipe smoking appears to be causally related to lip cancer. Cigarette 

smoking is a significant factor in the causation of cancer of the larynx. 

The evidence supports the belief that an association exists between tobacco 

use and cancer of the esophagus, and between cigarette smoking and cancer 

of the urinary bladder in men, but the data are not adequate to decide 

whether these relationships are causal. Data on an association between 

smoking and cancer of the stomach are contradictory and incomplete. 

THE TOBACCO H.~BIT AND NICOTINE 

The habitual use of tobacco is related primarily to psychological and 

social drives, reinforced and perpetuated by the pharmacological actions 

of nicotine. 

Social stimulation appears to play a major role in a young person’s early 

and first experiments with smoking. No scientific evidence supports the 

popular hypothesis that smoking among adolescents is an expression 

rebellion against authority. Individual stress appears to be associated more 

with fluctuations in the amount of smoking than with the prevalence of smoking. The overwhelming evidence indicates that smoking-its beginning, 

habituation, and occasional discontinuation-is to a very large extent psychologically and socially determined. 

Nicotine is rapidly changed in the body to relatively inactive substances 

with low toxicity. The chronic toxicity of small doses of nicotine is low 

in experimental animals. These two facts, when taken in conjunction with 

the low mortality ratios of pipe and cigar smokers, indicate that the chronic 

toxicity of nicotine in quantities absorbed from smoking and other methods 

of tobacco use is very low and probably does not represent an important 

health hazard. 

The significant beneficial effects of smoking occur primarily in the area 

of mental health, and the habit originates in a search for contentment. Since 

no means of measuring the quantity of these benefits is apparent, the Committee finds no basis for a judgment which would weigh benefits against 

hazards of smoking as it may apply to the general population. 

32 
THE COMMITTEE’S JUDGMENT IN BRIEF 

On the basis of prolonged study and evaluation of many lines of converging 

evidence, the Committee makes the following judgment: 

Cigarette smoking is a health hazard of sufficient importance in 

the United States to warrant appropriate remedial action. 

B. COMMENTS AND DETAILED CONCLUSIONS 

(A Guide to Part II of the Report) 

All conclusions formally adopted by the Committee are presented at the 

end of this section in bold-faced type for convenience of reference. In the 

interest of conciseness, the documentation and most of the discussion are 

omitted from this condensation. Together with the tab& of contents which 

appear at the beginning of each chapter in Part II, it is intended as a guide 

to the Report. 

CHEMISTRY AND CARCINOGENICITY OF TOBACCO AKD TOBACCO 

SMOKE 

Condensates of tobacco smoke are carcinogenic when tested by application 

to the skin of mice and rabbits and by subcutaneous injection in rats ( Chapter 9, pp. 143-145). Bronchogenic carcinoma has not been produced by the 

application of tobacco extracts, smoke, or condensates to the lung or the 

tracheobronchial tree of experimental animals with the possible exception 

of dogs (Chapter 9, p. 165). 

Bronchogenic carcinoma has been produced in laboratory animals by the 

administration of polycyclic aromatic hydrocarbons, certain metals, radioactive substances, and viruses. The histopathologic characteristics of the 

tumors produced are similar to those observed in man and are predominantly 

of the squamous variety (Chapter 9, pp. 166-167). 

Seven polycyclic hydrocarbon compounds isolated from cigarette smoke 

have been established to be carcinogenic in laboratory animals. The results 

of a number of assays for carcinogenicity of tobacco smoke tars present a 

puzzling anomaly: the total tar from cigarettes has many times the carcino. 

genie potency of benzo (a) pyrene present in the tar. The other carcinogens 

known to be present in tobacco smoke are, with the exception of dibenzo (a,ij 

pyrene, much less potent than benzo (a) pyrene and they are present in smaller 

amounts. Apparently, therefore, the whole is greater than the sum of the 

known parts. This discrepancy may possibly be due to the presence of 

cocarcinogens in tobacco smoke, and/or damage to mucus production and 

ciliary transport mechanism (Chapter 6, p. 61, Chapter 9, p. 144 and Chapter 10, pp. 267-269). 

There is abundant evidence that cancer of the skin can be induced in man 

by industrial exposure to soots, coal tar, pitch, and mineral oils. All of these 

33 
contain various polycyclic aromatic hydrocarbons proven to be carcinogenic 

in many species of animals. Some of these hydrocarbons are also present 

in tobacco smoke. It is reasonable to assume that these can be carcinogenic 

for man also (Chapter 9, pp. 146-148). 

Genetic factors play a significant role in the development of pulmonary 

adenomas in mice. It is possible that genetic factors can influence the smoking habit and the response in man to carcinogens in smoke. However, there 

is no evidence that they have played an appreciable role in the great increase 

of lung cancer in man since the beginning of this century (Chapter 9, p. 190). 

Components of the gas phase of cigarette smoke have been shown to produce various undesirable effects on test animals or organs. One of these 

effects is suppression of ciliary transport activity, an important cleansing 

function in the trachea and bronchi (Chapter 6, p. 61 and Chapter 10, 

267-270). 

CHARACTERIZATION OF THE TOBACCO HABIT 

The habitual use of tobacco is related primarily to psychological and 

social drives, reinforced and perpetuated by the pharmacological actions 

of nicotine on the central nervous system. Nicotine-free tobacco or other 

plant materials do not satisfy the needs of those who acquire the tobacco 

habit (Chapter 13, p. 354) . 

The tobacco habit should be characterized as an habituation rather than 

an addiction. Discontinuation of smoking, although possessing the difficulties attendant upon extinction of any conditioned reflex, is accomplished best 

by reinforcing factors which interrupt the psychogenic drives. Nicotine 

substitutes or supplementary medications have not been proven to be 

major benefit in breaking the habit (Chapter 13, p. 354). 

PATHOLOGY AND MORPHOLOGY 

Several types of epithelial changes are much more common in the trachea 

and bronchi of cigarette smokers, with or without lung cancer, than of nonsmokers and of patients without lung cancer. These epithelial changes 

(a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance of atypical 

cells with irregular hyperchromatic nuclei. The degree of each of 

epithelial changes in general increases with the number of cigarettes smoked. 

Extensive atypical changes have been seen most frequently in men who smoked 

two or more packs of cigarettes a day. 

Women cigarette smokers, in general, have the same epithelial changes 

men smokers. However, at given levels of cigarette use, women appear 

show fewer sty-pica1 cells than do men. Older men smokers have more atypical 

cells than younger men smokers. Men who smoke either pipes or cigars 

have more epithelial changes than non-smokers, but have fewer changes than 

cigarette smokers consuming approximately the same amount of tobacco. 

Male ex-cigarette smokers have less hyperplasia and fewer atypical cells 

than current cigarette smokers. 

It may be concluded, on the basis of human and experimental evidence, 

that some of the advanced epithelial hyperplastic lesions with many atypical 

34 
cells, as seen in the bronchi of cigarette smokers, are probably premalignant 

(Chapter 9, pp. 167-173 ) . 

Typing of Tumors.---Squamous and oval-cell carcinomas (Group I of 

Kreyberg’s classification) comprise the predominant types associated with 

the increase of lung cancer in the male population. In several studies, 

adenocarcinomas (Group II) h ave also shown a definite increase, although 

to a much lesser degree. The histological typing of lung cancer is reliable, 

but the use of the ratio of histological types as an index of the magnitude of 

increase in lung cancer is of limited value (Chapter 9, pp. 173-175). 

Functional and PuthoZogicaZ Changes.-Cigarette smoke produces significant funtional alterations in the trachea, bronchus, and lung. Like several 

other agents, cigarette smoke can reduce or abolish ciliary motility in experimental animals. Postmortem examination of bronchi from smokers shows 

a decrease in the number of ciliated cells. shortening of the remaining cilia, 

and changes in goblet cells and mucous glands. The implication of these 

morphological observations is that functional impairment would result. 

In animal experiments, cigarette smoke appears to aflect the physical 

rharacteristics of the lung-lining layer and to impair alveolar (air sac) 

stability. Alveolar phagocytes ingest tobacco smoke components and assist 

in their removal from the lung. This phagocytic clearance mechanism 

breaks down under the stress of protracted high-level exposure to cigarette 

imoke, and smoke components accumulate in the lungs of experimental 

animals (Chapter 10, pp. 269-270). 

The chronic effects of cigarette smoking upon pulmonary function are 

manifested mainly by a reduction in ventilatory function as measured by 

:he forced expiratory volume (Chapter 10, pp. 289-292). 

Histopathological alterations occur as a result of tobacco smoke exposure 

n the tracheobronchial tree and in the lung parenchyma of man. Changes 

-egularly found in chronic bronchitis-increase in the number of goblet 

,ells, and hypertrophy and hyperplasia of bronchial mucous glands-are 

nore often present in the bronchi of smokers than non-smokers. Cigarette 

smoke produces significant functional alterations in the upper and lower 

iirways to the lungs. Such alterations could be expected to interfere with 

he cleansing mechanisms of the lung. 

Pathological changes in pulmonary parenchyma, such as rupture of 

lveolar septa (partitions of the air sacs) and fibrosis, have a remarkably 

lose association with past history of cigarette smoking. These latter changes 

:annot be related with certainty to emphysema or other recognized diseases 

‘t the present time (Chapter 10, pp. 270-275). 

MORTALITY 

The death rate for smokers of cigarettes only, who were smoking at the 

ime of entry into the particular prospective study, is about 70 percent higher 

ban that for non-smokers. The death rates increase with the amount smoked. 

“or groups of men smoking less than 10, 10-19, 20-39, and 40 cigarettes 

md over per day, respectively, the death rates are about 40 percent, 70 per35 
cent, 90 percent, and 120 percent higher than for non-smokers. The ratio 

the death rates of smokers to non-smokers is highest at the earlier ages (&J50) represented in these studies, and declines with increasing age. The same 

effect appears to hold for the ratio of the death rate of heavy smokers to 

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 

The mortality ratio was increased as the number of years of smoking 

creased. In two studies which recorded the degree of inhalation, the mar. 

tality ratio for a given amount of smoking was greater for inhalers than 

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. 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 

difficult to avoid in mass studies may have resulted in some over-estimation 

of the true mortality ratios for the complete populations. In our judgment, 

however, such biases can account for only a part of the elevation in mortality 

ratios found for cigarette smokers (Chapter 8, p. %). 

Death rates of cigar smokers are about the same as those of non-smokers 

for men smoking less than five cigars daily. For men smoking five or more 

cigars daily, death rates were slightly higher (9 percent to 27 percent) than 

for non-smokers’in the four studies that gave this information. There is some 

indication that this higher death rate occurs primarily in men who have been 

smoking for more than 30 years and in men who stated that they inhaled 

smoke to some degree. Death rates for current pipe smokers were little if 

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. 

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 

studies (Chapter 8, p. 94). The explanation is not clear but may be 

a substantial number of such smokers stopped because of illness. 

Mortality by Cause of De&.--In the combined results from the seven 

prospective studies, the mortality ratio of cigarette smokers was particularly 

high for a number of diseases. There is a further group of diseases, including 

some of the most important chronic diseases, for which the mortality ratio 

for cigarette smokers lay between 1.2 and 2.0. The explanation of 

moderate elevations in mortality ratios in this large group of causes IS 

clear. Part may be due to the sources of bias previously mentioned or 

some constitutional and genetic difference between cigarette smokers 

non-smokers. There is also the possibility that cigarette smoking has some 

general debilitating effect, although no medical evidence that clearly supports 

this hypothesis can be cited (Chapter 8, p. 105) . 

In all seven studies, coronary artery disease is the chief contributor to 

excess number of deaths of cigarette smokers over non-smokers, with lung 

cancer uniformly in second place (Chapter 8, p. 108). 

36 
For cigar and pipe smokers combined, there was a suggestion of high 

mortality ratios for cancers of the mouth, esophagus, larynx and lung, and 

for stomach and duodenal ulcers. These ratios are, however, based on small 

numbers of deaths (Chapter 8, p. 107). 

CANCER BY SITE 

Lung Cancer 

Cigarette smoking is causally related to lung cancer in men; the 

magnitude of the effect of cigarette smoking far outweighs all other 

factors. The data for women, though less extensive, point in the 

same direction. 

The risk of developing lung cancer increases with duration of 

smoking and the numher of cigarettes smoked per day, and is 

diminished by discontinuing smoking. 

The risk of developing cancer of the lung for the combined group 

of pipe smokers, cigar smokers, and pipe and cigar smokers, is 

greater than for non-smokers, h u t 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 he established. 

Although there are suggestions of relationships between cancer 

of other specific sites of the oral cavity and the several forms of 

tobacco use, their causal implications cannot at present be stated 

(Chapter 9, pp. 204-205). 

Cancer of the Larynx 

Evaluation of the evidence leads to the judgment that cigarette 

smoking is a significant factor in the causation of laryngeal cancer 

in the male (Chapter 9, p. 212). 

Cancer of the Esophagus 

The evidence on the tobacco-esophageal cancer relationship supPorts the belief that an association exists. However, the data are 

not adequate to decide whether the relationship is causal (Chapter 

9, p. 218). 

Cancer of the Urinary Bladder 

Available data suggest an association between cigarette smoking 

and urinary bladder cancer in the male but are not sufficient to 

support a judgment on the causal significance of this association 

(Chapter 9, p. 225). 

37 
Stomach Cancer 

No relationship has been established between tobacco use and 

stomach cancer (Chapter 9, p. 229). 

NON-NEOPLASTIC RESPIRATORY DISEASES, PARTICULARLY CHRONIC 

BRONCHITIS AND PULMONARY EMPHYSEMA 

Cigarette smoking is the most important of the causes of chronic 

bronchitis in the United States, and increases the risk of dying front 

chronic bronchitis. 

A relationship exists between pulmonary emphysema and 

arette smoking but it has not been established that the relationship 

is causal. The smoking of cigarettes is associated with an increased 

risk of dying from pulmonary emphysema. 

For the bulk of the population of the United States, the impor. 

tance of cigarette smoking as a cause of chronic bronchopulmonary 

disease is much greater than that of atmospheric pollution 

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 prevalence 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 

otherwise substantiated (Chapter 10, p. 302). 

CARDIOVASCULAR DISEASE 

Smoking and nicotine administration cause acute cardiovascular effects 

similar to those induced by stimulation of the autonomic nervous system, 

but these effects do not account well for the observed association between 

cigarette smoking and coronary disease. It is established that male cigarette 

smokers have a higher death rate from coronary disease than non-smoking 

males. The association of smoking with other cardiovascular disorders 

less well established. If cigarette smoking actually caused the higher death 

rate from coronary disease, it would on this account be responsible 

many deaths of middle-aged and elderly males in the United States. Other 

factors such as high blood pressure, high serum cholesterol, and excessive 

obesity are also known to be associated with an unusually high death 

from coronary disease. The causative role of these factors in coronary 

disease, though not proven, is suspected strongly enough to be a major 

reason for taking countermeasures against them. It is also more prudent 

assume that the established association between cigarette smoking and coro38 
nary disease has causative meaning than to suspend judgment until no uncertainty remains (Chapter 11, p. 327). 

Male cigarette smokers have a higher death rate from coronary 

artery disease than non-smoking males, but it is not clear that the 

association has causal significance. 

OTHER CONDITIONS 

Peptic Ulcer 

Epidemiological studies indicate an association between cigarette 

smoking and peptic ulcer which is greater for gastric than for 

duodenal ulcer (Chapter 12, p. 340). 

Tobacco Amblyopia 

Tobacco amblyopia (dimness of vision unexplained by an organic lesion) has been related to pipe and cigar smoking by clinical impressions. The association has not been substantiated by 

epidemiological or experimental studies (Chapter 12, p. 342). 

Cirrhosis of the Liver 

Increased mortality of smokers from cirrhosis of the liver has 

been shown in the prospective studies. Tbe data are not sufficient 

to support a direct or causal association (Chapter 12, p. 342). 

Maternal Smoking and Infant Birth Weight 

Women who smoke cigarettes during pregnancy tend to have 

babies of lower birth weight. 

Information is lacking on the mechanism by which this decrease 

in birth weight is produced. 

It is not known whether this decrease in birth weight has any 

influence on the biological fitness of the newborn (Chapter 12, 

p. 343). 

Smoking and Accidents 

Smoking is associated with accidental deaths from fires in the 

home. 

No conclusive information is available on the effects of smoking 

on traffic accidents (Chapter 12, p. 345). 

MORPHOLOGICAL CONSTITUTION OF SMOKERS 

The available evidence suggests the existence of some morpbolog 

ical differences between smokers and non-smokers, but is too 

meager to permit a conclusion (Chapter 15, p. 387). 

39 
PSYCHO-SOCIAL ASPECTS OF SMOKING 

A clear cut smoker’s personality has not emerged from the results so far 

published. While smokers differ from non-smokers in a variety of characteristics, none of the st,dies has shown a single variable which is found solely 

in one group and is completely absent in another. Nor has any single variable been verified in a sufficiently large proportion of smokers and in suffi. 

ciently few non-smokers to consider it an “essential” aspect of smoking. 

The overwhelming evidence points to the conclusion that smok. 

. mg-its beginning, habituation, and occasional discontinuation-is 

to a large extent psychologically and socially determined. This 

does not rule out physiological factors, especially in respect to 

habituation, nor the existence of predisposing constitutional or 

hereditary factors (Chapter 14, p. 377). 
PART II 

Evidence of the 

Relation Between Smoking 

and Health 
Chapter 5 

Consumption of 

Tobacco Products in 

the United States 
List of Tables 

Page 

TABLE 1. Tobacco products: Consumption per capita, 15 years 

and over, United States, 1900-1962 . . . . . . . 45 

TABLE 2. Filter tip cigarettes: estimated output and percentage 

distribution . . . . . . . . . . . . . . . . . . 46 
Chapter 5 

CONSUMPTION OF TOBACCO PRODUCTS 

IN THE UNITED STATES 

The U.S. Department of Agriculture estimates that the total number of 

persons in the United States, including overseas members of the Armed 

Forces, who consume tobacco on a regular basis is close to 70 million ( 1). 

Consumption of tobacco products per capita. 15 years and over: has risen 

from 7.42 pounds in 1900 to 10.85 pounds in 1962. Cigarette consumption 

increased steadily from 1910. when the per capita consumption was 138 

cigarettes, to the 1962 figure of 3.9.58. Per capita cigar consumption remained steady at slightll- over 100 in the first two decades of the century. 

hut started to decrease in 1921. The figure for 1920 is 117, and for 1962 

it is 55. Per capita consumption of pipe tobacco remained steady until the 

mid-1940’s. In 1945 the figure was 1.59 pounds. but in 1962 it was just 

over half a pound (0.56 I. Consumption of chewing tobacco showed a decline durin? about the same period, from 1.09 pounds per capita in 1945 

to 0.50 in 1962. Consumption of snuff has shown very little change (2) 

[Table 1). 

TABLE I.--Consumption of tobacco products per person aged 15 years and 

over in the United States for selected years, 1900-1962 

1:: ’ 

611 

I, 365 

1.828 

3, 322 

3,888 3,986 

3.958 

Starting in 1050, production of filter tip cigarettes began to rise. Unofficial estimates for 1950 show that only about half of one percent of cigarettes produced were filter tip. In 1952, unofficial estimates show 1.3 percent of cigarettes produced were filter tips. 

27.6 percent. 

In 1956 the figure had reached 

From 1958 on, official estimates, based on figures reported 

to the Department of Agriculture by the industry, show a continuous increase from 45 3 percent filter tip cigarettes produced in 1958 to 54.6 percent 

Produced in 1462 ( 3 I (Table 2) . 

45 
TABLE T-Estimated output of filter-tip cigarettes and percentage of total 

cigarette production, United States, 1950-1962 

Filter-tip 

cigarettes 

(billions) 

1950.........~......-. 

1951....~..-......-- .. 

1952-........-......- - 

1953........- ......... 

1951.................. 

lY55 __ .. .._ __ ......... 

19.56.. ... .._ .......... / 

2. 2 

3.0 

5. fi 

12.4 

36.9 

77.0 

116.9 

Perw$ of Percent of 

total 

16% 3 9.0 

213.0 45.3 

238.8 48. 7 

253.0 277. 1 % 

292.5 54.8 

*Data from 1958 through 1962 arc official estimates from Censu.a ofManufactsrern. 

Source: U.S. Department of .4griculture, Economic Research Service. 

REFERENCES 

I. U.S. Department of Agriculture. Special report to the Surgeon General’s 

Advisory Committee on Smoking and Health. 

2. U.S. Department of Agriculture. Economic Research Service. Tobacco 

products. Consumption per capita. 15 years and over, United States, 

1900-62. 

3. U.S. Department of Agriculture. Economic Research Service. The 

tobacco situation. March 1962, March 1963, September 1963. 
Chapter 6 

Chemical and Physical 

Characteristics of Tobacco 

and Tobacco Smoke 

7 14-422 o-64-5 
Contents 

CHEMISTRY OF TOBlCCO ............... 

COMPOSITION OF CIGARETTE SMOKE ........ 

COMPOUNDS OF THE PARTICULA4TE PH.4SE OTHER 

THAN HIGHER POLYCYCLICS ............ 

Aliphatic and Alicyclic Hydrocarbons .......... 

Terpenes and Isoprenoid Hydrocarbon .......... 

Alcohols and Esters .................. 

Sterols ........................ 

Aldehydes and Ketones. ................ 

Acids ........................ 

Phenols and Polyphenols ................ 

Alkaloids, Nitrogen Bases, and Heterocyclics ....... 

Amino Acids ..................... 

Inorganic Components ................. 

Noncarcinogenic Aromatic Hydrocarbons ......... 

CARCINOGEXIC HYDROC.4RBONS -4ND HETEROCYCLICS IN TOB-4CC0 SMOKE ............. 

COCARCINOGENS .................... 

MECHAXISM OF THE FORM-4TlON OF CARCINOGEXS . 

THE GAS PHASE .................... 

EFFECTS ON CILIARY ACTIVITY ........... 

PESTICIDES AND -4DDITIVES ............. 

SUMMARY ....................... 

REFERESCES ...................... 

List of Tables 

TABLE 1. Major classes of compounds in the particulate phase 

of cigarette smoke . . . . . . . . . . . . . . 

TABLE 2. Carcinogenic polycyclic compounds isolated from 

cigarette smoke . . . . . . . . . . . . . . . . 

TABLE 3. Polycyclic hydrocarbons isolated from tobacco 

smoke . . . . . . . . . . . . . . . . . . . . 

TABLE 4. Some gases found in cigarette smoke . . . . . . . 

Page 

49 

50 

55 

58 

59 

60 

61 

61 

62 

63 

51 

56 

58 

60 

4a 
Chapter 6 

Tobacco is an herb which man has smoked for over 300 years. The 

plant was given the generic name Nicotiana after Jean Nicot. French ambassador to Portugal, who in 1560 publicly extolled the virtue of tobacco as 

a curative agent. The species Nicotiuna tabacum is now the chief source 

of smoking tobacco and is the only species cultivated in the United States. 

CHEMISTRY OF TOBACCO 

The tobacco leaf contains a complex mixture of chemical components: 

cellulosic products, starches, proteins, sugars, alkaloids, pectic substances, 

hydrocarbons, phenols. fatty acids, isoprenoids, sterols, and inorganic minerals. Many of the several hundred components isolated have been found to 

occur also in other plants. Two groups of components are specific to tobacco 

and have not as yet been isolated from other natural sources. One includes 

the alkaloid nicotine and the related companion substances nornicotine, 

mvosmine, and anabasine. These nitrogen-containing substances are all 

Nicotine Nornicotine Mycmmine Anabaaine 

basic and hence extractable with acid. Seven members of a second group 

of compounds fairly distinctive to tobacco have been isolated and characterized (1962-63) by D. L. Roberts and R. L. Rowland(36). They are described as isoprenoids, since the structures are divisible into units of isoprene, 

the building principle of rubber, of the red pigment of the tomato, and 

of the yellow pigment of the carrot, as illustrated in the following formulas: 

c 

Isoprenoid tobacco 

component 4 Isoprene units 

Although none of the 7 isoprenoid components of tobacco has been isolated 

from another source, the hydrocarbon cembrene from a pine exudate has 

the same 14-membered ring with the same complement of an isopropyl group 

at Cl and methyl groups at G, CB, and CIZ (9). 

49 
COMPOSITION OF CIGARETTE SMOKE 

Cigarette smoke is an heterogeneous mixture of gases, uncondensed vapors, 

and liquid particulate matter (32). As it enters the mouth the smoke 1s a 

concentrated aerosol with millions or billions of particles per cubic centimeter 

t 25, 30). The median size of the particles is about 0.5 micron ( 1) . For 

purposes of investigating chemical composition and biological properties? 

smoke is separated into a particulate phase and a gas phase, and the gas phase 

is frequently subdivided into materials which condense at liquid-air tempera. 

ture and those which do not. Th e 1 arge quantities of material required for 

investigation of the chemical components are prepared on smoking machines 

t 25) in which large numbers of cigarettes are smoked simultaneously in a 

fashion designed to simulate average smoking habits, and a yellow-brows 

condensate known as tobacco tar is collected in traps cooled to the temperature 

of dry ice ( -70” C.) or liquid nitrogen (-196” C.). The tar thus contains 

all of the particulate phase of smoke as well as condensable components of the 

gas phase. The amount of tar from the smoke of one cigarette is between 

3 and 40 mg., the quantity varyin g according to the burning and condensing 

conditions, the length of the cigarette, the use of a filter, porosity of paper, 

content of tobacco, weight and kind of tobacco. 

An important factor determining the composition of cigarette smoke is the 

temperature in the burning zone. While air is being drawn through the 

cigarette the temperature of the burning zone reaches approximately 884” C. 

and when the cigarette is burning without air being drawn through it the 

temperature is approximately 835’ C. (42). The smoke generated during 

puffing, when air is being drawn through the cigarette, is called main-stream 

smoke; that generated when the cigarette is burning at rest is called sidestream smoke. At the temperatures cited extensive pyrolytic reactions occur. 

Some of the many constituents of tobacco are stable enough to distil un. 

changed, but many others suffer extensive reactions involving oxidation. 

dehydrogenation, cracking, rearrangement, and condensation. The large 

number and variety of compounds in tobacco smoke tar is reminiscent of the 

composition of the tar formed on carbonization of coal, which in many cases 

is conducted at temperatures lower than those of a burning cigarette. It is 

thus not surprising that some 500 different compounds have been identified 

in either the particulate phase of cigarette smoke or in the gas phase. 

In one study (50) regular cigarettes (70 mm. long, about 1 g. eachj with. 

out filter tips produced 17-40 mg. of tar per cigarette. In another investigation (43) 174,000 regular size American cigarettes afforded a total of 4 kg. 

of tar, an average of 23 mg. per cigarette. In still another study (31) 34,000 

7O-mm. cigarettes were smoked mechanically on a constant puff-volume type 

machine with which 35-ml. puffs, each of two seconds duration, were taken 

at one minute intervals from each cigarette. Eight puffs were required to 

smoke each cigarette to an average butt length of 30 mm. The smoke M-as 

condensed in a series of three glass traps cooled in liquid air. The conden. 

sate was rinsed out of the traps with ether, water, and hexane. The yield of 

condensate nonvolatile at 25” C. and 25 mm. of mercury was 20.9 mg. per 

cigarette. 

50 
Procedures for gross separation into basic, acidic, phenolic, and neutral 

fractions and for further processing of these fractions vary from laboratory to 

laboratory. The criteria upon which identification is based also vary. The 

most reliable identifications are based upon an ultraviolet absorption spectrum and/or a fluorescence spectrum in good agreement over the entire range 

\tith that of an authentic sample and include one or more of the following: 

Rf value observed in a paper chromatogram 111) ; order of elution from 

alumina; mass spectrometry. 

COMPOUNDS OF THE PARTICULATE PHASE 

OTHER THAN HIGHER POLYCYCLICS 

This brief summary is based largely on the comprehensive review by 

Johnstone and Plimmer of the Medical Research Council at Exeter Uniirraity. England ( 24 I. It should be noted that water constitutes 27 percent 

Ilf the particulate phase. Th e major groups of compounds included are 

.ho\tn in Table 1. 

ALIPHATIC AND ALKYCLIC HYDROCARBONS 

Almost all of the possible hydrocarbons, C, through C,, saturated and 

urr+aturated, straight-chain and branched-chain, have been reported to be 

prcaen, in tobacco smoke. Intermediate, normally liquid paraffins are present. All the C,, through C,, n-a lkanes have been identified, as well as the 

CZ: and C,!,-c’,, isoparaffins. 

T4BL.E I.--Major classes of compounds in the particulate phase of cigarette 

smoke 

Percent in Sumber 01 

particu- comwmd 

late* phase 

- 

7.7-12.8 1 25 

5.3-8.3 18 

8. 5 21 

4. 9 

0.44 El 

1. G-3. 8 45 

Toxic action on lung 

Some irritant 

Possible irritation 

Some irritant 

Some irritant 

Some carcinogenic 

Irritant and possibly cocarcinokxnic 

TERPENES AND ISOPRENOID HYDROCARBONS 

isoPrene, the basic unit of the terpenes and of higher terpenoids has been 

!dcntified in 

mprrthadiene. 

cigarette smoke (34) as have its dimers, dipentene and 1,8-pand shown t 

The triterpene squalene, consisting of six isoprene units 

o b 

hilit! of its be* 

e present in smoke (47) is of interest because of the possimg cyclized to polycyclic compounds and because of its ready 

51 
CHa CE4 CHa 

C& 

HaC 

CH: CHa CHa 

Squalene 

reaction with air to form hydroperoxides (which would be destroyed during 

attempted isolation ) ; a hydroperoxide derived from cholesterol has been 

shown to be carcinogenic i cancer-causing) : at least under certain conditions 

of administration I 12) . Phytadienes. products of the dehydration of the 

diterpene alcohol phytol, are also present in smoke and subject to air oxidation to hydroperoxides. 

C& Crt CH: 

CHIOH 

HsC 

Phytol 

ALCOHOLS ANT) ESTERS 

A wide variety of mono- and dihydric alcohols, both aliphatic and aromatic, are present in tobacco smoke. Solanesol, a primary alcohol containing 9 isoprene units, has been found in both tobacco and tobacco smoke; 

20 g. of pure material was isolated from 10 lbs. of flue-cured aged tobacco 

(0.44 percent). Grossman et al i 13) found that pyrolysis of solanesol at 

500” C. gives isoprene, its dimer dipentene, and other terpenoid products and 

concluded that the alcohol is the source of terpenoid compounds which are 

important factors in the flavor of tobacco smoke. 

Ethylene glycol and glycerol have been found present in smoke, but it 

is not clear from the literature whether they are present in smoke from untreated tobacco or arise from addition of these humectant substances to 

tobacco to improve moistness. 

Many common esters, such as the ethyl esters of the C2, C,, and C, fatty 

acids, are present in smoke. Higher fatty- acids are found both as free acids 

and as esters. 

STEROLS 

Stigmasterol, p-sitosterol, and r-sitosterol have been isolated from tobacco smoke. Indeed the sterol fraction is reported (29) to constitute 

approximately 0.15 percent of whole tar. The sterols are of interest as 

possible precursors of polyc)-clic aromatic hydrocarbons and because of the 

evidence, noted above. that sterol hydroperoxides can be carcinogenic. 

ALDEHYDES AND KETONES 

Most common aldehydes of low molecular weight (acetaldehyde, propionaldehyde, acetone, methyl ethyl ketone, etc.) have been found present 

52 
-4 CHlOH 

HIC 

I 

5oo”= Ad + 

Isoprene 

I-&C ‘-.2Hz 

Dipentene 

(major product) 

Solanesol 

\ 

6 

(3 HsC’ CHa 

C& 

&C /‘hII., 

CH, 

I 

H:C 

J&C 

HIC 

CHa 

in tobacco smoke, as have such dicarbonyl compounds as glyoxal and diacetyl. Dipalmityl ketone exemplifies ketones of high molecular weight 

isolated from tobacco smoke. 

0 

16' 

C& 

Dipalmityl ketone 

ACIDS 

A large number of volatile and nonvolatile acids of low molecular weight 

are present in tobacco smoke. Fatty acids of chain length C,, to C,, are 

reported to constitute 1 percent of the whole tar and the bulk of these acids 

are present in the free form (46). Unsaturated fatty acids and keto acids 

‘e.g., pyruvic acid) are also present. 

53 
PHENOLS AND POLYPHENOLS 

Since the phenols and polyphenols present in tobacco leaf play an im. 

portant role in the curing and smoking quality of tobacco, a great deal of 

investigative work has been done on the estimation, separation, and ident& 

cation of complex tobacco phenols such as rutin and chlorogenic acid. The 

presence of simple phenols in tobacco smoke was established as early as 

1871. The phenol content of smoke became of increasing importance with 

OH 

HO H? \ - 0 CHCH~O~co,H 

- 

ir 

HOi OH 

Rharnnoae 

Rutin Chlorogenic acid 

the demonstration that phenol and substituted phenols can function as 

cocarcinogens; that is, they promote the appearance of skin tumors in mice 

following application of a single initiating dose of a known carcinogen (4). 

Furthermore, the smoke from one cigarette contains as much as 1 mg. of 

phenols (7). In add i t ion to simple alkylphenols, naphthols, and the poly. 

phenols, resorcinol and hydroquinone are also present. 

ALKALOIDS, NITROGEN BASES, AND HETEROCYCLICS 

Pyridine, nicotine, nornicotine, and other substituted pyridine bases con. 

stitute some 8-15 percent of whole tar; nicotine and nornicotine constitute 

about 7-8 percent of the total tar. The companion bases are products of 

the pyrolysis of the alkaloids present in tobacco leaf. Quinoline and three 

poly-cyclic heterocyclic compounds have also been identified in smoke (45) 

and will be discussed later since the three polycyclic compounds are carcinogenic. ‘4 pentacyclic compound related to xanthene, namely 1,8,9perinaphthoxanthene. has been identified in smoke (45). 

1,8,9-Perinaphthoxanthene 

AMINO ACIDS 

Although tobacco leaf contains a number of amino acids, relatively few 

have been found present in smoke; among these are glutamine and glutamic 

acid. 

54 
INORGANIC COMPONENTS 

It is estimated that the main-stream smoke from one cigarette contains 

about 150 1j.g. of metallic constituents. which are mainly potassium (90 

tIercent I _ sodium (5 percent I, and traces of aluminum, arsenic, calcium. and 

copper. Arsenic is reported to be present to the extent of 0.3-1.4 pg. in 

the smoke of one cigarette. Th e inorganic compounds are most likely 

chlorides. but metals themselves may be present. 

Apparently bery-ilium is present in tobacco in trace quantities. but is not 

1 olatilized in the smoking process ( 4s ) . Nickel is present in cigarettes in 

trace amounts and may occur in main-stream smoke to a small extent, 

l:robably as the chloride (31 t . Spectrographic analysis has shown the 

presence of chromium in smoke at a level of less than 0.06 ;tg. per cigarette. 

This level appears too low to represent a hazard 148). 

IVONCARCINOGENIC AROMATIC HYDROCARBONS 

The aromatic h>-drocarbons present in tobacco smoke have received 

an enormous amount of attention since some of them are carcinogenic. 

Toncarcinogenic hydrocarbons of smoke containing one to three rings 

include benzene. toluene and other alkplbenzenes, acenaphthene, acenaphthylene. flnorene. anthracene. and phenanthrene. Hydrocarbons of established carcinopenicity to mice all contain from four to six condensed rings. 

Ifowever. no less than 27 hydrocarbons containing four or more ‘condensed 

rings which have been tested for carcinopenicity with negative results have 

heen isolated from tobacco smoke tar. As methods of separation and 

identification improve, it is almost certain that additional hydrocarbons will 

be found present in smoke, because almost every conceivable ring system 

has been demonstrated to be present and the number of possible alkylated 

polycyclics is very large indeed. 

CARCINOGENIC HYDROCARBONS AND HETEROCYCLICS 

IN TOBACCO SMOKE 

In 1925-30 Kennaway et al. in seeking to identify the active substance 

in high-boiling fractions of coal tar distillates of established carcinogenicity 

to mice, discovered that dibenzo(a,h)anthracene (for formula, see Table 

21 prepared by synthesis evokes skin cancer when applied to the skin of 

mice (11). The hydrocarbon was recognized as different from the carcinogen of coal tar because its fluorescent spectrum did not match the characteristic three-banded spectrunr of the tars. In 1933 Cook and co-workers i 11) 

isolated the coal tar constituent responsible for the characteristic fluorescence 

and identified it as benzota) pyrene. 

the carcinogens now known. 

It is one of the most potent of all 

55 
TABLE 2.--Carcinogenic Polycyclic Compounds Isolated From Cigarette 

Smoke 

Compound 

1. Benzo(s)pyrene 

2. Dibenzo(s,i)pyrene 

3. Dibenao(s,h)snthrscene 

4. Benao(c)phenanthrene 

5. Dibens(s,j)acridine 

6, Dibenz(a,h)acridine 

7. 7H-Dibenzo(c,g)carbszole 

structllre 

’ I / / 

(I: d?? 1; > 

w I> ‘I \ ’ \ / 

Carcinogenicity 

Amount reported, 

rg/KMM cigarettes 

++++ 

++++ 

++ 

16 

(ave. of 10 reports) 

0.02-10 

(2 reports) 

(1 retort) 

•t- not stated 

+ 

2.7 

(1 report) 

0.1 

(1 report) 

0.7 

(1 report) 

56 
Since the discovery of carcinogenic hydrocarbons, a large number of 

polycyclic hydrocarbons and heterocyclic analogs have been tested for carcinogenicity to mice and to rats in many laboratories, both by application 

to the skin and by subcutaneous injection. Bioassays in different laboratories, often on independently prepared samples, are remarkably consistent 

and place a series of hydrocarbons in the same relative order of potency. 

A compilation (and its supplement) prepared by J. L. Hartwell (16) of the 

IKational Cancer Institute lists 2108 compounds of which 481 were reported 

to cause malignant tumors in animals. All but one of the polycyclic hydrocarbons listed in Table 2 as having been identified in tobacco smoke have 

already been documented in the Hartwell report and can be assigned a 

rating as very potent ( + + + + ), potent ( + + + ) , moderately carcinogenic I, + + ), or weakly carcinogenic ( + ) (31). Many other such compounds studied are reported in the Hartwell survey and in another by :Irthur 

D. Little, Inc. (31). The rating assigned to dibenzo (a,;) pyrene is based 

on experiments with over 10,000 inbred mice in which one subcutaneous 

injection in the groin of 0.5 mg. of hydrocarbon in tricaprylin produced 

50 percent sarcomas at the injection site in 14 weeks and 98 percent tumors 

in 24 weeks (20). Benzo(a)pyrene is one of the two most potent of the 

seven carcinogens detected in tobacco smoke and it is present in much larger 

quantity than any of the other carcinogens listed. Two polycyclic hydrocarbons isolated from tobacco smoke but not yet adequately tested for 

carcinogenicity are: benzo (j ) Auoranthene and dibenzo (a,l) pyrene. 

Identification of benzo (a)pyrene is reported in 19 separate investigations; the amount given in the table per 1000 cigarettes (70 mm. long, 

Neighing about 1.0 g. each) is the average of 10 values selected on the 

basis of the quality of criteria used for identification (31). Compounds 

1, 2, 3, 4, and benzo (j) fluoranthene were identified in one laboratory over 

a period of years and are listed together in a review by Van Duuren (44). 

Isolation of the three heterocyclic carcinogens (5,6,7) is reported by Van 

Duuren (45). 

Because of losses in the process of fractionation and purification, the 

amount of carcinogens reported in a given investigation may be less than the 

amount actually present. Wy n d er and Hoffman (50) investigated this 

point by adding a known amount of radioactive C”-1abelled benzo(a)pyrene 

to a smoke condensate and applied the usual procedure for isolation of 

benzo(a)pyrene, which involved, in the last stages, chromatographing twice 

on silica gel and four times on paper. The activity of the benzo(a) pyrene 

finally isolated indicated a loss of 3540 percent of carcinogen during processing. Th e amount of benzo(a) pyrene given in Table 2 thus should be 

multiplied by a factor of 1.5 to give the estimated true amount. Probably 

the amounts of the other carcinogens in smoke are also at least 1.5 times the 

reported amounts. 

Relatively little work has been done on the components of smoke produced 

with cigars and pipes. Table 3 summarizing a comparative study made in 

one laboratory (5) indicates that the amount of benzo(a)pyrene, the only 

carcinogen in the group studied, increases sharply from cigarettes to cigars 

to pipes. 

57 
TABLE 3.-Polycyclic hydrocarbons isolated from tobacco smoke 

[,,g. pm 1000 g. of tobxcm consumrd~ 

COCARCINOGENS 

Assays of tobacco smoke tars for carcinogenicity are done by applying a 

dilute solution of tar in an organic solvent with a camel’s hair brush to the 

backs of mice beginning when the animals are about six weeks old. Applica. 

tion is repeated three times a week for a period of a year or more. The results 

of a number of such assays present a puzzling anomaly: the total tar from 

cigarettes has about 40 times the carcinogenic potency of the benzo( a) pyrene 

present in the tar. The other carcinogens known to be present in tobacco 

smoke are, with the exception of dibenzo(a,i) pyrene, much less potent than 

benzo (a) pyrene and they are present in smaller amounts. Apparently, there. 

fore, the whole is greater than the sum of the known parts (27, 33,49). 

One possible or partial explanation of the discrepancy is that the tar con. 

tains compounds which, although not themselves carcinogenic, can enhance 

the cancer-producing properties of the carcinogens. Berenblum and Shubik 

(3), reporting on cocarcinogenesis. described the potentiating effect of croton 

oil, which itself is noncarcinogenic except in certain strains of mice (4a), on 

the action of hydrocarbon carcinogens. Phenol is reported to have a similar 

potentiating effect (4. 50) and, as noted above. cigarette smoke contains 

considerable phenolic material. Long-chain fatty acid esters (39) and free 

fatty acids (19) have been shown to function as cocarcinogens, and sub. 

stances of both types occur abundantly in tobacco smoke. It is possible that 

the potentiatinp action of croton oil is due to the presence of fatty acids and 

their esters. A further observation of possible importance is that some poly 

cyclic hydrocarbons. though very weak or inactive as carcinogens, are capable 

of initiating malignant growth under the influence of a promoter. Thus 

henz (a) anthracene, identified in cigarette smoke, is verv weak or inactive in 

initiating malignant growth by itself. but initiates carcinogenesis under the 

influence of croton oil as promoter (15). 

If more were known about the possible cocarcinogenicity of the many 

inactive components of tobacco smoke, some of the apparent discrepancy 

between isolation and bioassay data might disappear. It is possible that some 

of the carcinogenicity of smoke is due to hydroperoxides formed from unsaturated smoke components and destroyed in the isolation procedures. 

Furthermore both sets of data are far from precise; for example, one estimate of the amount of the highly potent dibenzoi a,i)pyrene per 1000 

cigarettes (Table 2) is 0.02~~. and another is 1Opg. 

However. it is not necessary to wait for an exact balance of the two sets 

of data to draw a conclusion from each. The isolation experiments, taken 

58 
alone, indicate that cigarette smoke contains a number of identified chemicals 

which are carcinogenic to mice. The bioassavs suggest that cigarette smoke 

probably contains components which. actin g in a manner as yet undescribed, 

are involved in the induction of tumors in mice. 

Assessment of all conceivable synergistic effects presents a gigantic problem 

for exploration. Tobacco smoke contains considerable amounts of phenols 

and fatty acids, both of which, as previously mentioned, enhance the activity 

of known carcinogens. Cellulose acetate filters now in use remove ‘XL80 

percent of acidic constituents of tobacco smoke. 

MECHANISM OF THE FORMATION OF CARCINOGENS 

Most of the carcinogenic compounds identified in cigarette smoke tar are 

not present in the native tobacco leaf but are formed by pyrolysis at the high 

burning temperature of cigarettes. Van Duuren (4.4) reports formation of 

benzo(a) pyrene and pyrene on pyrolysis of stigmasterol, a smoke comHO 

Stigma&sol Benro(a)pyrene Pyrene 

ponent. Similar pyrolysis of pyridine or of nicotine gives dibenzo( a,j) 

acridine and dibenzo (a,h) acridine, both of which are carcinogenic (Table 

2). Pyrolysis of nontobacco cigarettes made from vegetable fibers and 

spinach resulted in formation of benzo( a jpyrene (50). 

Hurd and co-workers (22) by careful experimentation have elaborated 

plausible mechanisms for the formation of polycyclic aromatics by pyrolysis 

of materials of low molecular weight at temperatures in the range 800-900” C. 

Postulated radical intermediates are: 

(a) CHz=C=kH - CH~-C+ZH 

(b) EH-cH=I~H - ~H=cHGH 

tc) CH=CH~H=CH 

These radicals can arise from propylene, toluene, picoline, or pyridine. A 

variety of polycyclic hydrocarbons can be generated by reaction of these 

radicals with themselves or with other small radicals present in the heating 

zone. For example, dimerization of (b ) should give benzene. 

59 
Jt thus appears that the pyrolysis of many organic materials can lead to 

the formation of components carcinogenic to mice. Cigarette paper con. 

sists essentially of cellulose. Pyrolysis of cellulose has been shown to produce 

henzo(a)pyrene. The observation (2’) that treatment of tobacco with 

copper nitrate decreases the benzo (a) pyrene content of the cigarette smoke 

suggests a possibility for improvement by the use of additives or catalysts. 

The fact that side-stream smoke contains three times more benzo (a) pyrene 

than main-stream smoke has been cited (50) as evidence that more efficient 

oxidation could conceivably lower the content of carcinogenic hydrocarbons. 

THE G.4S PHASE 

The gas phase accounts for 60 percent of total cigarette smoke. Hobbs 

et al. ( 34, 35‘1 found that 98.9 mole percent of the gas phase is made up of 

the following seven components: 

Yitrogen ____------- --------- ________. 73 mole percent 

Oxygen---- --------_____------_______ 10 

Carbon-dioxide ____- -- _______-__----_ - 9.5 

Carbon-monoxide--------------------- 4.2 

Hydrogen---------------------------~ 1. 

Argon------------------------------. 0.6 

Methane----------------------------- 0.6 

98. 9 

The approximately one percent of the gas phase not accounted for by the 

seven major constituents contains numerous compounds, no less than 43 

of I\ hirh have been identified as present in trace amounts. Some of these 

are listed in Table 4 (1). 

TABLE 4.-Some gases found in cigarette smoke 

(1 (PPm) 

100 

NX) 

5. cinl 

2d 

0. 5 

Unknown 

l-one 

Sonc 

sonr 

Irritant 

Irritant 

Irritant 

Irritnnt 

Irritant 

Irntant 

Irritant 

Irritant 

r.“known 

i;;itant 

Repiratory enzyme poison 

Unknown 
EFFECTS ON CILIARY ACTIVITY* 

An important line of investigation was opened up by the report by Hilding 

(1s) that cigarette smoke is capable of inhibiting the transport activity of 

ciliated cells such as found in the respiratory tract. It has been suggested 

( 10. 17 I that failure of ciliary function to provide a constantly moving 

stream of mucus enables environmental carcinogens to reach the epithelial 

cells. Kensler and Battista t 28) describe development of a method of 

bioassay for inhibition of ciliary transport activity involving exposure of 

the trachea of a rabbit to the test material. The smoke from a regular 

cigarette was found to inhibit transport activity by 50 percent after exposure 

to two or three puffs. Several commercial filter cigarettes gave essentially 

the same result. The fact that these filters lower the phenol content by 

70 to SO percent and trap about 4.0 percent of the particulate phase suggested 

that neither phenolic nor particulate materials are responsible for the inhibition noted. The next trial was with an absolute filter. that is, one which 

removes the entire particulate phase and gives nonvisible gas. The observation that such treatment did not significantly alter the inhibitory effect 

of the puff established that components of the gas phase are responsible for 

inhibition of ciliary transport activity. Assays of known components of 

the gas phase showed the followin g compounds to possess such activity: 

hydrogen cyanide, formaldehyde. acetaldehyde. acrolein, and ammonia, although 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 tobacco were lead arsenate and paris green (the mixed acetate-arsenite salt of 

copper). Analysis of 6 brands of American cigarettes purchased in 1933 

showed a range of 7.5-26.4 parts of As,O, per million, with an average value 

of 13.9 ppm. (6). Cogbill and Hobbs (S) found that main-stream smoke 

of Cigarettes containing 7.1 pg. of arsenic per cigarette contains 0.031 pg. per 

puff. This amount would be equivalent to 0.25 pg. of arsenic per cigarette 

(8 puffs), and hence a smoker consuming 2.5 packs of such cigarettes per 

day might inhale 12.5 pg. of arsenic per day. By comparison, analysis of the 

atmosphere of New York City over a 12-year period indicated an average 

content of 100-400 pg. of arsenic per 10 cubic meters, which is an approximate daily intake per person (38). 

Extensive Federal efforts to discourage the use of arsenicals for the control 

of tobacco hornworms on the growing tobacco crop resulted in a sharp de- 

‘This tapir is disrussel~ more fully in ~haptrr IO. 

61 
cline in the arsenic content of cigarettes after 1950. Thus, the average 

arsenic content of 17 brands of cigarettes analyzed in 1958 was 6.2 ppm. of 

As,O, (14). 

It seems unlikely that the amount of arsenic derived even from unfiltered 

cigarettes is sufficient to present a health hazard. 

Chemicals recommended by the Department of Agriculture for the control 

of tobacco insects are: malathion, parathion, Endosulfan, DDT, TDE, end&, 

dieldrin, Guthion, aldrin, heptachlor, Diazinon, Dylox, Sevin, and chlordane 

(42a). Trace amounts of TDE and endrin have been detected in commercial 

cigarettes and cigarette smoke. Guthion and Sevin residues were detected 

in main-stream cigarette smoke at levels approximating 0.3 percent and l 

percent of that added to cigarettes prior to smoking. Tobacco treated with 

Guthion and Sevin at the recommended levels showed no measurable contamination of main-stream cigarette smoke (4b). (For discussion of carcinogenicity of tobacco pesticides, see Chapter 9.) 

Cigarette manufacture in the United States includes use of additives such 

as sugars, humectants, synthetic flavors, licorice, menthol, vanillin, and rum. 

Glycerol and methylglycerol are looked on with disfavor as humectants because on pyrolysis they yield the irritants acrolein and methylyglyoxal. 

Additives have not been used in the manufacture of domestic British cigarettes 

since the Customs and Excise Act of 1952, Clause 176, and probably longer, 

inasmuch as Section 5 of the Tobacco Act of 1842 imposed a widespread 

prohibition on the use of additives in tobacco manufacture. 

SUMMARY 

Of the several hundred compounds isolated from the tobacco leaf, two 

groups are specific to tobacco. One of these groups includes the alkaloid 

nicotine and related substances. The other includes compounds described as 

isoprenoids. Cigarette smoke is an heterogeneous mixture of gases, uncondensed vapors, and particulate matter. In investigating chemical composition 

and biological properties, it is necessary to deal separately with the particulate 

phase and gas phase of smoke. 

Components of the particulate phase other than the higher polycyclics 

include aliphatic and alicyclic hydrocarbons, terpenes and isoprenoid hydrocarbons, alcohols and esters, sterols, aldehydes and ketones, acids, phenols 

and polyphenols, alkaloids, nitrogen bases, heterocyclics, amino acids, and 

inorganic chemicals such as arsenic. potassium, and some metals. Seven 

polycyclic compounds isolated from cigarette smoke have been estahlished to 

be carcinogenic. They are shown in Table 2. The over-all carcinogenic 

potency of tobacco tar is many times the effect which can be attributed to 

substances isolated from it. The d’1 ff erence may be associated in part with 

the presence in tobacco smoke of cocarcinopens, several of which have been 

identified as smoke components. 

Components of the gas phase of cigarette smoke have been shown to produce various undesirable effects on test animals or organs, one of which is 

suppression of ciliary transport activity in trachea and bronchi. 

62 
REFERENCES 

1. Albert, R. E., Nelson, N. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

2. Alvord, E. T., Cardon, S. Z. The inhibition of formation of 3,4-benzpyrene. Brit J Cancer 10: 49%506, 1956. 

3. Berenblum. I.. Shubik, P. The role of croton oil applications, associated 

with a single painting of a carcinogen, in tumour induction of the 

mouse skin. Brit J Cancer 1: 379-82. 1947. 

1. Boutwell, R., Bosch. D. K. The tumor-promoting action of phenol 

and related compounds for mouse skin. Cancer Res 19: 413-24, 1959. 

4a. Boutwell, R., Bosch, D. K., and Rusch, H. P. On the role of croton oil 

in tumor formation. Cancer Res 17: 71, 1957. 

4b. Bowery, T. G., Guthrie, F. E. Determination of insecticide residues on 

green and flue-cured tobacco and in main-stream cigarette smoke. 

Agriculture and Food Chem 9( 3) : 193-7, 1961. 

5. Campbell, J. M., Lindsey, A. J. P o 1 ycyclic hydrocarbons in cigar smoke. 

Brit J Cancer 11: 192-5, 1957. 

6. Carey, F. P.. Blodgett. G.: Satterlee, H. S. Preparation of samples for 

determination of arsenic. 0. xygen-bomb combustion method. Industr 

Eng Chem Anal Ed 6. 327-30. 193-1. 

7. Clemo, G. R. Some aspects of the chemistry of cigarette smoke. Tetrahedron 3: 168-74, 1958. 

8. Copbill, E. C., Hobbs, M. F,. Transfer of metallic constituents of cigarets to the main-stream smoke. Tobacco Sci 1: 68-73: 1957. 

9. Dauben, W. G., Thiessen, W. E., Resnick. P. R. Cembrene, A 14-membered ring diterpene hydrocarbon. J Amer Chem Sot 84: 2015-6, 

1962. 

10. Falk, H. L.. Tremer, H. M., Kotin, P. Effect of cigarette smoke and 

its constituents on ciliated mucus-secreting epithelium. J Nat Cancer 

Inst 23: 999-1012, 1959. 

11. Fieser, L. F., Fieser, M. Topics in organic chemistry. New York, 

Reinhold, 1963, p. 43-56. 

12. Fieser, L. F., Greene, T. W., Bischoff, F., Lopez, G., Rupp, J. J. [Communication to the editor] A carcinogenic oxidation product of cholesterol. J Amer Chem Sot 77: 3928-9, 1955. 

13. Grossman, J. D.. Deszyck, E. J., Ikeda, R. M., Bavley, A. A study of 

pyrolysis of solanesol. Chem Industr 1950-1962. 

la. Guthrie, F. E., McCants, C. B., Small, H. G., Jr, Arsenic content of 

commercial tobacco, 1917-1958. Tobacco Sci 3: 624, 1959. 

15. Hadler, H. I., Darchun, V., Lee, K. Initiation and promotion activity 

of certain polynuclear hydrocarbons. J Nat Cancer Inst 23: 1383-7, 

1959. 

16. Hartwell, J. L. S urvey of compounds which have been tested for carcinogenic activity, Federal Security .4gency, Public Health Service 

Pub No. 149, 1951. 583 p, 

17. Hilding, A. C. On cigarette smoking, bronchial carcinoma and ciliary 

action. 3. Accumulation of cigarette tar upon artificially produced 

714-422 O-64-6 63 
deciliated islands in the respiratory epithelium. Ann Othol 65: 116 

30, 1956. 

18. Hilding. A. C. On cigarette smoking. bronchial carcinoma and ciliary 

action. 2. Experimental study on the filtering action of cow’s lungs, 

the deposition of tar in the bronchial tree and removal by ciliary action, 

New Eng J Med 251: 1155-60, 1956. 

19. Holsti. P. Tumor promoting effects of some long chain fatty acids in 

experimental skin carcinogenesis in the mouse. Acta Path Microbial 

Stand -16: 51-8, 1959. 

20. Homburger, F., Tregier, A. Modifying factors in carcinopenesis. Progr 

Exp Tumor Res 1: 31 l-28, 1960. 

21. Hurd, C. D., Macon, A. R. Pyrolytic formation of arenes. 4. Pyrolysis 

of benzene, toluene and radioactive toluene. J -\mer Chem Sot 84: 

4524-6, 1962. 

22. Hurd, C. D., Macon, A. R., Simon. J. I.. Levetan, R. V. Pyrolytic formation of arenes. 1. Survey of general principles and findings. J Amer 

Chem Sot 84: 4509-15, 1962. 

23. Hurd, C. D., Simon, J. I. Pyrolytic formation of arenes. 3. Pyrolysis 

of pyridine: picolines and methylpyrazine. J Amer Chem Sot 84: 

4519-24, 1962. 

24. Johnstone, R. A. W., Plimmer, J. R. The chemical constituents of tobacco and tobacco smoke. Chcm Rev 59: 885-936, 1959. 

25. Keith, C. H.: Newsome, J. R. Quantitative studies on cigarette smoke. 

1. An automatic smoking machine. Tobacco 144: (13) 26-32. 

May 29, 1957. 

26. Keith, C. H., Newsome, J. R. Quantitative studies on cigarette smoke, 

2. The effect of physical variables on the weight of smoke. Tobacco 

144 (14) : 26-31, Apr 5, 1957. 

27. Kennaway, E., Lindsey, A. J. Some possible exogenous factors in the 

causation of lung cancer. Brit hIed Bull 14: 124-31, 1958. 

28. Kensler, C. J., Battista, S. P. Components of cigarette smoke with ciliarydepressant activity. New Eng J Med 269: 1161-1166, 1963. 

29. Kosak, A. I., Swinehart. J. S., Taber. D., Van Duuren, B. L. Stigmaster01 in cigarette smoke. Science 125: 991-2, 1957. 

30. Langer, G.. Fisher, N. A. Concentration and particle size of cigarettesmoke particles. AM&\ Arch Industr Health 13: 372-8: 1956. 

31. Liggett & Myers Tobacco Co. Arthur D. Little, Inc. Special report to the 

Surgeon General’s Advisory Committee on Smoking and Health. 

32. Lindsey, A. J. Some observations upon the chemistry of tobacco smoke. 

In: James, G., Rosenthal. T.. eds. Tobacco and health. Springfield, 

Ill.. Thomas, 1962. Chapter 2: p. 21-32. 

33. Orris, L., Van Duuren, B. L.. Kosak. A. I.. Nelson. N.: Schmitt, F. L. 

The carcinogenicity~ for mouse skin and the aromatic hydrocarbon 

content of cigarette-smoke condensates. J Nat Cancer Inst 21: 

557-61, 1958. 

34. Osborne, J. S., Adamek, S.. Hobbs: M. E. Some components of gas 

phase of cigaret smoke. Anal Chem 28: 211-5, 1956. 

64. 
35. Philippe, R. J.. Hobbs, M. E. Some components of the gas phase of 

cigaret smoke. Anal Chem 2::: 2002-6. 1936. 

36. Roberts. D. L.. Rowland, R. I,. >Iacrccyclic diterpenes a and B-4, 8, 

13.Duvatriene -I.:<-dials from tobacco. J Org Chem 27: 396%95, 

1962. 

37. Ro\$land, R. L.. Rodgman. A.. Schumacher. J. 5.. Roberts. D. L., Cook, 

L. 0.. Walker. W. E. 1063 I In press). 

;<X. Satterlee, H. S. The problem of arsenic in American cigarette tobacco. 

New Eng J lied 25-l: 11 1951. 1936. 

39. Setala: H. Tumor promoting and co-carcinogenic effects of some nonionic lipophilic~~h! drophilic t surface active) agents. -Acta Path 

Microbiol Stand ( Suppl No. 115 ) p. l-93, 1956. 

$0. Shubik, P.. Hartwell. J. L. S LI 1 1 1 ) I ement 1. Department of Health. Cducation and Welfare. PHS Pub So. 149. 195i. 

41. Tarbell, D. S.. Brooker. E. G.. Vanderpool, A.. Con\+ay. W.. Claus, C. J., 

Hall. T. J. A system for paper chromatography of 3,4-benzpyrene, 

some derivates and other pal!-cyclic aromatic hy-drocarbons. J Amer 

Chem Sot 77: 767-G, 1955. 

42. Touey, G. P.. Ilumpoher. R. C. ;\I easurement of the combustion-zone 

temperature of cigarettes. T o 1 )acco 144: (81 18-22, Feb 22, 1957. 

42a. U.S. Department of Agriculture. Insecticide recommendations of the 

Entomology Research Di, ision for the Control of Insects Attacking 

Crops and Livestock for 1063. Handbook No. 120, Agricultural Research Service and Federal Extension Service, 1963. 

43. Van Duuren: B. L. Identification of some polynuclear aromatic hydrocarbons in cigarette smoke condensate. J Nat Cancer Inst 21: 1-16, 

1958. 

-44. Van Duuren, B. L. Some aspects of the chemistry of tobacco smoke. 

In: James. G., Rosenthal, T. eds. Tobacco and health. Springfield, 

Ill., Thomas. 1962. Chapter 3, p. 33-47. 

45. Van Duuren, B. L. The polynuclear aromatic hydrocarbons in cigarette smoke condensate. 2. J Nat Cancer Inst 21: 623-30, 1958. 

46. Van Duuren, B. L.: Schmitt, F. L. Isolation and identification of some 

components of cigarette smoke condensate. J Org Chem 23: 473-5, 

1958. 

47. Van Duuren, B. L., Schmitt, F. L. Isolation and identification of 

squalene from cigarette smoke condensate. Chem Industr, 1006-7, 

1958. 

18. Williams, J. F.. Garmon, R. G. Beryllium in cigaret tobacco. Tobacco 

Sci 5: 25-7, 1961. 

49. Wynder, E. L., Fritz, L.. Furth, Iv. Effect of concentration of benzopyrene in skin carcinogenesis. J Nat Cancer Inst 19: 361-70, 1957. 

50. Wynder, E. L.: Hoffmann, D. Present status of laboratory studies on 

tobacco carcinogenesis. Acta Path Microbial Stand 52: 119-32, 

1961. 

51. Wynder, E. L.. Hoffman. D. A study of tobacco carcinogenesis. 7. 

The role of higher polycy-clic hydrocarbons. Cancer 12: 1079-86, 

1959. 

65 
Chapter 7 

Pharmacology and 

Toxicology of 

Nicotine 
Contents 

Page 

GENERAL PHARMACOLOGIC ACTION OF NICOTINE ON 

SERVE CELLS .................... 

EFFECTS ON THE CENTRAL NERVOUS SYSTEM ... 

CARDIOVASCULAR EFFECTS. ............. 

GASTROINTESTINAL EFFECTS. ............ 

DISTRIBUTION AKD FATE. .............. 

CHRONIC TOXICITY .................. 

SUMMARY ....................... 

REFERENCES. ..................... 

Figure 

FIGURE I. Summary diagram of routes for the metabolism 

of nicotine in mammals . . . . . . . . . . . . . . . . . 

69 

69 

70 

71 

71 

73 

74 

75 

72 
Chapter 7 

GENERAL PHARYACOLOGIC ACTION OF NICOTINE ON 

NERVE CELLS 

The pharmacology and 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 of nicotine involves a direct effect on sy-mpathetic 

and parasympathetic ganglion cells ( 18 I. This usually occurs as a transient 

excitation, followed by depression. or even paralvsis with effective doses. 

The ganglia are rendered more sensitive to acetylcholine initially and thus 

make preganglionic impulses more effective. Paralysis is associated with 

diminished sensitivity of ganglia to acet\lcholine 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 I 161. In the central nervous system, as in ganglia, 

primary stimulation is succeeded b! depression. Furthermore. nicotine like 

acetylcholine discharges epinephrine from the adrenal glands and other 

chromaffin tissue (20) ; it also releases antidiuretic hormone from the 

posterior pituitary by stimulating the supraopticohypophyseal system 13 ) . 

Nicotine also augments various reflexes by excitation of chemoreceptors in 

the carotid body ilO). 

The pharmacological response of the whole organism at any one time 

therefore, representing as it does the algebraic sum of stimulant and depressant effects resulting from many direct. reflex, and chemical mediator 

influences on autonomic nervous transmission and excitabilitv of virtually all 

organ systems, defies accurate description. The wide variation in smoking 

habits leads to every conceivable pattern of fluctuating blood levels of nicotine during the day. This su ggests strongly that nicotine-sensitive cells may 

be shifting continuously from excitation to depression. Such activity probably accounts for the unpredictable effects observed in different individuals 

and in the same individual at different times. Using the classic pharmacological approach, it is therefore virtually impossible to make reliable statements regarding the effect of smoking on the many organ systems. In order 

to characterize the biological effects of nicotine in man, it thus becomes necessary to place heavy reliance on symptoms and signs derived from clinical and 

epidemiological studies. 

EFFECTS ON THE CENTRAL NERVOUS SYSTEM 

The action of nicotine on central nervous system functions has recently 

been reviewed ( 20 1. Very little of the reported work involves human 

69 
experimentation, and most of it is with doses much larger than are ass,,. 

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. Electra. 

encephalographic (EEG) studies in the intact rabbit (21) indicate that nice. 

tine, in doses of 0.5 to 3.0 milligrams per kilogram, produced an “arousal 

reaction” involving the hippocampus. In a later stage of the same reaction 

there appeared a discharge pattern similar to that noted in convulsions. 

Lesions in the septum abolished the “arousal reaction,” chlorpromazine and 

evipan abolished the discharge pattern. None of the congeners of nicotine, 

including lobeline, produced similar patterns. 

Knapp and Domino ( 12) found that concentrations of nicotine (10 to 

20 pg/kg), a level commonly reached in man by smoking, produced EEG 

arousal patterns in four species of animals, the rabbit, cat, dog, and monkey, 

after neopontine transection. Th ese 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 electroencephalogram) 

in 25 human subjects before and 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 to carbon monoxide and nicotine resulting 

in cerebral anoxia and/or release of epinephrine. Hauser et al. (9), who 

studied the EEG changes on cigarette smoking in healthy young adults, obtained highly variable responses usually toward an increase in the dominant 

alpha frequency of 1 or 2 cycles per second. Some subjects showed similar 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 of 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 meaningful 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. 

CARDIOV.-\SCULAR EFFECTS 

The cardiovascular effects of nicotine are described in Chapter 11, Cardio. 

vascular Diseases. 

70 
GASTROINTESTINAL EFFECTS 

hlost but not all experimental and clinical evidence supports the popular 

\ iew that smoking reduces appetite ( 6: 17 p. 271 I. This reduction has been 

attributed both to direct effects on gastric secretions and motilit! and to 

reflexes arising from local effects on the taste buds and mucous metnbranes 

in the mouth. The unpredictable and temlborary elevation of blood sugar 

is probably too small to contribute significantly f 17. p. 326). Nicotine 

effects on the hypothalamus. comparable to the appetite reduction produced 

II! other stimulants like amphetamine. and psychological mechanisms may 

pIa!- significant roles ( 23 1. Hunger contractions are inhibited but gastric 

movements of digestion do not appear to he influenced sigtlificantlv 1)~ 

moderate smoking (4 I. 

Nausea, often associated with \-omiting. is 1,~ far the most common 

31 tnptom related to the gastrointestinal tract. This effect probably originales centrally in the tnedullarv emetic chemoreceptor trigger zone ( 14). 

It is now generally agreed that nicotine stimulates peristalsis but the 

mechanism is a cotnplex one. probahl! in\-&+ local. central and reflex 

actions. Schnedorf and Ivy 121 I found \tide individual variation in gastrointestinal passage time in medical student smokers and non-smokers but 

- #rained the impression that smokin g tends to augment motility of the colon. 

These effects are probably related to actions on the parasympathetic gan$ia 

in the bowel. The summative effects of all of these pharmacological actions 

nn the whole intestinal tract do not produce a consistent pattern. Excessive 

smoking may be associated \+ith diarrhea. constipation. or alternating patterns between the two extremes. The only consistency is that s\mptoms 

attributable to nicotine effects on the gastrointestinal tract are very common. 

DISTRIHUTION AND FATE 

Nicotine is actively and rapidly metabolized by man and other mammals, 

the metabolites being in large measure excreted in the urine. If any tissue 

storage occurs, it is in such small quantity as to elude current analytical 

Mnics. Nicotine is a rather unstable molecule \\hich in neutral or alkalifte conditions undergoes a varietv of changes. A review of the current 

‘oncepts of the known and sugiested pathways for the metabolism of 

nicotine is shown in Figure 1 (18). The main intermediate appears 

to be I - j -cotenine which yields y- (3.pyridyl) --/-methylamino butyric 

acid. Cotenine has 10~ toxic& and lacks the potent pressor activity of 

nicotine. 

r) ogs receiving 150 tnp/kg.‘day orally for 108 days exhibited no weight 

“W or other objectire simns (2) . 

irltrrvals for 6 da ‘s 

Man has ingested 500 mg orally at g-hour 

) witChout untoward effects. Ro evidence has been preynted that the other known metabolites of nicotine carry an\- significant 

“stemic toxicity. 
SUMMARY DIAGRAM OF ROUTES 

FOR THE METABOLISM OF NICOTINE IN MAMMALS 

(Some hypothetical intermediates are shown in brackets.) 

N,<WLiW Ryhprroxkie wydr<,xy”icdi”r* Ilydruxycotinlne 

y-(a-l’yr,dyl)-y-mrLhylnmino),ulyreld~.~~d~ “~Stdh~lC”tl”ill~ 

CH) y-(3-l’yiidyI)-y-n,~~rllyiR Acid ”,i”~~bntyr,r cutinine Cotinlnn Mrthon1um Ion 

[VI 
CHROItlC TOXICITY 

Evaluation of the chronic toxicity of tobacco smoke may be considered 

in several categories: la) the systemic toxicity of nicotine or its congeners, 

I b I the systemic toxicity of other constituents of smoke or tobacco, carbon 

monoxide and other compounds, (c) specific organ toxicity in certain susceptible individuals, such as those with Buerger’s disease and allergic responses, (d I local effect of irritants on mucous and pulmonary membranes 

by tars. phenols, the oxides of nitrogen, and others. The latter three types 

of potential toxicity are discussed in Chapter 9. Cancer, and Chapter 10. 

Non-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 dealing with 

a comparatively simple organic compound of known composition and reaction. Whereas there is a voluminous literature of studies involving 

chronic exposure to nicotine or tobacco smoke in many animal species (17, 

pp. 501-504), 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 subconvulsive J . which is greatly in excess 

of any human smoking exposure. Even though some authors I 11) observed 

weight loss and degenerative vascular changes in rats under these severe 

conditions. others 122i noted some weight loss but no histologic change. 

In life span experiments in rats, with tobacco smoke in amounts approximating human smoking exposure, very little systemic toxicity was noted 

18, 13). Even though animal experimentation is inadequate, especially in 

long-term effects of nicotine on large animal species. existing data permits 

a tentative conclusion that the chronic systemic toxicity of nicotine is quite 

low in small to moderate dosage. 

The clinical literature is devoid of human data concerning chronic exposure to nicotine alone, and the general statements regarding the chronic 

toxicity of nicotine for man represent inferences drawn from chronic exposure to tobacco in various forms, including industrial poisoning. Repeated 

exposure to tobacco in 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 little concern 

here. The question is whether prolonged exposure to nicotine, in the quantities absorbed systemically from smoking or other tobacco use, produces 

toxic effects whidh result in unpleasant symptoms, dangerous signs, specific 

degenerative disease, or shortening of the life span. Unfortunately even a 

tentative answer to this question must be obtained indirectly and by making 

certain assumptions. Inasmuch as nicotine is systemically absorbed from 

all routes of administration, smoking, chewing, snuffing, or “snuff dipping,“* 

it appears logical to assume that if the amounts of nicotine absorbed in the 

various methods of 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 

“A small amount of snuff is placed in the groove between the teeth and thp lower lip 

Or beneath the tonwe and held there from 30 minutes to several hours. r 

73 
absorbed (50-60 mpi from 6 cigars uninhaled equals that from 30 ciga. 

rettes inhaled ( 19). Chewing tobacco may yield 8 to 87 mg in 6 to 8 hours 

(24’) ; in chewing snuff. 20-60 mg of nicotine (7). 

The following variables play a role in the amount of nicotine absorbed 

(17, p. 8, : 

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 with which the smoke comes in contact: 

3. Degree and depth of inhalation; 

4. Degree of habituation 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. Agglomeration of smoke particles (more important in cigarette. 

smoking). 

There is no acceptable evidence that prolonged exposure to nicotine creates 

either dangerous functional change of an objective nature or degenerative 

disease. The minor evidences of toxicity, nausea, digestive disturbances 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. In view of the mortality ratios of pipe and cigar 

smokers, it follows logically that the apparent increase in morbidity and 

mortality among cigarette smokers relates to exposure to substances in smoke 

other than nicotine. Unfortunately, th ere are no useful mortality statistics 

in those who cheu, snuff. or “dip” tobacco, and the literature regarding industrial exposure is so confusing that little help is available here. The type 

of projection made above. however unsatisfactory, is not inconsistent with 

the animal toxicity data as well as the fact that nicotine undergoes very rapid 

metabolism to substances of low toxicity. The evidence therefore supports 

a conclusion that the chronic toxicity of nicotine in amounts ordinarily obtained in common forms of tobacco use is very low indeed. 

SUMMARY 

The pharmacological effects of nicotine at dosage levels absorbed from 

smoking (l-2 mg per inhaled cigarette) are comparatively small; the 

response in 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. Th e 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 pressure, 

suppression of appetitite. stimulation of peristalsis and. with larger doses. 

nausea of central origin which may be associated w-ith vomiting. 

Nicotine is rapidly metab-olized by man and certain other mammals. The 

primary pathway through ( - I cotenine to r- ( 3-pyridyl ) -y-methylaminobutyric acid is described in detail. The known metabolites have verv- low 

toxicity. 

The rapidity of degradation to non-toxic metabolites, the results 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 tobacco use is very low and probably does not represent a significant health 

problem. 

REFERENCES 

1. Bickford. R. G. Physiology and drug action: An electroencephalographic analysis. Fed Proc 19: 619-25. 1960. 

2. Borzelleca. J. F.. Bowman. E. F.. McKennis. H.. Sr. Studies on the 

respiratory and cardiovascular effects of ( - I cotenine. J Pharmaco1 Exp Ther 137: 313. 1962. 

3. Burn. J. H.. Truelove, L. H.. Burn. I. The antidiuretic action of nicotine and of smoking. Brit Med J 1: 403-6, 1915. 

4. Carlson. A. J., Lewis. J. H. Contributions to the physiology of the 

stomach. 14. The influence of smoking and of pressure on the abdomen (constriction of the belt) on the gastric hunger contractions. 

Amer J Physiol 34: 149-54, 1914. 

5. Comroe. J. H.. Nadel. J. The effect of smoking and nicotine on respiration. In: James. G., Rosenthal. T. eds. Tobacco and health. Springfield. Thomas, 1962. Chapter 17, p. 233-43. 

6. Effect of smoking on appetite and on peripheral vascular disease. 

[Queries and minor notes] JAMA 119: 534, 1942. 

7. Gaede. D. Sur wirkung des schnupftabaks. Naunyn Schmiedeberg 

Archiv Exp Path, 130-45: 1944. 

8. 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, H., Schwarz. B. E., Roth. G., Bickford, R. G. Electroencephalographic changes related to smoking. Electroenceph Clin Neuro10. H 

physiol 10: 576, 1958. 

eymans. C.. Bouchaert. J. J.. Dautrebande. L. Sinus carotidien et 

reflexes respiratories. 3. S ensibilite des sinus carotidiens aux substances chimiques. Action stimulante respiratorie reflexe du sulfure 

de sodium, du cyanure de potassium, de la nicotine et de la labeline. 

Arch Int Pharmacodyn 40: 54-91, 1931. 

‘1. Hueper, W. C. Experimental studies in cardiovascular pathology. 7. 

Chronic nicotine poisoning in rats and dogs. Arch Path (Chicago) 

35: 846-56, 1943. 

75 
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. 

hakrauch. Ein beitrag zur wirkung von tabakfeuchthaltemittein. 2 

Ges Exp Med 118: 553-72, 1952. 

1 l. Laffan. R. J.: Borison, H. L. Emetic action of nicotine and lobeline. 

J Pharmacol Exp Ther 121: 468-76, 1957. 

15. Lambiase. M.. Serra, C. Fumo e sistema nervoso. 1. Modificazioni 

tlell’attivita elettrica corticale da fumo. Acta Neurol (Napoli) 12: 

-175-93, 1957. 

16. Langley. J. N. On the reaction of cells and of nerve-endings to certain 

poisons, chiefly as regards the reaction of striated muscle to nicotine 

and to curari. J Physiol (London) 33: 374-413, 1905. 

17. Larson, P. S., Haag, H. B., Silvette, 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. Nicotine content of smoke from cigars and cigarets. [Queries and minor 

notes] JAMA 130: 825,1946. 

20. Rapela. C. E., Houssay, B. A. ,\cci6n de la nicotina sobre la secrecibn 

de adrenalina y nos adrenalina de la sangre venosa suprarrenal del 

perro. Rev Sot Argent Biol 28: 219-24, 1952. 

21. Schnedorf, J. G., Ivy, A. C. The effect 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 nicotine on central nervous system function. Pharmacol Rev 14: 137-73. 

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 
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 .......... I35 

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 ........ 9i) 

Inhalation of Smoke .................. 91 

Ex-Cigarette Smokers ................. 92 

Ex-Cigar and Pipe Smokers ............... 94 

EVALUATION OF SOURCES OF DATA ......... 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 

SUMMARY ....................... 108 

Total Mortality .................... 

Cigarette Smokers .................. 

ii 

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 
Figure 

!hXJRE 1. Death rates (logarithmic scale) plotted against age 

for current cigarette smokers and non-smokers, U.S. veterans 

study . . . . . . . . . . . . . . . . . . . . . . . . . 

List of Tables 

TABLE 1. Outline of prospective studies of smoking and mortality. 

TABLE 2. Mortality ratios of current smokers by type of 

smoking . . . . . . . . . . . . . . . . . . . 

TABLE 3. Mortality ratios for current smokers of cigarettes only, 

by amount smoked . . . . . . . . . . . . . . 

?'.ABLE 4. Mortality ratios for current smokers of cigars only, by 

amount smoked . . . . . . . . . . . . . . . . 

TABLE 5. Mortality ratios for current smokers of pipes only, by 

amount smoked . . . . . . . . . . . . . . . . 

TABLE 6. Mortality ratios by age group for current smokers of 

cigarettes only, men in 25 States . . . . . . . . . 

'I'ABLE 7. Increase in natural logarithm of death rate per 1,000 

man-years for each j-year increase in age, 6 prospective studies . . . . . . . . . . . . . . . . . . 

TABLE 8. Mortality ratios by age at which smoking was started 

and by amount smoked for current smokers of 

cigarettes only . . . . . . . . . . . . . . . . . 

TABLE 9. Mortality ratios for current smokers by type of smoking 

and by length of time smoked . . . . . . . . . . 

TABLE 10. Mortality ratios for smokers of cigarettes only by 

inhalation status and amount of smoking . . . . . 

TABLE 11. Mortality ratios for ex-smokers and current smokers of 

cigarettes . . . . . . . . . . . . . -, . . . . . 

TABLE 12. Mortality ratios for ex-smokers of cigarettes only by 

number of years since smoking was stopped and by 

amount smoked . . . . . . . . . . . . . . . . 

TABLE 13. Mortality ratios for ex-cigarette smokers by number 

of years of smoking, U.S. veterans study . . . . . 

TABLE 14. Mortality ratios for ex-smokers of cigars only and 

pipes only and for current cigar and pipe smokers . 

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 . . . . . . . . . . . . . . . . . . 

TABLE 16. Percentages of usable replies in five studies . . . . . 

TABLE 17. Mortality ratios for cigarette smokers by populationsize of city . . . . . . . . . . . . . . . . . . 

TABLE 18. Age-adjusted death rates per 1,000 (over approximately 

22 months) for variables that may be related to 

mortality . . . . . . . . . . , . . . . . . . . 

88 

83 

85 

86 

86 

87 

87 

89 

89 

90 

91 

93 

93 

93 

94 

95 

96 

99 

100 

714-422 o-64-7 79 
TABLE 19. Total numbers of expected and observed deaths and 

mortality ratios for smokers of cigarettes only in 

seven prospective studies . . . . . . . . . . . . 

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) . 

TABLE 21. Mortality ratios for coronary artery disease for smokers 

of cigarettes only by amount smoked. . . . . . . 

TABLE 22. Lung cancer mortality ratios for current smokers of 

cigarettes only by amount smoked . . . . . . . . 

I'ABLE 23. Expected and observed deaths and mortality ratios for 

current cigarette smokers, for selected causes of 

death, by amount smoked, in six studies . . . . . 

TABLE 24. Numbers of expected and observed deaths and mortality ratios for cigar and pipe smokers, in five studies . 

TABLE 25. Percentage of total number of excess deaths of cigarette 

smokers due to different causes . . . . . . . . . 

TABLE 26. Numbers of expected and observed deaths for smokers 

of cigarettes only, and mortality ratios, each prospective study and all studies . . . . . . . . . . . . 

TABLE 27. Age-adjusted death rates (per 1,000 person-years) for 

1954 respondents, 1957 respondents, and nonrespondents in U.S. veterans study . . . . . . . . 

TABLE 28. Illustration of calculation of non-response bias . . . . 

T.~BLE 29. Mortality ratios in respondents and computed values 

for the complete population . . . . . . . . . . . 

TABLE 30. Proportions and death rates for Berkson’s example . . 

page 

102 

105 

106 

106 

106 

107 

108 

109 

114 

115 

116 

116 

80 
Chapter 8 

PROSPECTIVE STUDIES 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 1959. 

In brief, the seven groups of men are as follows: 

(1) British doctors, a questionnaire having been sent to all members of 

the medical profession in the United Kingdom by Doll and Hill, 

1956 (5). 

(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 white 

men between the ages of 50 and 69. Hammond and Horn, 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 suspected of being subject to a higher than usual occupational risk of 

developing lung cancer. Dunn, Linden and Breslow, 1960 (7). 

(5) California members of the American Legion and their wives. Dunn, 

BuelI and Breslow (8). 

(6) Pensioners of the Canadian Department of Veterans Affairs, i.e., veterans 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). 

It will be noted that the studies cover different types of population groups 

in three countries. Study (2), often referred to as the Hammond and Horn 

study, terminated after 44 months’ follow-up, and the data discussed here 

for this study are essentially the same as those already published (10) I 

All other studies have accumulated substantial amounts of data beyond 

that which has been published. The authors and agencies responsible for 

81 
the studies supplied their 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. 

rollment, 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 nCw American Cancer Society study. The number 

of months of follow-up varied from about 22 to 120. 

Although several of the studies obtained some data on women, only the 

California Legion study (8 1 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. 

DATA ON SMOKING HISTORY 

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 of 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. 

*&s 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 numbers of subjects are too small to give reliable data 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 measure for this purpose is the age-specific death rate, in which the rate is computed 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 
TABLE l.--Outline of prospective studies of smoking and mortality 

Authors Doll RT IIill (5) IIsmmand L 

Horn (10) 

Subjects Hritish doctors White men in 9 states 

-- 

Number of usable replies 

Date of enrollment 1 Oct. 1951 1 Jan-Mar. 1952 

Number of desths 4,534 11,870 

Person-years of exposure 269,iKm @Km 

- 

. 

.- 

.- 

.- 

.- 

._ 

._ 

- 

Darn (6) 

U.S. veterms 

248,ooo 

Jan. 1954 and 

Jan. 1957. 

30.75+ 

78 

24,519 

1,312,MKl 

- 

._ 

.- 

._ 

.- 

.- 

.- 

.- 

- 

Dunn, Linden, Dunn, Buell, Best, Josie, Walker 

Breslow (7) 

IIsmmond (11) 

Hreslow (R) (21 

California oceu- California Ameri- Csnsdisn pensioners Men in 25 States 

pstional groups can Lenion mm- (veterws and de. 

hers pendents) 

Nov,fl$y’ 1 May-Nov. 1957 / Sept. 1955-July, 1956 1 O;t.I;5(t-Fcb 

35+?9 3%75+ 35-75+ 35-89 

About 48 About 24 72 About 22 

1,714 1 1,704 I 9,070 1 11.612 
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. Th is 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 death 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 than 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 U.S. 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. Th ese products are added and finally divided by the 

total standard 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 computed in different ways will of course give somewhat different results and 

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 adjustment 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 had higher 

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 known or suspected to influence death rates, such as economic 

level, residence, hereditary factors, exposure to 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 published, the death rates of smokers and non-smokers have not been adjusted 

so as to equalize the effects of these disturbing variables. This issue will 

be discussed later in this chapter. 

A further complexity in interpreting the results comes from interrelationships 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 
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 subclassified in order to make the adjustments? the numbers of deaths per subclass 

are small, with the consequence that the adjusted death rates are somewhat 

unstable. 

Consequently, like previous reporters on 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 shows the mortality ratios to non-smokers for men who were smoking regularly at the time of enrollment. 

For males smoking cigarettes only, the over-all death rate is higher than 

that for non-smokers in all studies, 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 the increases in death rates 

are in all cases lower 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 11 percent. 

The study of men in 25 states, however, gives slight decreases for both types, 

as does the British study for the two types combined. 

TABLE 2.-Mortality ratios of current smokers by type of smoking 

G3rettes only.--...--.-....--.---.-.-.--. 1.70 1. )13 

%uettes and other _.._._._..__..__..__.. 1.45 1. 54 

%irs only... _._- __.__..__ -_ ___._.__ _.... 1. 10 0. 97 

Rwsonly... _..___.__..__ .__.. __-- __.___. 1. 05 0.86 

’ The California occupational and Legion studies give mortality ratios of 1.78 and 1.58 respectively. for 

811 cigarette smokers (current and ex-smokers). 

MORTALITY RATIOS BY A~IOUNT SMOKED 

For smokers of cigarettes only who were smoking at the time of entry, 

the mortality ratio increases consistently with the amount smoked in each 

of the seven studies, with one exception for the California occupational study, 

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 into two amounts of smoking (Table 4). 

Men 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.” 

TABLE 3.-Mortality ratios for current smokers of cigarettes only, by amount 

Cigarettes per British 

day doctors 

ILess than 10..~ 

l&20.. .._ _.__. 

21-39............. 

40 and OWL 

1.06 

1. 31 

3 1.62 

4 2.33 

Men in 9 U.S. 

states vetemus 

California C~$JXSI Canadian Men in 25 

oceups- veterans states 

tional’ 1 

~___ --- 

1.33 1.35 

1.66 1.S 

1.93 1.99 

2. ‘Xl 2.22 

*Current and ex-cigarette smokers combined. 

’ “Less than 10” is “less than 5” plus “about $5”; “10-20” is “about 1”: “21-39” is “about I>$“. 

* Less than 1 pack. 

3 m-34. 

’ 35 plus. 

3 More than 1 pack. 

0 About 1 pack. 

7 More than 1 pack. 

TABLE 4.-Mortality ratios for current smokers of cigars only, by amount 

smoked 

Number per day 

For current pipe smokers (Table 5), men smoking less than 10 pipefuls per 

day have death rates very close to those of non-smokers. For heavy pipe 

smokers (10 or more per day) two studies show increases of 15 and 12 percent in death rates, hut the other two studies show little or no increase. The 

over-all mortality ratio of 1.05 does not differ statistically from unity. The 

*Statistical significance throughout this report refers to the 5 percent level unless otherwise specified. In testing whether an observed mortality ratio of smokers 

relative to non-smokers is greater than unity, the probability is calculated that a ratio 

as large as or larger than the observed ratio would occur by chance if the smokers and 

non-smokers were drawn from two populations having the same death rate. If this probability is less than 0.05 (5 percent) the observed increase in the death rate of smokers 

relative to non-smokers is said to be statistically significant at the 5 percent level. The 

results of significance tests will be quoted only for mortality ratios in which the number 

of deaths r&es a doubt as to whether the difference from unity could be due to sampling 

errors. 

86 
British doctors study gives a mortality ratio of 0.91 for cigar and pipe smokers 

together (presumably mostly pipe smokers) who consume more than 14 gms. 

of tobacco daily. 

TABLE L-Mortality ratios for current smokers of pipes only, by amount 

smoked 

Study 

-__- Owr-all 

Pipes per day ratio 

%tFs g 

U.S. Canadian Men in 25 

veterans veterans states 

______ _______ __-- 

l-9....---- __....___ --.___--- ___...__. --.._ 1.00 1.03 1.07 0.92 1.01 

1001 mOIe.---.....-......------....-..---. 1.15 1.12 1.01 0. i6 1.05 

MORTALITY RATIOS AT DIFFERENT AGES 

As indicated previously, the mortality ratios presented in previous tables 

for different groups of smokers represent a kind of average over the agedistribution of the smokers concerned, and do not necessarily apply to 

smokers of any specific age. For cigarette smokers, the studies show that 

the mortality ratio declines with increasing age, being higher for men aged 

40-50 than for men over 70. This effect is illustrated in Table 6 from 

the study of men in 25 states, which gives the mortality ratio computed 

separately for five age classes. 

The drop in mortality ratio with each increase in age appears fairly consistently for every amount of smoking. For smokers of cigarettes only as a 

whole, the death rate is more than double that for non-smokers in the age 

range 40-49, but only about 20 percent higher for men over 80. The picture is, of course, different if we look at the absolute excess in death rates 

at different ages. Owing to the marked increase in death rates with age, the 

absolute excess also increases steadily with increasing age. 

A more thorough investigation of the relation between death rates and 

age for different groups of smokers has been made by Ipsen and Pfaelzer 

(14). If th e 1 o g arl ‘th m of the age-specific death rate is plotted against age, 

the resulting points lie reasonably close to a straight line. For the U.S. 

TABLE &-Mortality ratios by age group for current smokers of cigarettes 

only, men in 25 States 

Number of cigarettes per day 

Age at start of study 

4Cb49 50-59 es369 70-79 ss89 

- ___~ 

‘~..--~......~~-.-~....-~.-.~...~..~~~.... 

$-$Q~~:~~ ‘~lQ.-....~~~~~.--_~....~.-~~~~~~~-~~-.~~~ -___ _ .._.. . . . . . . . . . . ..--....---. 

2. 27 1.44 1.40 1. 40 1.08 

2.22 3062.12 2.05 13794 1.78603 1.482 50 0. 1.65 53 16

______ ________ 

m amOUnts~----...-..--....---.-.--..-.-- 2.33 2.06 1.70 1.47 1. 22 

87 
veterans study, Figure 1 shows the points and fitted lines for non-smokers 

and for current smokers of cigarettes only. (The lines were fitted by the 

standard method of least squares, weighting each point by the number of 

deaths involved.) 

If the lines for cigarette smokers and non-smokers were parallel, this 

would imply that the mortality ratio of the smokers to the non-smokers was 

constant at all ages, because the vertical distance between the two lines at 

any age is the log of the mortality ratio for that age. In Figure 1, however, 

DEATH RATE (logarithmic scale) PLOTTED AGAINST AGE, 

PROSPECTIVE STUDY OF MORTALITY IN U.S. VETERANS 

AGE IN YEARS 

FIGURE 1. 

88 
the slope is slightly less steep for the cigarette smokers than for the nonsmokers. This indicates that the mortality ratio is declining with increased 

ageTable 7 shows these slopes (increase in the natural logarithm of the death 

rate for each 5-year increase in age) computed from six of the studies. 

The salient features are as follows: (1) In each study the slope for cigarette 

smokers is smaller than the slope for non-smokers; (2) Within the cigarette 

smokers the slope tends to decline, with some inconsistencies, as the amounts 

smoked become greater; (3) for cigar or pipe smokers the slopes are closer 

to those for non-smokers. 

TABLE 7.-Increase in natural logarithm of death rate per 1,000 man-years 

for each S-year increase in age, 6 prospective studies 

Type of smoking 

British Men in 9 U.S. California California Men in 25 

doctors states veterans occupstional 1 

Le@on 1 ~ States 2 

_______~_____ -___ 

Non-smokers _. _ _ ..-.. ,593 ,474 ,499 ,469 502 ,490 

Ciaarcttes by amount per day. ,492 42i ,448 ,436 : 476 ’ .438 

I- ______ 

l-9 ._...__.--...._..___-..-. 516 

: 551 ::: 

490 ’ 

1454 : ii: 

567 

10-m. __..... ~.. .._........_. : 471 

,445 

21-39x . . . . ..~..-..___-.....-. 477 

40+ -......-......._..-_~...~~ :401 :E . . . . . . ..‘“i. ....e--:““;- -...:“‘” 

:t: 

,401 

_______ 

rigors..............-.....-... 

Pipes _.__..._.__.._ _ __....._ __ } .m { :E 

463 .._._...._.. .-..__._.... 

1458 ..___.._.... _-..__...... 

,457 

,458 

I “Cigarettes” includes “cigarettes and other” and current and m-smokers 

’ First 10 months’ experience. 

AGE AT WHICH SMOKING WAS STARTED 

The study of U.S. veterans and the study of men in 25 states provide data 

on the death rates of current smokers of cigarettes only, classified by the 

age at which the person started to smoke. Since in both studies the men 

who start to smoke early tend to smoke greater amounts per day than men 

who start later in life, the mortality ratios to non-smokers are presented 

separately for different amounts of smoking (Table 8). 

TABLE EL-Mortality ratios by age at which smoking was started and by 

amount smoked for current smokers of cigarettes only 

Age started to smoke 

Number of cigarettes per day 

Over-all 

ratio 

1-B 10-20 21-39 a+ 

U.S. veterans: 

Under 20.-e- ____.____ -- _____ .._____._ 

*24..- ..__.. 

2.Sor 

-__- . . ..__ _..._.__ _..._ 

Men in over.. __..___..._.___...._---.... 

25 States: 

Under 15 _._..._ -- . . . . . ..__..______.._. 

E-19 -_...___ -- __......_ _.._______ ____ 

20-24~..~.~~. 

~orover 

__._ -- .._____..____ -- _.___ 

. ..___ _..___._. _____--_______ 

1.60 1.89 2. 16 2. 45 1.96 

1.40 1. 72 1. 87 2. 23 1. 72 

1. 15 1.50 1.47 1. 11 1.39 

1.79 ‘2.23 ’ 2.21 2. 15 2.17 

1.75 ’ 1.83 ’ 2.01 2. 38 1.99 

1.25 Il.52 2 1.62 1.93 1. 59 

1.03 ’ 1.36 2 1.45 1. 56 1.34 

’ 19-19 cigarettes per day. 

’ WV cigarettes per day. 

89 
For a fixed amount of smoking, the mortality ratios (with one exception) 

exhibit a consistent and rather striking increase as the age at which smoking 

was started decreases. Th’ 1s increase appears in all smoking groups of 

Table 8. For men who started smoking cigarettes under the age of 20, 

the over-all death rate was about twice that for non-smokers, whereas for 

those who did not start until they were over 25 the death rate was only about 

35 percent higher. 

MORTALITY RATIOS BY DURATION OF SMOKING 

Three studies have some data available on the number of years during 

which the subjects had smoked. Th e comparison of mortality ratios for 

different lengths of time smoked is of interest in relation to two questions 

raised by Dorn (6) in an earlier analysis of the U.S. veterans’ data. Is there 

a minimum period of use during which no effect on the death rate is notice. 

able? Is there a maximum period after which no increase in the relative 

death rate is perceptible? 

For current cigarette smokers the results (Table 9) are not clear-cut. In 

the U.S. veterans study, men smoking for less than 15 years had death rates 

about the same as non-smokers. There is a rise of about 50 percent in the 

mortality ratio for those who had smoked 15-35 years, with a further rise 

for those smoking longer than 35 years. The study of men in nine states 

shows a rise from under 25 years to 25-34 years duration, but no further 

rise thereafter. In the Canadian study the mortality ratio with cigarette 

smokers is just as high for durations less than 15 years as for durations of 

15-29 years, though there is a rise (to 1.73) for smokers of cigarettes only 

who have been smoking more than 30 years. 

TABLE 9.-Mortality ratios for current smokers by type of smoking and by 

length of time smoked 

Number of years smoked 

Typr of smoking U.S. veterans Canadian veterans Men in 9 States 

<15 1 15-24 2534 35f <15 / 15-29 so+ -<25 2&34 35+ 

-j-~~-~~~--.--- 

Cignrettes only __ 0.92 I 1.52 1.50 1.88 1.52 j 1.41 1. 73 1.46 1. 74 l.iS 

Cigarettes and 

other .._._...... 1.07 1.41 1. 33 1. 49 1. 24 1.27 1.22 ____... _.__.___ _-.-.... 

Cigars only O.Y2 I 0.94 0. 95 1. 12 1.06 0.81 1.31 ______. _-__.___ _-...... 

Pipes only. ._... ~~. 1.01 1.34 0. 97 1.07 1.36 0.93 1.09 ___.__.. ______. - _-...... 

Thus, all three studies show some increase in the mortality ratios with 

longer duration of smoking, but the pattern is irregular. In a further break. 

down of the data by amount smoked, Hammond and Horn (10) found no 

trend with duration for men smoking more than a pack a day, but the other 

two studies show an upward trend for this group of smokers. 

For cigar smokers the only groups showing an increase in death rates over 

non-smokers are those smoking for the longest period (Table 9). The increases of 12 percent for the 35 years or over group in the U.S. study and of 

90 
31 percent for the 30 years or over group in the Canadian study are both 

statistically significant. 

For pipe smokers no trend with duration of smoking is discernible. The 

two figures which stand out (1.34 in the U.S. study and 1.36 in the Canadian 

study) are both based on relatively small numbers of deaths. 

INHALATION 0F SMOKE 

In two of the studies the subjects were questioned as to whether they 

inhaled. In the study of men in 25 states each subject was asked to place 

himself in one of the four classes: do not inhale, inhale slightly, inhale 

moderately, inhale deeply. In the Canadian veterans study the subject simply 

classified himself as an inhaler or non-inhaler. 

For current smokers of cigarettes only in the U.S. study, 6 percent of the 

subjects stated that they did not inhale, 14 percent inhaled slightly, 56 percent 

moderately and 24 percent deeply. In the Canadian study 11 percent 

classified themselves as non-inhalers. 

Since inhalation practices may vary with the amount smoked, the results 

for cigarette smokers (Table 10) are given separately for different amounts. 

For the men in 25 states an increase in the degree of inhaling for a fixed 

amount of smoking is in general accompanied by an increase in the mortality 

ratio. The relation of inhalation to mortality appears quite marked: for 

instance, non-inhalers who smoke 20-39 cigarettes daily have mortality 

ratios no higher than moderate or deep inhalers who smoke l-9 cigarettes 

daily. With the very heavy smokers (LM)+ ) the figures in Table 10 suggest 

that the mortality ratio may remain the same for non-, slight, and moderate 

inhalers. The ratios of 2.05 (non-) and 1.97 (slight) are, however, based 

on only 26 and 41 deaths, respectively. 

TABLE lO.-Mortality ratios for smokers of cigarettes only by inhalation 

status and amount of smoking 

Cigarettes per day 

Degree of inhalation Overcall 

ratio 

1-9 l&l9 !2G39 JO+ 

~-___~ 

1.29 1.46 1. 56 2. 05 1.49 

1.2Q 1.68 1.34 1. 97 1.6s 

1.61 1.82 1.84 2.01 1.87 

1. 88 1. 76 2. 18 2. 50 2. m 

1.053 

2 

‘1.50 1.11 

31.03 . . ..__ . . . . . 1.08 

~1.71 . ..-------.- 1. 52 

’ &Omts are lifetime maximum amounts smoked. 

’ *D-20 cigarettes per day. 

’ over 20 ci garettes per day. 

Looking along the rows of the U.S. veterans study it will be seen that for 

each degree of inhalation the mortality ratio increases with the amount 

*moked. Ipsen and Pfaelzer (14) have shown that the logarithms of the 16 

death rates at age 61 (app roximately the average age) can be adequately rep91 
resented as an additive function of the amount of smoking and the degree of 

inhalation (although other types of mathematical relationship would also fit 

the data). In their analysis, the average change in logarithm of death rate 

from “no inhalation” to “deep inhalation” is as great as the difference be. 

tween consumption of less than 10 cigarettes and consumption of more than 

40 cigarettes daily. 

In the Canadian data the inhalers have higher mortality ratios than the 

non-inhalers for each amount of smoking. No trend with amount of smok. 

ing appears for the non-inhalers, but the ratios in this row are based on 

rather small numbers of deaths. 

For cigar smokers (current and ex-smokers) in the 25-state study 19 per. 

cent stated that they inhaled to some extent. The mortality ratio is 0.89 for 

non-inhalers and 1.37 for inhalers. The latter increase of 37 percent (based 

on 91 deaths) is statistically significant, but as the data have not been sub 

classified by amount of smoking the result may be partially a reflection of 

the increase in death rates noted in Table 4 for heavy cigar smokers. In the 

Canadian study, 13 percent of the cigar smokers classified themselves as inhalers, but the number of deaths is insufficient to present a breakdown of the 

mortality ratio by inhalation status. 

Among the pipe smokers there were 28 percent who inhaled in the U.S. 

study and 18 percent in the Canadian study. The U.S. mortality ratios are 

0.8 for non-inhalers and 1.0 for inhalers; the Canadian data contain too few 

deaths to allow a breakdown by inhalation. 

Ex-CIGARETTE SMOKERS 

For men who had stopped smoking prior to the date of enrollment, Table 

11 gives the mortality ratios from five studies for “cigarette only” smokers 

and “cigarette and other” smokers. The corresponding results for current 

cigarette smokers (from Table 2) are given for comparison. The distinction 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 below those for current smokers and above those for non-smokers. In interpreting comparisons of ex-smokers and current smokers there are at least 

three relevant factors. If smoking is injurious to health, cessation of smok, 

ing would be expected to reduce the mortality ratio. Secondly, some men 

stop smoking because of illness. In the 25-State study, over 60 percent of 

the men who had stopped smoking within a year prior to entry stated that a 

disease or physical complaint was one of the reasons for stopping (12). 

This factor would tend to make mortality ratios for ex-smokers higher than 

those for current smokers. F’ ma 11 y, ex-smokers may have previously smoked 

smaller amounts than current smokers. This factor is not the explanation 

of the drops in mortality ratios in Table 11. In a further breakdown by 

amount of smoking, made for the three largest studies, the mortality ratio 

for ex-smokers is consistently below that for current smokers for each amount 

smoked. 

92 
TABLE Il.-Mortality ratios for ex-smokers and current smokers of cigarettes 

British Men in 9 U.S. Canadian Men in 25 

doctors states veterans veterans states 

Ex-cigarettes.......---.-.................. 1.04 / 

Current cigarettes _.... _________.......... 1.44 / 

Ex-Cigarettes and other .._............._... 

Current cigarettes and others- .._.......... 

TABLE 12.-Mortality ratios jar ex-smokers of cigarettes orzly by number of 

years since smoking was stopped and by amount smoked 

Study 

Number of years stopped 

____- Current 

/ l-l / 1-9 j 5-9 I 10+ 

smokers 

<1 

1 These dtrta are from Hammond and Horn, 1958. 

TABLE 13.-Mortality ratios for ex-cigarette smokers by number of years of 

smoking, U.S. veterans study 

Cigarettes per day 

Number of years of smoking 

Cl5 I lb24 

Age at which smoking was stopped 

<45 4554 55+ 

______ 

l-20 -_...__.__. _.________________________________ ___._ 1.09 1.24 1.51 . . ..__._._.- 

zO+ .-..__. ._._________________------------.---- . . . .._ 1. 12 1.59 1.86 . . ..__._.... 

Some supplementary analyses throw a little further light on this topic. 

In the two American Cancer Society studies (Table 12) a breakdown is 

given by the number of years since smoking was stopped. 

Except for the smokers of under one pack a day in the 25-State study, 

the mortality ratio for men who had stopped less than a year is higher than 

that for current smokers. Thereafter the ratio drops steadily as the interval 

since smoking was stopped increases. 

In the U.S. veterans study, further breakdowns are available by the 

numbers of years during which the ex-smokers were smoking and by the 

age at which smoking was stopped (Table 13)) as well as by the amount 

of smoking. The mortality ratios are about the same for those smoking 

less than 15 years as for those smoking 15-24 years. Thereafter the ratios 

rise with longer durations of smoking. Table 13 also shows that mortality 

ratios were higher for those who stopped smoking at later ages. 

93 
Ex-CIGAR AND PIPE SMOKERS 

Mortality ratios for smokers of cigars only and pipes only who had 

stopped smoking prior to the date of entry are given in Table 14, the ,.or. 

responding ratios for current smokers being included for comparison. 

For ex-cigar smokers the mortality ratios are higher than those for non. 

smokers and higher than those for current smokers in all four studies pr,, 

sented. The same is true for ex-pipe smokers with the exception of the 

Canadian study. 

The interpretation of this result is not clear to US. According to Ham. 

mond and Horn (10) and Dorn (6)) the explanation may be that a sub. 

s.tantiaI number of cigar and pipe smokers give up because they become ill: 

some data from cigarette smokers that support this explanation have re 

cently been analyzed by Hammond (12). Further analysis of the B.S. 

veterans data indicates that mortality ratios run highest in ex-smokers who 

smoked heavily and for a long time. 

TABLE 14.-Mortality ratios GOT ex-smokers of cigars only and pipes only 

and for current cigar and pipe smokers 

Type of smoker British 

doctors 

Ex-cigar....~...............~~~..~~~~~~.~ .- . .._....___. 

Current cigar ....... .._...___.___---- .... ._._ ........ 

Ex-pipe..........-.-...--...-...- ...... ..- ’ 1.12 

Current pipe.........---- .............. ..- ’ 0.95 

_________ 

1.05 1.30 1. 17 

1. 10 1.07 1. 11 

1.24 

0.91 ~~~~% 

1.29 1.38 1.01 1.23 

1.05 1.06 1. 10 0. .!a 

1 Pipe and cigar combined. 

EVALUATION OF SOURCES OF DATA 

THE STUDY POPULATIONS 

Various reasons dictated the particular choices made of the seven study 

populations, considerations of feasibility playing an important role. None 

of the populations was designed, in particular, to be representative of the 

U.S. male population. ,!ny answer to the question “to what general populations of men can the results be applied?“, must involve an element of unverifiable judgment. However, three of the studies have populations with 

widespread geographic distribution within the United States, as do the 

British and Canadian studies within their respective countries. Taken as a 

whole, the seven populations offer a substantial breadth of sampling of the 

type of men and environmental exposures to be found in North America and 

Britain, as well as providing some variation in methodological approach, 

although the basic plan was similar in all studies. 

The seven studies differ considerably in size. They vary also in the extent 

to which they are free from methodological weakness. The studies of men 

in nine states and men in 25 States, for instance, suffer from the difficulties 

94 
that the populations studied are hard to define, that the smokers and nonsmokers were recruited by a large number of volunteer workers, and that 

completeness in the reporting of deaths was hard to achieve, since this depends on reports from the volunteers. On the other band these studies have 

the advantage of being large and of having a broad geographic representation of the U.S. male population, while the second study is the only one that 

attempts to investigate many other relevant variables in which smokers and 

non-smokers may differ. In the California occupational study the focus of 

interest is occupational differences in lung cancer mortality, smoking history 

being recorded primarily in order to be able to adjust comparisons among 

different occupational groups for differences in amount smoked. In the 

analysis we have not attempted to rate the studies as to over-all quality or to 

assign differential weights to their results, except that in the smaller studies it is 

recognized that mortality ratios are subject to larger sampling errors. Our 

attitude is to attach importance only to results that appear to be generally 

confirmed by the studies. 

Some idea of the relative death rates in these studies as compared with the 

1960 white male population of the United States is given in Table 15, which 

shows the age-adjusted death rates for ages 35 and over, using the age distribution of the U.S. white male population as a standard. (The choice of 

1960 for the comparison is arbitrary, but the white male rate changed little 

between 1955 and 1960.) 

In all studies the death rates for non-smokers are markedly below those 

of U.S. white males in 1960. Even the smokers of one pack of cigarettes or 

more daily have death rates that average slightly below the U.S. white male 

figure. To some extent this is to be expected, since hospitalized and other 

seriously ill persons are not recruited in such studies. The sizes of the differences appear, however, surprising for the studies with United States populations. Hammond and Horn (lo), in a special investigation on this question, concluded that the discrepancy in their study was due to the screening 

out of sick persons in recruiting plus probably a selection towards men of 

higher economic levels. Th ey point out that their death rates are substantially 

above those for males who had held ordinary life insurance policies for from 

TABLE 15.-Age-adjusted death rates per 1,000 man-years for current 

smokers of cigarettes only (aged 35 and over), by amount smoked, in seven 

studies and for U.S. white males 

Study 

Current smokers of 

cigarettes only 

U.S. white 

males, 1960 

Less than 1 pack 

1 pack or more 

19. 2 23.2 22.9 

‘22.4 ’ 27.1 ’ 22.6 

18. 1 23 9 22.9 

’ 14.2 ’ 18.0 1 22. A 

16.4 16. 3 22.9 

22.1 24.2 22.9 

1 18.5 2 19.2 22.9 

’ These 6qures may be too low by about 1.7 percent, since the person-years 

included so& contribution by men who had not been fully traced. 

used in the computation 

714-422 o-64--8 95 
5 to 15 years. The U.S. veterans’ study population also came mainly from the 

middle and upper socioeconomic classes (6). 

Another reason might be a failure to trace all deaths. In mass studies 

it is almost impossible to devise infallible provisions for recording every 

death. The study directors were, however, experienced in handling this 

problem and it seems unlikely that more than, say, 5 percent of the deaths 

would be missed. (Moreover, in the studies of veterans it is to the family’s 

advantage to report the death.) 

Another contribution probably came from the failure to obtain data for 

some members of the population. Evidence on this point is available from 

the British doctors and the U.S. veterans’ studies, in which death rates for 

the complete population (respondents and non-respondents) are available. 

In these studies the death rate for the whole population exceeded that in 

the respondents, but by only 5 percent to 10 percent, so that non-response 

appears unlikely to be a major cause of the discrepancy. 

So far as interpretation of results is concerned, the discrepancy raises 

two points. It is clear that the seven prospective studies involve populations which are healthier than U.S. males as a whole. Secondly, the low 

death rates for non-smokers suggest the possibility that the studies recruited 

unusually healthy groups of non-smokers. In the case of the five studies 

which had clearly defined populations, this selection would arise only if 

the non-smokers who refused to enter the study had death rates much 

higher than those who were enrolled. This point is discussed in the next 

section. 

NON-RESPONSE BIAS 

In all five studies that had a clearly defined target population, sizeable pro. 

portions of the population were omitted. The major reason was failure to 

answer the questionnaire; in addition, certain replies were rejected as too 

incomplete. The percentages of the populations for which usable replies 

were obtained were approximately as shown in Table 16. 

TABLE 16.-Percentages of usable replies in five studies 

British 

doctors 

U.S. 

veterans 

California CMiali;ia Canadian 

occupa- veterans 

tional 

68 68, 85 85 56 57 

In the U.S. veterans study, 68 percent replies were obtained from the 

19% questionnaire. A second questionnaire, sent in 1957, enrolled an additional 17 percent, for whom data are available during the period 1957-60. 

In the two American Cancer Society studies it is not possible to present 

meaningful percentages, since each research volunteer selected her own 

small part of the study population from among her acquaintances. 

The possible effects of these amounts of non-response on the mortality 

ratios have received little discussion. Some pieces of information about 

% 
non-respondents are available in two studies. From a recent sample, Doll 

(4) states that (a) the death rate of non-respondents in the British doctors 

study is higher than that of respondents; (b) consequently the death rate 

for respondents is lower than that of British doctors as a whole, perhaps 

by as much as 5 percent to 10 percent; (c) there are relatively more smokers 

among the non-respondents than among the respondents. In the U.S. veterans’ study, the death rate for the whole study population exceeded that for 

the original 68 percent responders by 7 percent in 1958 and 5 percent in 

1959. From this study one can also calculate mortality ratios separately, 

during 1957-60, for the 1954 respondents and the 1957 respondents. The 

results for smokers of cigarettes are as follows : 

1954 I957 NOllrespondents respondents respondents 

(68 percent) (17 percent) (1.5 percent) 

Current cigarettes only------------- 1.87 1.71 ? 

Current cigarettes and other-------- 1.56 1.33 ? 

Those who did not respond in 1954 but did respond in 1957 show lower 

mortality ratios than the original set of men giving usable replies. By 

making guesses about the mortality ratios in the 15 percent of non-responders, 

one can compare the resulting mortality ratio in the whole population with 

that found in the original 68 percent. To consider how much of an overestimate 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 cigarettes only and 1.44 for cigarettes and other. Thus, with a non-response 

rate of 30 percent, the computed mortality ratio might overestimate by 0.1 

or 0.2. 

Berkson (1) produced a set of assumptions under which, with a mortality 

ratio of 1 in the whole population and a response rate of 71 percent, the 

mortality ratio in the respondents is found to be 1.5. Non-respondents are 

assumed to be of two types. One group, destined to have a high death rate, 

refuses because they don’t feel well. This group has a high refusal rate 

(50 percent) for both smokers and non-smokers, since the reason for refusal 

is illness and not smoking. In the remainder of the non-respondents, the 

refusal rate is higher among smokers than non-smokers. Qualitatively, 

these assumptions are not unreasonable and agree in direction with the 

results quoted previously for the British doctors and U.S. veterans’ studies. 

Korteweg (15) worked further examples of Berkson’s model as applied to 

individual causes of death in the first report of the study of men in nine 

states. He concluded that the response bias in the mortality ratio might be 

as high as 0.3. Both Berkson and Korteweg, had, of course, to make some 

arbitrary assumptions about the sizes of biases from different sources. 

Further discussion of the non-response bias and computations as to its 

magnitude are given in Appendix I. The computations indicate that reported mortality ratios lying between 1 and 2 might overestimate by as 

much as 0.3, a mortality ratio of 5.0 might overestimate by 1.0, and one of 

10.0 might overestimate by 3.0. Thus, under assumptions that are rather 

extreme, although consistent with the available data about non-respondents, 

97 
the mortality ratios of cigarette smokers would still remain substantial+ 

higher than unity after adjustments for these amounts of over-estimation. 

MEASUREMENT OF SMOKING HISTORY 

Measurement of the type and amount of smoking, being based on a single 

mail questionnaire, was admittedly crude. Consider men recorded as current smokers of cigarettes only. Subsequent to enrollment, some of these 

presumably stopped smoking, at least temporarily, and some took up other 

forms, with or without cigarettes. 

Similarly, some men recorded as non-smokers may have begun to smoke 

cigarettes subsequently. Consequently, the group designated as “current 

smokers of cigarettes only” presumably contained men who were, for some 

period of time “ex-smokers” or “cigarette and other” ,aokers, while men 

designated as “non-smokers” contained some who smoked cigarettes for a 

time. It seems likely that this dilution of the contrast between the two 

groups would make the mortality ratio of cigarette smokers, as reported in 

previous tables, underestimate the mortality ratio of unchanging cigarette 

smokers relative to unchanging non-smokers, particularly when we note 

that the groups labeled “ex-smokers of cigarettes” and “cigarette and other” 

smokers both had mortality ratios lower than the group labeled “current 

smokers of cigarettes only”. 

As regards number of cigarettes per day, two types of errors of measure. 

ment may occur. There will be “random” errors of measurement (some 

men overestimate the amount and others underestimate it) that tend to 

cancel out over all men in the study. The effect of such errors is that 

the reported data underestimate the increase in the mortality ratio per 

additional cigarette smoked daily, the computed increase being an estimate 

of B/ (1 + h) , where B is the true increase and h is the ratio of the variance 

due to errors of measurement in the amount smoked to its total variance, 

Yates (17). There may also, however, be systematic errors in reporting 

the amount smoked. Heavy smokers may tend to underestimate the amount 

smoked. If this happens, the reported increase in mortality ratio per 

additional cigarette smoked will be an overestimate of the true increase, 

although the upward trend of mortality ratio with increasing amount 

smoked will remain. 

On balance, we are inclined to agree with the opinion expressed by the 

authors of several of the studies to the effect that the general result of errors 

in reporting smoking history is to depress the mortality ratios of smokers 

relative to non-smokers, so that reported ratios will tend to be underestimates 

so far as this source of error is concerned. 

STABILITY OF THE MORTALITY RATIO 

The sampling distribution of the mortality ratio has not to our knowledge 

been at all thoroughly investigated and appears to be complicated. As a 

rough approximation (Appendix II), the ratio of smoker deaths to smoker 

98 
plus non-smoker deaths may be regarded as a binomial proportion with 

mean AR/ ( 1 + AR) where R is the true mortality ratio, A is the ratio of the 

expected smoker deaths to the observed non-smoker deaths and the sample 

size is the number of smoker plus non-smoker deaths. From this approximation, confidence limits for R may be derived. This approximation requires 

that (1) the age distributions of smokers and non-smokers do not differ 

greatly and (2) all age-specific death rates are small. An alternative normal 

approximation that avoids assumption (1) is also given in Appendix II. 

The sampling variation of the estimate of R is seldom of major import 

in this part of the report, since the ratios for total mortality are mostly based 

on relatively large numbers of deaths. The estimate has a positive mathematical bias, negligible with large but not with small numbers of deaths. 

In another sense the particular mortality ratio used in this report has a 

different kind of bias. Since the standard age-distribution used in this 

ratio is the age-distribution of the smokers, who are somewhat younger than 

the non-smokers, the mortality ratios apply to populations slightly younger 

than the combined population of the study. This is not in our opinion a serious objection, but may sometimes be relevant in questions of interpretation. 

OTHER VARIABLES RELATED TO DEATH RATES 

As mentioned previously, the smokers and non-smokers in these studies 

may differ with respect to other variables that might influence the death rate. 

Except in the new 25State study, no attempt was made to measure these 

variables apart from urban-rural residence, and previous reports on these 

studies give little discussion of this problem. For urban-rural residence, Doll 

and Hill (5) found that the proportions of smokers of different amounts 

in the study population were about the same in rural areas, small cities and 

large cities. In th ree studies the mortality ratios of cigarette smokers were 

computed separately by size of city (6, 10, 11). In the study of men in 

25 States, the data refer to men who smoked 20 or more cigarettes a day 

and said that they inhaled moderately or deeply. In all three studies the 

mortality ratios show little change with size of community (Table 17). 

In the 25State study, over 20 other variables that may be associated with 

death rates were recorded. The study population was broken down into 

subgroups for many of these variables separately: for instance, into smokers 

who have long-lived parents and grandparents and those whose parents and 

TABLE 17.-Mortality ratios for cigarette smokers by population-size of city 

Population-size 

Study 

&h’& i I$X& / ;$; 1 Rural 

’ hcludes towns of less than 10,ooO. 
grandparents were short-lived. Included among these variables were reh. 

gion, educational level, native or foreign birth, residence by size of town 

and occupational exposure, use of alcohol, use of fried food, amount of 

nervous tension, use of tranquilizers, and presence or absence of prior 

serious disease. For cigarette smokers who smoked more than a pack a day 

and inhaled moderately or deeply, the mortality ratio was computed within 

each subgroup. For example, the mortality ratio was 1.99 for men with 

long-lived parents and 2.30 for men with short-lived parents. In every 

subgroup the mortality ratio was well above unity, the lowest among 71 

computed ratios being 1.57 (for men with a history of previous serious 

disease). 

These data provide information on the association of the other variables 

with mortality as well as on the association of smoking with mortality. For 

six of the most relevant variables, Table 18 gives age-adjusted death rates, 

using the combined populations of non-smokers and cigarette smokers ag 

the standard population. The death rates apply to a period of roughly 

22-months follow-up. As already mentioned, the cigarette smokers (of 

more than a pack per day who inhaled moderately or deeply) have higher 

death rates than the non-smokers in every cell of Table 18. Since not all 

respondents answered these supplementary questions, the results may be 

subject to some additional non-response bias. 

As would be expected, death rates are relatively high for men with previous serious disease and for men from short-lived families, and are sometihat 

TABLE I&-Age-adjusted death rates per 1,000 men (over approximately 

22 months) for variables that may be related to mortality 

Long-lived Short-lived No pr+~us PIemus 

Type of smoking parents and parents and ?teornu; serious 

grandparents grandparents disease 

_____- 

None __._........_~.~...................~. 14.8 21. 1 11.5 42. 8 

Cigarettes 1~ . . ..~-....................--.. 27.1 44.8 22.3 05.0 

___- 

Single Married Use tram Do not use 

quilizers tranquilizers 

-___ 

18.9 29.1 182 

33.0 52. 4 31.8 

Educational level 

I / I 

Degree of exercise * 

NCIIR Slight Moderate HIBVY 

-~_- _-- 

Sone...........~..........~.~..~~~........ 23.8 14. 7 11.0 9.5 

Cigarettes ~~~.-~..~............~---~-.....- 34. 1 25.5 20.8 19. i 

1 Smokers of more than a pack per day who inhaled moderately or deeply. 

2 Confined to men with no history of heart disease, stroke, high blood pressure or cancer (except skin) 

who were not sick at the time of entry. 

100 
higher for single than for married men. The size of the excess death rate 

for users of tranquilizers compared to men who do not use them is perhaps 

surprising 129.1 against 18.2 and 52.4 against 31.8). However, the tranquilizers in question required a doctor’s prescription, so that some men in 

this group are presumably under medical attention for illna. The group of 

users is small, comprising only about 10 percent of those who answered this 

question. Death rates tend to decrease slightly as the educational level 

increases; this association may represent some facet of the association of 

death rates with socio-economic level. Degree of exercise displays an interesting association with mortality, the death rate declining steadily with 

additional degrees of exercise. In particular, the two “no exercise” groups 

show marked elevations in death rates. These groups, however, amount to 

only 2 percent of the respondents to this question. 

From the same data, Ipsen and Pfaelzer (14) made a further analysis 

of seven variables that appeared to be related to mortality? in order to see 

whether any of the variables had a stronger association with mortality than 

did cigarette smoking. They concluded that apart from previous serious 

disease, none of the other variables examined had as high a correlation with 

mortality as smoking of cigarettes. Further, the correlation of any of these 

other variables with cigarette smoking was too weak to reduce markedly 

the correlation of cigarette smoking with mortality after adjustment for 

the other variable. 

In the analyses above, smoking was matched against each variable separately. In addition, Hammond (11) carried out a “matched pair” analysis, 

in which pairs of cigarette smokers and non-smokers were matched on height, 

education, religion, drinking habits, urban-rural residence and occupational 

exposure. The percentage who had died in the 22 months was 1.64 for 

smokers and 0.88 for nonsmokers. 

These informative analyses are available, unfortunately, for only one of 

the studies. However, in order that the association of cigarette smoking 

with mortality should disappear when we adjust for another variable, the 

correlations of this variable with smoking and with the death rate must 

both be higher than the correlation between smoking and the death rate. 

Except for the breakdowns by longevity of parents and grandparents, 

the analyses throw little light, however, on the objection that a part of the 

differences in death rates may be constitutional, psychological or behavioral; 

i.e., that regular cigarette smokers are the kind of men who would have 

higher death rates even if they did not smoke. Further discussion of this 

Point appears in the next section. 

MORTALITY BY CAUSE OF DEATH 

In all seven studies the underlying cause of death, as specified in the International Statistical Classification of Diseases, Injuries and Causes of Death, 

Was abstracted from the death certificate. In the two American Cancer Society studies, further confirmation of the cause of death, including histological 

evidence, was sought from the certifying physician for all cancer deaths; this 

101 
procedure w-as also followed in lthe British doctors’ study for all certificates 

in which lung cancer was mentioned as a direct or contributory cause. With 

these exceptions the data presented here represent the results of routine death 

certification. 

For current smokers of cigarettes the total mortality, after adjustment for 

differences in age composition, was found previously (Table 2) to be about 

‘70 percent higher than that of non-smokers in these studies. The primary 

objective in this section is to examine whether this percentage increase appears to apply about equally to all principal causes of death, or whether the 

relative increase is concentrated in certain specific causes or groups of 

causes. 

RESULTS FOK CIGARETTE SMOKERS 

For 24 causes of death, plus the “all other causes” category, Table 19 shows 

summary data over all seven studies.* In four of the studies the data are 

those for current smokers of ciga.rettes only, but in the two California studies 

and the 25-State study the cause-of-death breakdown was available only for all 

cigarette smokers including “cigarette and other” smokers and current and 

ex-smokers. 

For each listed cause, Table 19 shows the total numbers of expected and 

observed deaths of cigarette smokers summed over all seven studies, and 

TABLE 19.-Total numbers of expected and observed deaths and mortality 

ratios for smokers of cigarettes only 1 in seven prospective studies 

Underlying cause of death Expected Observed 

- ---__ 

Cancer of lung (162-3) _............_. ~- ._.. 

Bronchitis and emphysema (502. 527.1) *..- 

Cancer of larynx (161)~ . . . . . .._.._....... 

Cancer of oral cavity (140-S) .- . . .._..___ -_ 

Cancer of esophaeus (1.50) ._~ . .._.... --. 

Stomach and duodenal ulcers (540-l) _ _ _ 

Other circulatory diseases (451468) _....... 

Cirrhosis of liver (5811... . . .._. . .._.... -._ 

Cancer of bladder (181) __.. _.._..__ 

Coronary artery disease (420) _ _.-.-_. 

Other heart diseases (421-2, 43a-41.. _...._. 

Hypertensive heart disease (44W3) 

General arteriosclerosis (450) . . . ..___ 

Canwrofkidney cls0) ~... ..__. -__ 

All other cancer.. ._._._... . . . . .._....... 

Cancer of stomach (151). . . . . . . .._ __.... -. 

Influenza. wwumonia (486-493) .-_. ____ 

170.3 

89. 5 

14.0 

E:‘: 

105.1 

254.0 

169.2 

111.6 

6.430.7 

526.0 

% ; 

79.0 

1.061.4 

285.2 

303.2 

1,%x3.7 

1.461.8 

253.0 

1,063.2 

156.4 

290.6 

207. 8 

422.6 

15,653.Q 

Allothercauses-......_....-..-.-........- 

Cerebral vascular lesions (33~~4) .._._ ..-__ 

Canwr or prostate (177) ~~.._. . . .._.__..___. 

.4ccidents. suicides, violence (KGQ99~ _ _ _ 

Nephritis (592-4) ..__ -._- _.__... _..._ 

Rheumatic heart disease (400-416). .._..._. 

Cancerofrectum (154~~~ ..__.... .._____. 

Cancer of intestines (1.52~31.. _....._____.. 

All causes. _ ___.____._.__. --- ___.____...... 

I,=3 

546 

2; 

113 

El 

379 

216 

11,177 

E 

310 

120 

1,524 

413 

415 

1,946 

1,844 

318 

1,310 

173 

ii 

395 

26,223 

- 

I 

-- 

- 

Mortality 

ratio 

10.8 

6. 1 

5. 4 

4.1 

3.4 

2.8 

2. 6 

2. 2 

1.9 

1. 7 

1. 7 

1. 5 

1. 5 

1.5 

1.4 

1.4 

1.4 

1.3 

1.3 

1.3 

1.2 

1.1 

1. 1 

1.0 

0.9 

1.68 

11.7 

7.5 

5.8 

3.9 

3.3 

5.0 

2.3 

2. 1 

2.2 

1.7 

1.5 

1.5 

1.7 

1. 4 

1. 4 

1.3 

::3” 

1.3 

1.0 

1.3 

1.5 

1.1 

0.9 

0.9 

1.65 

1 Current cigarettes only lor four studies: all cigarettes (current and ex-) for the two California studies 

and the study of men in 25 States. 

1 “Bronchitis and emphysema” includes “olher bronchopulmonary diseases” for men in nine States and 

Canadian veterans. 

Median 

mortality 

ratio 

*The individual results for the seven studies are shown for reference purposes in 

Table 26. 

102 
the resulting mortality ratios, arranged in order of decreasing ratios. The 

combination of the results of the seven studies in this way is open to criticism, 

since it gives more weight to the larger studies than may be thought advisable, and since the true mortality ratios for specific causes presumably differ 

somewhat from study to study. However, for some causes of death that 

are of particular interest the numbers of deaths are small in all studies, 

so that some procedure for combining the results is highly desirable. As 

an alternative measure of the combined mortality ratio, the median of the 

>even mortality ratios (obtained by arranging the seven ratios in increasing 

order and selecting the middle one) is also shown for each cause in Table 

19. The median, of course, gives equal weight to small and large studies. 

Although there are some changes in the ordering of the causes when medians 

are used instead of the ratios of the combined deaths, the general pattern 

in Table 19 is the same for both criteria. 

Table 19 also presents the total numbers of non-smoker deaths on which 

the combined mortality ratios are based. 

Lung cancer shows the highest mortality ratio in every one of the seven 

studies, the combined ratio being 10.8. Other causes that exhibit substantially higher mortality ratios than the ratio 1.68 for all causes of death 

in Table 19 are bronchitis and emphysema, cancer of the larynx, cancer of 

the oral cavity and pharynx, cancer of the esophagus, stomach and duodenal 

ulcers, and a rather mixed category labeled “other circulatory diseases,” 

which includes aortic aneurysm, phlebitis of the lower extremities, and 

pulmonary embolism. For three of these cause-cancer of the larynx, 

oral cancer and cancer of the esophagus-the numbers of non-smoker 

deaths are small, so that the over-all mortality ratio cannot be regarded as 

accurately determined. 

The U.S. veterans’ study and the 25-State study provide an additional 

breakdown for two of the causes listed in Table 19. For the rubric 527.1 

iemphysema without mention of bronchitis), these studies give mortality 

ratios of 13.1 and 7.5, respectively. For ulcer of the stomach they give 

5.1 and 4.3, whereas for ulcer of the duodenum their mortality ratios are 

2.3 and 1.1. Bronchitis and emphysema also show a high rate, 12.5, in the 

British doctors’ study. 

There follows a list of 14~causes whose mortality ratios are not greatly 

different from the ratio of 1.68 for all causes in Table 19. These causes 

range from cirrhosis of the liver, with a ratio of 2.2, down to a ratio of 1.2 

for the miscellaneous class which contains accidents, suicides and violent 

deaths. Th’ 1s group includes the leading cause of death, coronary artery 

disease, with a ratio of 1.7, cerebral vascular lesions with a ratio of 1.3, 

and the “all other causes” group with a ratio of 1.3. For each of these 14 

causes the mortality ratio differs from unity, by the approximate statistical 

test of significance. 

Finally, th ere are four causes-nephritis, rheumatic heart disease, cancer 

of the rectum and cancer of the intestines-whose mortality ratios are close 

to unity. 

For smokers of cigarettes and other, the data from four studies agree in 

general with the ordering of causes in Table 19, although the mortality 

ratios for most causes are slightly lower than with smokers of cigarettes 

103 
only. These and the corresponding data for ex-cigarette smokers are shown 

in Table 20. 

Data on ex-cigarette smokers can be obtained from four studies. & 

causes of death with mortality ratios of 2.0 or higher are, in decreasing 

order, bronchitis and emphysema (7.6)) cancer of the larynx (5.4)) cancer 

of the lung (4.8), stomach and duodenal ulcers (3.1)) oral cancer (2.0) 

and other circulatory diseases (2.0). 1 

The group of 17 causes with mortality ratios below 2 in Table 19 requires 

discussion. If cancer of the bladder (mortality ratio 1.9) and coronary 

artery disease (mortality ratio l-.7) are omitted, since they receive detail4 

consideration elsewhere in this report, the numbers of expected and observed 

deaths for this group as a whole are as follows: 

Expected Observed Mortality Ratio 

8,241.3 1.0,789 1.31 

If we exclude from this total the four causes at the foot of Table 19, for 

which the mortality ratios are 1 and smaller, the corresponding totals 

become: 

Expected Observed 

7,164.0 9,699 

Mortality Ratio 

1.35 

In either case the excess of observed over expected deaths is close to 2,500 

or about 25 percent of the total excess in observed deaths in Table 19. Thus, 

although the mortality ratios for these groups are only moderately over 1, the 

group as a whole contributes substantially to the total number of excess ob. 

served deaths. The group consists mainly of a miscellaneous collection of 

chronic diseases. 

Several tentative explanations of this excess mortality ratio can be put for. 

ward. Part may be due to the sources of bias previously discussed. It was 

indicated in the section on “Non-Response Bias” that the bias arising from 

non-response might account for a mortality ratio of 1.3. Relatively hi& 

mortality ratios in certain causes of death that have not yet been examined 

individually may also be a contributor, although as these causes are likely 

to be rare, the contribution from this source can hardly be large. 

Part may be due to constitutional and genetic differences between cigarette 

smokers and non-smokers. Except for the breakdown mentioned previously 

by longevity of parents and grandparents in the men in 25 States study, there 

is no body of data available that provides a comparison of cigarette smokers 

and non-smokers on these factors as they affect longevity. But it is not unreasonable to speculate that the kind of men who become regular cigarette 

smokers are, to a moderate degree, less inherently able to survive to a ripe old 

age than non-smokers. We know of no way to make a quantitative estimate 

of the difference in death rates that might be attributable to such constitu. 

tional and genetic factors. 

Studies reported in Chapters 1.4 and 15 indicate that some average differences can be detected between smokers and non-smokers on behavioral, 

psychological and morphological characteristics. Nevertheless, the same corn. 

parisons show considerable overlap between the individual men in a group of 

smokers and a group of non-smokers. For what they are worth, these corn. 

104 
TABLE 20.-Expected and observed dea.ths and mortality ratios for current 

smokers of cigarettes and other (three studies) 1 and for ex-cigarette 

smokers (four studies) 2 

Underlying cause of death 

- 

Cmeer of lung (162-3)..-.---.. 

Bronchitis and emphysema 

(502, 527.1) a... . . . . . . . ..____ 

Cancer of larynx (161) _.... 

Carver of oral cavity (14&E) _ 

Cancer of esophagus (150) 

Bt?maeh and duodenal ulcers 

WC-1) _..________ --_- ___._. 

Other circulatory diseases 

(451468) .~ _.___.________._. 

Cirrhosis of liver (581)L .____.. 

Cancer of bladder 081) ..____.. 

Coronary artery disease (420. 

Other heart diseases (421-2. 

4). _ __ _ ___ _ _ _ _ _. _ _ _ _ _ _ _ _ _ _ _. 

Cancer of prostate (177) __._. 

Accidents, suicides, violance 

o3no-Qw) ___ _______________ 

Nephritis (5924) .._________ 

Rheumatic heart disease (400- 

- 

.- 

Cigarettes and other 

- 

Number of deaths 

Expected -L 3bserved 

60.9 510 8.4 30. 4 145 4.8 

53.2 191 3.6 17. 4 133 7.6 

1. 6 20 12. 5 1.3 7 5.4 

11. 1 42 3.8 5.9 12 2.0 

13. 1 57 4. 4 5. 4 6 1.1 

23.0 99 40 3. 1 

99.0 

57.3 

58.2 

2,335.0 

227 

85 

3,z 

4.3 

2. 3 

1. 5 

1.3 

1.4 

1.4 

1.2 

1.4 

1. 5 

1.2 

1.4 

0.8 

1.0 

1.0 

1. 2 

1. 1 

1.4 

0.9 

0.7 

1. 1 

45.8 

22.4 

29.8 

1,245.0 

93 

z 

1,731 

2. 0 

1.2 

1.0 

1.4 

225. 9 321 124.1 178 1.4 

144.4 

106.8 

25.0 

272.9 

101.0 

199.2 

769.3 

174 

146 

3;: 

139 

% 

93.0 

63.7 

13.9 

199.3 

51.4 

55. 1 

308.1 

1.4 

1.2 

1.8 

1. 2 

1.3 

1.0 

1. 2 

634.0 

97. 1 

28.7. 1 

30.7 

96.0 

89.7 

149.6 

605 

118 

321 

57 

316 

44 

169.6 

21. 7 

86 

1E 

47.9 

43.3 

85.8 

159 

23 

59 

i; 

1. 1 

1. 1 

0.9 

1. 1 

1.2 

0.9 

1. 1 

1.4 / 3,045. 5 1 4,107 1.35 

I Mntish doctors, U.S. veterans and Canadian veterans. 

* British doctors. men in nine States, U.S. veterans, and Canadian veterans. 

’ “Bronchitis and emphysema” includes “other bronchopulmonary diseases” for men in nine States and 

Canadian veterans. 

Mortality 

ratio 

Ea.cigarette 

Expected 

_- 

3hserved 

Mortality 

ratio 

parisons suggest by analogy that the differences in death rates from constitutional or genetic factors may be moderate or small rather than large.* Further, it seems unlikely that constitutional or genetic differences between cigar 

and pipe smokers and between these groups and non-smokers can have any 

substantial effect on their death rates, since the over-all death rates of these 

three groups differ only slightly. 

Finally, part of the difference may represent a general debilitating effect of 

cigarette smoking in addition to marked effects on a few diseases. Pearl’s 

hypothesis that smoking increases the “rate of living” is of this type, though 

there are difficulties in making this hypothesis precise enough to be subject 

to medical investigation. Hammond (13) has suggested that the explanation might lie in the effect of cigarette smoking in decreasing the quantity of 

oxygen per unit volume of blood, but there are numerous medical objections 

to this hypothesis. This Committee has no information that would lead it 

to favor one or another of the possible explanations put forward above. 

‘This question is discussed more fully in Chapter 9, p. 190. 

105 
h~oRT.amY RATIOS FOR CIGARETTE SMOKERS BY AMOUNT SMOKES 

For coronary artery disease and lung cancer, the mortality ratios are given 

by amount smoked in Tables 21 and 22 for current smokers of cigarettes only. 

In Table 21 an increasing trend with amount smoked appears in all five 

studies. The two California st-udies, in which the data are for all cigarette 

smokers (current and ex-smokers combined) show a less marked trend. 

TABLE 21.--Mortality ratios for coron.ury artery disease for smokers q 

cigarettes only by amount smoked 

Number of packs per da)- British Men in 9 U.S. 

doctors states veterans 

Canadian M;t”,$a 

veterans 

-___ --- 

<y.-.- . . . . . . . . . . . . . . . . . . . . 1.0 1.2 1.3 1.7 

55-l _...... -- . . . . . . . . . . . . . . . . .._..._...... 1. 5 1.9 1.8 1. 7 

1.3 

l-Z......~...-....-.........~--..~-........ ’ 1.7 2. 1 1.7 1 2.0 2. a 

Over2~~ . . ..__.. ~.~ ._.... - . . . . . . . . . . . . . ..- .----------- 2. 4 1.9 ._..._.. :: 

1 More than one pack. 

TABLE 22.-Lung cancer mortality ratios /or current smokers of cigarettes 

only by amount smoked 

Number of packs per day British Men in U.S. 

doctors 9 States veterans 

<!/j ~~ ...~...~~~~~_.~ 4.4 5.8 5.2 

35-l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~~~ . . . . ~. 10.8 7.3 9.4 

l-2 ~~.~~~.~..~ _... ~... 143.7 15. 9 18. 1 

Ovcr2-.-........................~...~.~~.~~~.......... ------------ 21.7 23.3 

’ Over one pnek. 

The trends in lung cancer mortality ratio with amount smoked are steep 

in all four studies. The two California studies also show marked trends 

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 obse.rved deaths and mortality ratios for current 

cigarette smokers, for selected causes of death, by amount smoked, in six 

studies 

One pack or less I 

I 

More than one pack 

Causes of death Number of deaths 

,------- 

I Expected Observed 

Bronchitis and emphysema.mm 44.6 225 

Cancer of larynx..---.-.--~--. 3.6 

Cancer of oral cavity...-mmmmm. 16.8 ii 

Cancer al esophagus.. .-. ~. 13.2 

Stomach and duodenal ulcers. 32. 5 12 

Othercirculatory-.-~~~~~~~~.. 98. 5 253 

Cancer of the b1adder.m.mmmm.m 57.3 80 

Mortality 

ratio 

5.0 

5.3 

3.2 

3.0 

3.4 

2.6 

1.4 

/ Number of deaths 

Expected Observed 

.~ 

Mortality 

ratio 

8. 5 

7. 5 

4.1 

4.9 

2.9 

2.9 

3.1 

106 
men in the 25State study. Cancer of the bladder is included in Table 23 

aa 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 in Table 24, which lists the total expected deaths, 

total observed deaths and mortality ratios from five studies (British doctors, 

U.S. Veterans, Canadian Veterans, and men in 9 and 25 States). Causes 

of death with relatively high mortality ratios are oral cancer (3.4)) cancer of 

the esophagus (3.2)) cancer of the larynx (2.8), cancer of the lung (1.7), 

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 1 

Number of deaths 

Underlying cause of death 

Expected 

Cancer of oral cavity (14o-8). . .._....._ ... _.__._._._._....------.- .. 

hxer of esophagw (150) _..._....________._.-..........-..-...- .. .. 

CancerofkLrynx (161) ___.__..__ _ -_- _.___ ......... .._____._......- ..- 

CFmeerofbm~(162-3) ___________ -_- _._ ......... -_- ._._._._ ....... .._ 

Cfrrhmisafliver (581) . .._._ 

Stomach and duodenal ulcers (540-l) ______._._._._.._...--.-.- 

Cheer of kidney (180). 

....... 

... ....... .___ 

... .... _...__..._...........-.- 

._._......_..._._.._.- 

.... 

.. 

Cancer of intestines (152-3). __._._..._._ 

Other circulatory diseases (451468). .._ 

...... ._._._._._.._.._._ ._ 

._ ........ _ ... 

........ 

..... 

. ._. ._._. ._ ._ ._ 

Allothercancer -.... ._................._.~.~.~.~...........~.~ 

Cmer0fprostnte ............. ._._._._.....-..-..-.- ...... 

Gmwr of stomach 

(177) _._. 

(151) .......... __- ___. ._ ........ ..- .. ..-.- ...... -. 

CalIcerofrectllm (154) ____ _._ .... -_- _ .._ _.___.__..._._..-. ... ..- 

Hypertensive heart d&ease (44&3) ._._.._._..._.__._...........-.- .... 

Other heart diseases (421-2,43M) _._. ....... .._ ................ .._ ._ 

Sronchitis and em .. .._._ ._ 

Cerebral vascular 

hysema (502, 627.1) _____ ._-_-._ 

lt, SIOIIS (33~). .___ ._ ... ._-_-_ 

............ 

_ _._ ..___. ..... 

CWmrysrteryd~se (420). .._._....._ .._ --_-- ._._ ... ._._.._..._ _ 

Allother c8uses..-...-.-......-.....----.-....-...-..-.-.- ....... ..- 

hfiUenza and pneumonia (4W-493) ___ ... __.__........_....._..-. 

Accidents. suicides, violence (80&999) ____._ 

Cencerofbladder (131) ..- .._._. ..... _._._ ._........._._.......-.-.- 

Oenersl arteri0s&r0& (450) .____ .__..._. 

Nephritis (592-4) ______._ .. 

........ ..... 

-_-__ __ .__ 

_ .____._ __ 

........ ..__._ 

........ 

.. 

......... 

_.__._. .._. _ 

Rheumatic heart disease (4oC1-416) _____..____._......_..-.......-.- ................ 

.A**eauses..~....~.~..~.~~~~~~~.~.....~~.~~~~~~.~.~....--........- ..- 

- 

13.5 

10.2 

3.2 

65.2 

47.5 

35.2 

30.8 

174.6 

89.1 

39% 7 

127.2 

116.8 

78. 2 

194.5 

272.6 

33.7 

685. 3 

2,721. 5 

612.9 

93.8 

347.1 

63.1 

124.1 

63.6 

100.5 

ii 

ll”3 

:i 

2:: 

105 

450 

144 

132 

2: 

303 

7% 

2,842 

587 

3: 

1:; 

ii 

i:d 

2.8 

1.7 

1.6 

1.6 

1.3 

1.3 

1.2 

1.1 

1. 1 

1. 1 

1.1 

1.1 

1.1 

1.1 

1.1 

1. 0 

1. 0 

0. 9 

0. 9 

0.9 

0. 9 

0.9 

0. 7 

0,500.Q 6,919 1.06 

Observed 

1 Includes British doctors men in 9 States, U.S. veterans, Cenadisn veterans, and men in 25 States; 

hcludes er-smokers for men’in 9 States; excludes pipe smokers for Canadian vetmans. 

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 
THE CONTRIBUTION OF DIFFERENT CAUSES TO EXCESS MORTALITY 

Several of the reports previously published on these studies have included 

a table showing how the exces number of deaths of cigarette smokers over 

non-smokers is distributed among the principal cauSes of death. For each 

cause, the difference between the observed and the expected number of 

deaths for cigarette smokers is divided by the total excess for all causes, 

and multiplied by 100 to express the figures on a percentage basis. Table 

25 presents these percentages for the seven 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 excess deaths of cigarette smokers 

v , 

due to differen; causes ’ 

Underlying cause 

1 British 

1 doctors 

I 

Coronaryartcrydisease~.~.~... 

Other heart disease .__.......... 

Cerebral vascular lesions ~~~~~. 

Other circulatory diseases. .~~~. 

Ca”c!eroflu”g.~~ 

Cancer of oral cavity, esophaRllS, larynx . . . . . . . . . . . 

Other cancer 

Bronchitis and emphysema.. .- 

Influenza and pneumonis~ ..~. 

Stomach and duodenal ulcers~ 

Cirrhosis of liver . . . . . . . . . . . ~. 

.4ccidents, suicides, violence -.. 

All other causes . . . . . . . . . . . . . . 

.4llcauses~~~~.~.~ ~...~.. 

Men in 

9 states 

51. 9 

3. 1 

4. 5 

2. 7 

13. 5 

38.6 43.5 

6. 8 1.4 

4.9 5.3 

7. 1 1. 7 

14. 9 20.2 

2.9 2. 7 0.2 

9. 8 8.9 6. 3 

1. 1 4. 0 1. 3 

1. 6 0.4 2. 4 

3.1 1.4 -1. 7 

1. 6 2.5 6. 9 

1.2 2. 0 8.3 

3.0 5.8 4.2 

100.0 100.0 100.0 

:alifornis 

OCCUPBtional 

LC 

.- 

- 

‘aliforni: 

Legion 

43.5 44. 2 

4. 5 5.9 

6.5 -1. 8 

0.2 5. 6 

16.8 18. 3 

3.0 2. 2 

-2.2 7. 2 

5.6 8. 2 

1.5 1. 5 

2.2 2.9 

2. 2 0.8 

3. 7 4. 6 

12. 5 0. 4 

loo. 0 100.0 

:anadiar 

veterans 

Men in 

15 states 

51. 1 

5. 5 

3.3 

4.4 

13. 6 

2.2 

7.6 

3. 8 

1.5 

1.3 

0.9 

0.8 

3.4 

100.0 

1 All cigarette smokers (current and ex-) for the two Calilornis and me” in 25 States studies; current 

cigarette smokers only for the remainder. 

As previous writers have noted, all studies agree in showing coronary 

artery disease as the prime contributor to excess mortality, with lung cancer 

in second place. Other rubrics that show a substantial contribution in some 

studies, though not in all, are bronchitis and emphysema, cancers other 

than those of the mouth and lungs, and heart disease other than 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 death rate for smokers of cigarettes only who were smoking at the 

time of entry is about 70 percent higher than that for non-smokers. 

108 
TABLE 26.-Numbers of expected and observed deaths for smokers of cigarettes only, and mortality ratios, each prospective 

study and all studies 

British doctors Men in 9 State8 U.S. vetrrans California occupational 

TI Deaths Deaths 

-n 

Cause of death Deaths Deaths 

Expeete d Observed 

Nortalit 

ratio 

Expected Observe 

dortalit: 

ratio 

d 

-- 

I 

I 

Expecte 

-- 

515 

141 

ii 

i; 

2z 

111 

3.035: 

244 

223 

163 

34 

457 

ii 

530 

467 

106 

306 

30 

tz 

152 

12.0 

9. 8 

5. 8 

6.6 

6. 4 

3. 1 

3. 4 

3. 6 

1.8 

1.7 

2.0 

1.6 

1. 7 

1. 5 

1. 4 

1. 5 

1. 6 

1. 5 

1. 5 

2. 0 

1.3 

1.6 

1. I 

.9 

1. 3 

2 

.c 

7. 2 

24:; 

11. 5 

14. 7 

2. 2 

273. 9 

23. n 

27. 2 

.O 

72:: 

31. 4 

10. 3 

68.9 

42. 2 

8. 6 

108.4 

16.0 

22. 9 

13. 6 

23.7 

7, 236 1. 79 818. 5 

6.4 

4. 2 

:i 

3.3 

17:; 

13:: 

366.9 

78. 8 

21. 0 

21.2 

81:; 

28.3 

47. 0 

144.0 

161.1 

29.0 

89. 2 

8. 1 

10. 2 

4. 2 

26.1 

Ibserw 

kfortalitg 

ratio 

15. 9 

4.3 

1.0 

7 

:5 

1.6 

4.0 

6. 0 

2. 0 

1.0 

1. 0 

-. _ _ _ _ _ 

1.5 

.8 

2. 4 

1. 5 

1. 8 

5 

1:5 

1:: 

1.0 

.9 

B1 

_- 

-A 

d 

-- 

Expecte 

- 

d( 

-- 

Ibserve~ 

- 

-- -- 

129 20.2 

53 12. 5 

7 _-____ --_ 

6 ________ 

1: --___ T:!- 

E -..!:“- 

12 .Q 

i% 

1.5 

1. 5 

32 1. 6 

21 1.0 

8 ..____ --. 

3’; 1:: 

1:; 12 

192 1. 2 

15 

90 1:: 

17 2. 1 

E 

1.3 

3. 6 

23 1. 1 

_______ 

1,672 1.44 

21.4 

12. I 

1.3 

7.8 

2. 7 

12. 2 

19. 7 

23.5 

17. 2 927.7 

72. 5 

89. 7 

9. 1 

14.0 

132.9 

33. 7 

15.6 

209. 5 

208.8 

32. 4 

174.1 

43.3 

48. 4 

29.8 

65.6 

2,227.7 

233 

34 

E 

1R 

ii 

49 

1,7;: 

108 

107 

:: 

230 

4’: 

E4 

51 

192 

ii 

25 

35 

3,781 

10.0 

2. 3 

13. 1 

2.8 

6. 6 

5.0 

2. 7 

2. 1 

2. 4 

1.9 

1. 5 

1. 2 

2. 0 

1. 5 

1. 7 

2. 3 

2. 6 

1.3 

1.3 

1. 6 

1. 1 

.8 

.9 

.8 

.5 

43.3 

14.4 

2.4 

8. 1 

5. 2 

21. 5 

66.4 

31. 2 

31. 4 

1,803.3 

122.2 

138.7 

97. 0 

a. 1 

315. R 

61. 5 

22.6 

354.x 

309.1 

53.7 

241.5 

16. 6 

67.4 

68.7 

121.2 

138 

11 

3 

4’ 

:i 

:3” 

551 

l 

5 

1:: 

;: 

101 

76 

16: 

10 

31 

if 

Cancer of lung ____. _ ._________________._ (162-3) 

Bronchitis, emphysema _..__..______ (602, 627.1) 

fhlcer of larynx ___.____......__.. _______ (161) 

Canox of oral cavity.-- _._.___________ --(140-E) 

Cancer of esophagus ..______..._____ ----e-(150) 

Stomach and duodenal ulcers _____ --.-(540. 541) 

Other circulatory diseases ._____________ (451-68) 

Cirrhosis of liver. _________......__...-.--- (581) 

Cancer of bladder. .___ - . . . . .._.___ _______ (181) 

Coronary artery disease. .___..__________._ (420) 

Other heart diseases..- ___._..._._ (421-2, 430-4) 

Hypertensive heart diseases .._____...___ (441~3) 

Oenersl arteriosclerosis .___._____________.. (450) 

Cancer of kidney. _______.._..._.___. ..__ (180) 

Allothercirncrr..--...- _...________.. ._________ 

Cancer of stomach . . ..________________--.. (151) 

Influenza, pneumonia- __......_..__._ __ (480-93) 

Allothercauses .__.._. _...____...... ._._____ -_ 

Cerebral vascular lesions- ___._________.. (33M) 

Cancer of prostate __....._...._.__.... (177) 

Accidents. suicides, violence~~.~.~.....(EBB) 

h’ephritis . ..__... --...- _._.____________. (592-4) 

Rheumatic heart disease- _ _......._._. (41X-16) 

Cancer of rectum _..- _._._._._._... ._._ (154) 

Cancer of intestines...- _.______________. (152-3) 

1. 70 4,043. 1 1,456 1. 78 
E TABLE; %-Numbers of expected and observed deaths for smokers of cigarettes only, and mortality ratios, each prospective 

study and all studies-Continued 

I California Legion Canadian veterans Men in 2.5 States Total, all studies 

fortalit 

ratio 

dortslit: 

ratio 

lortalit] 

ratio 

10.8 

6. 1 

5.4 

4. 1 

3.4 

2.8 

2.6 

2.2 

1.9 

1. 7 

1. 7 

1. 5 

1. 5 

1. 5 

1.4 

1.4 

1.4 

1.3 

1.3 

1.3 

1.2 

1. 1 

1. 1 

1.0 

.9 

1.68 

dortalit 

ratio 

-- 

Deaths 

Lrpeetet 

4.0 

8. 4 

1. 5 

1.9 

5. 1 

27.1 

36. 5 

5:: 

6.8 

PI. 8 

2. 2 

1.8 

4.0 

1.7 

2.0 

1. 2 

:! 

1. 1 

1. 2 

1.5 

2. 4 

1.5 

.9 

7.9 

41. 5 

37.6 

22. 3 

682. 5 

75.3 

36.2 

14.7 

2: 

41.2 

135.0 

361.5 

294.1 

32.3 

1.4 101.3 

_ _ _ _ _ _ _ - 11.6 

1.3 48.1 

.8 41.3 

.4 46.6 

1.58 2,420.l 

- 

-A 

Median 

nortslity 

ratio 

Cause of death Deaths T Deaths Deaths I 

r 

_- 

- 

317 

166 

5 

ii 

ii 

: 

‘,5g 

iFi 

1:; 

76 

159 

366 

266 

48 

YI cxpectec 

- 

1 ( 

_- 

Observed 

9.6 

7.5 

3.7 

9.2 

2. 4 

170.3 

89.5 

14.0 

37.0 

33.7 

1,833 

546 

175; 

113 

1.9 105.1 

2.5 254.0 

1.5 169.2 

2.2 111.6 

1.7 6,430.7 

1.4 526.0 

2.2 469.2 

1.2 210.7 

1.2 79.0 

1. 5 1,061.4 

1. 3 285.2 

1.7 303.2 

1.3 L568.7 

1.2 1,461.a 

1.0 2.53.0 

ifi 

379 

216 

11,177 

868 

E 

120 

1, 524 

413 

415 

1.946 

1,844 

318 

1. 1 l,Q63.2 1,310 

1. 1 156.4 173 

1. 1 290.6 309 

1.7 207. 8 213 

.8 422.6 395 

1.63 

_- 

1 

- 

15.653.9 

Expected Expecte dC )bservec 

_- 

- 

1( 

_- 

_- 

- 

11.7 

4.6 

3.9 

3.3 

6.9 

2.3 

1.3 

1.7 

1.8 

2. 1 

1.6 

3.3 

1.4 

1.4 

1.9 

1.2 

1.0 

1:: 

1.7 

1. 5 

:i 

1. 4 

1.66 

41.5 

15. 4 

6.3 

3.6 

8.4 

38.6 

81.0 

49. 1 

22.8 

1,863.6 

146.3 

71.5 

29.6 

24.1 

279.4 

68.6 

58.0 

E: : 

74.9 

363.7 

58.8 

79.4 

38.2 

106.2 

4,1@3.3 

399 

115 

z 

20 

1: 

72 

3,2!! 

195 

154 

35 

42 

i: 

416 

477 

75 

325 

62 

E 

81 

6,813 

11. 7 

7.5 

5.8 

3.9 

3.3 

5.0 

2.3 

2. 1 

2. 2 

1.7 

1.5 

1.5 

1.7 

1.4 

1.4 

1.3 

1. 6 

1.3 

1.3 

1.0 

1.3 

1. 5 

1. 1 

:: 

19.9 

3.6 

4.0 

5. 2 

1.8 

1.8 

16.7 

13. 1 

1.8 

312.8 

13. 1 

24.9 

39. 1 

8.3 

75.4 

20.5 

14.7 

39. 1 

57. 1 

22.1 

45.0 

14:; 

12.0 

33.2 

799.4 

All other cancer: _ ______________ :--: 

Cancer of stomech~ ______.._._. (151) 

Influenza, pneumonia. _ _____ (48CGU) 

All other causes ______________...__.. 

Cerebral vascular lesions-. _ _ _ W0-S) 

Cancer of prostate- _______---___ (177) 

Accidents, suicides, violence 

(SoctQw 

Nephritis .~ ____________. _ __._ (592-4) 

Rheumatic heart disease...-(4W16 

Cancer of rectum.--- ___________ (154 I 

Cancer of intestimx . .._______ (1523) 

All cmlses ______ _ ___________________-. 1.86 
The death rates increase with the amount smoked. For groups of men 

smoking less than 10, 10-19, 20-39, and 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 in these studies: and declines with 

increasing age. The same effect appears to hold for the ratio of the death 

rate of heavy smokers to that of light smokers. 

In the studies that provided this information. the mortality ratio was 

substantially higher for men who started to smoke under age 20 than for 

men who started after age 25. In general, the mortality ratio was increased 

as the number of years of smoking increased, although the pattern of increase was irregular from study to study. 

In two studies 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 

years of cessation increased. 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. 

(These results were available in one study only.) 

Taken as a whole the seven studies offer a substantial breadth of sampling 

of the type of men and environmental exposures to be found in North 

America and Britain, although none of the groups studied was planned as 

a random sample of the U.S. male population. 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 be 

under-recruited 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 the 

study. For men designated 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 mortality ratios. 

The studies suffered from a failure to obtain substantial portions of the 

study populations selected for investigation. For a non-response rate of 

32 percent in the prospective studies, calculations based on the available 

information 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 0.3. 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 ‘subdivided by size of city, 

the mortality ratios differed little in the four sizes of communities studied. 

714-422 CM4-9 111 
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 ratio,. 

Although similar information from other studies would have been wc~. 

come, it is our judgment that the mortality ratios are unlikely to be explaintxl 

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 ,-,a 

whether there are basic constitutional differences between cigarette smokers 

and non-smokers that would affect their longevity. As described elsewhere 

in this report, differences have been found between cigarette smokers and 

non-smokers on certain psychological and behavioral 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-smokers, 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 (9 percent to 27 percent) than for non. 

smokers in the four studies that gave this information. There is some indication that this higher death ra.te 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 all four studies in which this comparison could 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 epidemiological studies on excigar and ex-pipe smokers are inadequate to 

explain this puzzling phenomenon. According to Hammond and Horn (10) 

and Dom (61 the explanation may be that a substantial number of cigar 

and pipe smokers stop smoking because of illness. 

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 
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 1.7. 

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 mortality ratios in this large group of causes is not clear. Part may be due 

to the sources of bias previously mentioned or to some constitutional and 

genetic difference between cigarette smokers and non-smokers. There is 

the possibility that cigarette smoking has some general debilitating effect, 

although no medical evidence that clearly supports this hypothesis can be 

cited. The substantial number of possibly injurious agents in tobacco and 

its smoke also may explain the wide diversity in diseases associated with 

smoking. 

In all seven studies, coronary artery disease is the chief contributor to 

the excess number of deaths of cigarette smokers over non-smokers, with 

lung cancer uniformly in second place. 

For 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 duodenal ulcers. These ratios 

are, however, based on small numbers of deaths. 

APPENDIX I 

APPRAISAL OF POSSIBLE BIASES DUE TO NON-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 1957-1959 and 32 percent 

during the 3-year period 19561956: 32 percent for the British doctors’ 

study; and about & percent for the California Legion study and the Canadian 

veterans’ study. In forming a judgment 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 population might differ from that found in the respondents. 

The only useful information in any detail about the non-respondents comes 

from the U.S. veterans’ study. Table 27 shows data on death rates in 1958 

and 1959 (16). 

For the present purp ose the 1957 respondents will be regarded as a part 

Of the 32 percent of non-respondents to the original questionnaire for whom 

*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 19% 

respondents, 1957 respondents, and non-respondents in U.S. VeteranJ 

Study 

oroups 

Proportion 

pap&ion 

Death rates 

- 

1953 1858 

-- 

13.29 

19.26 

12.81 

19. aJ 

--- 

17.96 

22.07 

16.37 

21.81 

-- 

21.99 19.84 

1958 and 1.27 in 1959. For smokers the corresponding figures are 1.18 iii 

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 19% 

respondents was 17.77 as compared with 19.05 for the complete study pop& 

tion. The ratio 19.05/17.77 is 1.07, so that in 1958 the death rate for the 

study population was 7 percent higher than for the 1954 respondents. In 

1959 the corresponding death rates were 17.46 for 1954 respondents and 

18.31 for the complete population, the ratio being 1.05. These ratios agree 

with Doll’s judgment (4) that in the British 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 nonrespondents in 1954 contain a higher proportion of smokers than the respondents. In the 1954 respondents, non-smokers contributed 183,094 

person-years of experience during 1957-1959 as compared with 179,750 

person-years for current smokers of cigarettes only, non-smokers representing 50.6 percent of the total of the two groups. Among the 1957 respondents 

the corresponding figure was 46.8 percent. A further decline may have occurred 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 mortality ratio of current smokers of cigarettes only. 

1. The proportions of the relevant groups in the complete population are 

as follows: 

clroups / NOW 

smokers 

/ Citw&t.~. 1 Total 

Non-respondents... . . .._........... 

Respondents-... . . . . . . . . . . . . . . . . . . 

Complete population.. . ..~_.. 

This assumes that in the 68 percent of respondents, non-smokers constie 

tute 50 percent of non-smokers, plus cigarette smokers, but in the non-rem 

spondents this figure has dropped to 4-I percent. 

114 
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 concrete 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. veterans’ study in which, as already 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 individual 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 calculations 

made on assumptions (3a) and (3b) for a mortality ratio of 1.7 among 

respondents. 

TABLE 28.-Illustration of calculation of non-response bias 

Assumption (3a) Assumption (3b) 

Mortality ratios 

Non- Cigarette 

smokers smokers 

--- 

Nm-respondents ______ ’ (1.865) 

~esPonaents ____ 

1. 700 1 (1.772) Non-respondents-~.. 

1. KQ 1.7w 1 (1.330) Respondents. _....... 

Complete population. 6 (1.252) 6 (1.700) z (1.43.5) 

MR ---_____..._______ 

Complete population 

’ (1.36) M.R-.-.- ..______._. 

Mortality ratios 

Non- Cigarette 

smokers smokers 

--- 

’ Cl,@) 1.370 8 (1.772) 

1. Mm 1.700 ’ (1.350) 

The figures without parentheses in the mortality ratio tables represent the start of the computations. 

The indexes (11 etc.) show the order in which other figures are computed. For assumption (3aJ: 

U.330) ‘=[(0.34)(1.ooo)+(0.34)(1.700J1/(0.63) 

(u36) ‘=(1.1)(1.360) 

(1.772) '=[(1.4~)-(0.88)(1.3W)]/(0.32) 

(1.365) ‘= (0.32)(1.772)-(0.13)(1 700) 

wm) &o 14)(1383)+(034)(1’Oca) 

(1.7W “=~(0:13)(1:700)+(0.~)(1:7~) 

(1.36 1 ‘=1.700/1.262 

Thus, the mortality ratio drops from 1.7 to 1.36 in the complete population 

under assumption (3a) and to 1.48 under assumption (3b) . One consequence 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 

‘@jpondent population. 

For the high mortality ratios the assumptions may appear unduly extreme. 

For instance, under assumption (3a) with mortality ratio 10.0 in the responder% 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-ree’pondents. 

It may be of interest to quote Berkson’s (1) example in the same form 

(Table 30). 

TABLE 29.-Mortality ratios in respondents and computed values for the 

com.plete population 

In complete population 

In respondents (63 percent) 

Asumption (3b) 

1.00 

1.14 

1.23 

1.43 

1.57 

3.43 

5.65 

1.06 

1. 23 

1.40 

1. 56 

1. 73 

4.07 

7.41 

TABLE 30.-Proportions and death rates for Berkson’s example 

Proportions Death rates 

-~ 

OPXlp 

NOll- Smokers Total NIXI- Smokers 

Total 

smokers smokers 

------ 

Non-respondents . .._______..__ 0.03494 Respondents... ._.____.. . . . .._ 

0.28360 0. 23854 60.121 4. 217 19506 .51640 .71146 1.553 2.332 6.174 

2.113 

~-___ ---- 

Total ____ -.-- _______._._ .20000 .sotmo 1.00000 3. cm0 3.009 3.cm 

In their general direction, Be&son’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 death rate in the 

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 (60.121/1.553), 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 and non-smokers are likely to be most marked. Further, as we in. 

terpret his writing, the example was intended as a warning against the type 

of subtle bias that can arise whenever a study has a high proportion of nonrespondents, rather than a claim. that this numerical estimate of the bias actually 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 nonsmokers, each group is subdivided into age-classes (usually 5-year). For 

the ith age-class let y, denote the number of smoker deaths and xi the number of non-smoker deaths. The “expected” number of smoker deaths in the 

ith class (expected on the assumption that smokers 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) x1 =h,x, (say) 

The estimated mortality ratio R is defined as 

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 

are high in all seven studies, this evidence is more impressive than R values 

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 a measure of the stability of the combined R is needed. 

Assumptions 

In attempting to get some idea of the stability of “R without too much complexity, the following assumptions will be made. 

1. The numbers of deaths y, and x, are distributed as Poisson variables. 

As Chiang (3) has shown, a more accurate assumption is to regard yi and ~1 

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 Poisson assumption, which is slightly conservative, is reasonable. 

2. The quantities h, can be regarded as known constants. This is not 

quite correct. Initially, the h, are the ratios of the numbers of smokers to 

non-smokers in the age-classes, which can 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, however, this assumption should introduce little error. 

3. The variates yi and yj are uncorrelated. An error in the age assigned 

to a death, putting it in the wrong age-class, induces a negative correlation 

between yl and yj. The existence of such errors should have no effect on 

117 
the variance ascribed to Zyi on the assumption of independence. The sanrc 

remarks apply to the assumption that xi and xj are uncorrelated. 

4. The variates xi and yi are uncorrelated. An error in assigning a death 

to the correct smoking category would induce a negative correlation between 

xi and yi. Such errors should of course not be allowed to happen, sine 

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 Xyr of R follows a Poisson distc. 

bution. The denominator ZXixi is a linear function of independent Poisson 

variates, and numerator and denominator are independent of one another, 

The exact distribution of a ratio of this type has not been worked out. Two 

appro+mate methods of obtaining confidence limits for the true mortality 

ratio R will be @en. 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 to 

interpret. 

The Binomial Approximation 

If the ~~ can be regarded a.s approximately constant (=A, say) then 3 

becomes of the form Y/AX, where y and x are independent Poisson variates. 

Since AX then represents the expected number of deaths of the smokers, 

the quantity A is estimated as the ratio of the expected number of smoker 

deaths to the number of non-smoker deaths. 

By a well-known result it fol.lows that x/(y 4-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= I/ (1 +AR) 

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 smokers are as follows: 

NOllsmokers 

Smokers 

Observed Observed Expected 

____________ 

Number of deaths . .._. -.. __..__.. 16(x) 1WY) 9.71(xX) 

Hence, ~=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)/)rp 

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 8, 1.5, is not significantly above unity. 

118 
Unfortunately the assumption that A( is constant is not true in these studies. 

For instance, in the study of men in 25 States hi 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 yi with age is less drastic but is still noticeable. 

The Normal Approximation 

This approach avoids the assumption that the A~ are constant. but makes 

other assumptions that are shaky with small numbers of deaths. If R is the 

true mortality ratio, the quantity 

y-Re 

where e=Xhix, is the expected number of smoker deaths. will follow a 

distribution that has mean zero. If ,.L,. mi denote the true means of y, and 

xi. respectively, the variance of (y-Re) is 

The basis of this approximation is to regard the quantity 

y-Re 

dZ(p~+Wh:rn,) 12’) 

as normally distributed with zero mean, since yi and xi are regarded, as 

previously, as independent Poisson variates. The 95 percent confidence 

limits for R are then obtained, by a standard device, by setting the absolute 

value of this quantity equal to 1.96 and solving the resulting quadratic 

equation for R. 

Since the p, and the mi are unknown, a further approximation is to 

substitute y as an estimate of I+, and 2,1:x, as an estimate of Lhim,. 

ExampZe. For the example previously discussed the data are as follows: 

y=15: e=9.71: ‘,h+,=6.059 

Ou squaring (2)) the quadratic equation becomes 

(15-9.71R)2=3.84( 15+6.059R2) 

The roots are found to be 0.7 and 3.4, in good agreement with the limits 

0.7 and 3.3 given by the binomial approximation. This agreement is better 

than will usually be found with small numbers of deaths. 

The following are 4 comparisons of the confidence limits for cigarette 

smokers in the same study. 

Cause of death 

Number of deaths 

Non- Cigarette snwkers 

smokers 

observed 

( 9.5 percent limits 

Mortality ! 

ratio 

/ Binomial 1 Normal 
The lower confidence limits agree well, but the upper limit runs high* 

for the normal approximation. For cigarette smokers the normal me&d 

is perhaps more accurate. Tbe binomial method has some advantage ir, 

simplicity. 

REFERENCES 

1. Berkson, J. The statistical study of association between smoking and 

lung cancer. Proc Staff Meeting, Mayo Clin 30: 31948, 1955. 

2. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mar. 

tality 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. 

Special Reports No 47,275-85,1%1. 

4. Doll, R. Personal communication to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

5. Doll, R., Hill, A. B. Lung cancer and other causes 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 Sot 

Stat Sect Amer Stat Assn 34-71, 1958. 

7. Dunn, J. E., Jr., Linden, G., Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub 

Health 50: 1475-87, 1960. 

8. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department of 

Public Health. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

9. Hald, A. Statistical tables and formulas. Wiley, New York, 1952. 

10. Hammond, E. C., Horn, D. S mo k’ mg and death rates-report on fortyfour months of follow-up on 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 the Surgeon General’s Advisory 

Committee on Smoking and Health. 

12. Hammond, E. C. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

13. Hammond, E. C. The effects of smoking. Sci Amer 207: 3-15, 1%2. 

14. Ipsen, J., Pfaelzer, A. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

15. Korteweg, R. The significa.nce of selection in prospective investiga. 

tions into an association between smoking and lung cancer. Brit 

J Cancer 10: 282-91,1956. 

16. Krueger, D. Personal communication to the Surgeon General’s Advisory Committee on Smoking and Health. 

17. Yates, F. Sampling methods for censuses and surveys. Griffin, Lonm 

don, (Section 9.4)) 1960. 
Chapter 9 

Cancer 
Contents 

CANCER MORBIDITY AND MORTALITY ....... 

Sources of Information ................ 

Sex Ratio ...................... 

Geographic Variation ................. 

Urban-Rural Gradients. ................ 

Income Class ..................... 

Occupation ...................... 

Ethnic Group ..................... 

Trends ........................ 

Age-Specific Mortality From Lung Cancer ........ 

Effects of Changes in Lung Cancer Diagnosis on Time 

Trends ....................... 

CARCINOGENESIS ................... 

Fundamental Problems in Carcinogenesis in Relation to 

Induction of Neoplastic Changes in Man by Tobacco 

Smoke ..................... 

Threshold ..................... 

Carcinogenicity of Tobacco and Tobacco Smoke in Animals. . 

Skin ........................ 

Subcutaneous Tissue ................. 

Mechanism of the C#arcinogenicity of Tobacco Smoke 

Condensate .................... 

Other Materials of Possible Importance in Carcinogenicity ...................... 

Pesticides ..................... 

Lactones ..................... 

Radioactive Components .............. 

Summary. ..................... 

Carcinogenesis in Man ................. 

Polycyclic Aromatic Hydrocarbons .......... 

Industrial Products ................. 

soot ....................... 

Coal Tar and Pitch. ................ 

Mineral Oils ................... 

Summary. .................... 

CANCER BY SITE ................... 

Lung Cancer ..................... 

Historical ..................... 

Retrospective Studies ................ 

Methodologic Variables. .............. 

Form of Tobacco Use. ............... 

Page 

127 

127 

133 

133 

133 

133 

134 

134 

135 

136 

139 

141 

141 

143 

:-ii 

144 

144 

E 

145 

145 

146 

146 

146 

147 

147 

147 

147 

148 

148 

149 

149 

150 

151 

155 

122 
CANCER BY SITE-Continued 

Lung Cancer-Continued 

Retrospective Studies-Continued 

Amount Smoked ................. 

Duration of Smoking. ............... 

Age Started Smoking ............... 

Inhalation. .................... 

Histologic Type .................. 

Relative Risk Ratios from Retrospective Studies .... 

Prospective Studies ................. 

Experimental Pulmonary Carcinogenesis ........ 

Attempts to Induce Lung Cancer with Tobacco and 

Tobacco Smoke ................ 

Summary. ................... 

Susceptibility of Lung of Laboratory Animals to Carcinogens .................... 

Polycychc Aromatic Hydrocarbons ........ 

Viruses. .................... 

Possible Industrial Carcinogens .......... 

Summary. ................... 

Role of Genetic Factors in Cancer of the Lung. .... 

Summary. ................... 

Pathology-Morphology ................ 

Relationship of Smoking to Histopathological Changes in 

the Tracheobronchial Tree ........... 

Summary. .................... 

Conclusion ................... 

Typing of Lung Tumors .............. 

Conclusions ................... 

Evaluation of the Association between Smoking and Lung 

Cancer ..................... 

Indirect Measure of the Association ......... 

Direct Measure of the Association ......... 

Establishment of Association ........... 

Causal Significance of the Association ....... 

The Consistency of the Association. ........ 

The Strength of the Association .......... 

The Specrficity of the Association ......... 

Temporal Relationship of Associated Variables ... 

Coherence of Association ............. 

(1.) Rise in Lung Cancer Mortality ....... 

(2.) Sex Differential in Mortality ........ 

(3.) Urban-Rural Differences in Lung Cancer Mortahty. ................. 

(4.) Socio-Economic Differentials in Lung Cancer 

Mortality ............... 

(5.) The Dose-Response Relationship. ...... 

(6.) Localization of Cancer in Relation to Type of 

Smoking ................ 

Hietopathologic Evidence .............. 

Page 

155 

158 

158 

159 

159 

160 

161 

165 

165 

165 

166 

166 

166 

166 

167 

167 

167 

167 

167 

172 

173 

173 

174 

175 

175 

179 

179 

182 

182 

183 

183 

185 

185 

185 

185 

186 

186 

187 

188 

189 

123 
CANCER BY SITE-Continued 

Lung Cancer-Continued 

Constitutional Hypothesis .............. 

Genetic Considerations ............... 

Epidemiological 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 .................. 

Epidemiologieal 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 Evidence. .............. 

Retrospective Studies ............... 

Prospective Studies ................ 

Page 

190 

190 

192 

192 

192 

192 

192 

193 

193 

194 

195 

196 

196 

1% 

1% 

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 

124 
CANCER BY SITE-Continued 

Stomach Cancer-Continued 

Carcinogenesis . . . . . . . . . . . . . . . . . . . 

Evaluation of the Evidence . . . . . . . . . . . . . . 

Conclusion . . . . . . . . . . . . . . . . . . . . . 

SUMMARIES AND CONCLUSIONS . . . . . . . . . . . 

Lung. . . . . . . . . . . . . . . . . . . . . . . . . 

Oral Cancer. . . . . . . . . . . . . . . . . . . . . . 

Larynx. . . . . . . . . . . . . . . . . . . . . . . . 

Esophagus . . . . . . . . . . . . . . . . . . . . . . 

Urinary Bladder . . . . . . . . . . . . . . . . . . . . 

Stomach . . . . . . . . . . . . . . . . . . . . . . . 

REFERENCES. . . . . . . . . . . . . . . . . . . . . . 

Figures 

1. Mortality from cancer (all sites), U.S. Death Registration 

Area of1900,1900-1960. . . . . . . . . . . . . . . 

2. Age-adjusted mortality rates for cancer-all sites, in 17 

countries,1958-1959 . . . . . . . . . . . . . . . . 

3A. Age-adjusted mortality rates for cancer of six sites in six 

selected countries-males . . . . . . . . . . . . . . 

3B. Age-adjusted mortality rates for cancer of six sites in six 

selected countries-females . . . . . . . . . . . . . 

4. Comparison of age-adjusted mortality rates by sex, United 

States, 1959-1961, with incidence rates from State registries of New York and Connecticut . . . . . . . . . . 

5. Trends in age-adjusted mortality rates for cancer by sexall sites and respiratory system in the United States, 

1930-1960 . . . . . . . . . . . . . . . . . . . . . 

6. Trends in age-adjusted mortality rates for selected cancer 

sites by sex in the United States, 1930-1960 . . . . . . 

7. Age-adjusted mortality rates for cancer of the lung and 

bronchus by birth cohort and age at death for males, 

United States, 1914, 1930-1932, 1939-1941, 1949-1950, 

1959-1961 . . . . . . . . . . . . . . . . . . . . . 

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 . . . . . . . . . . . . . . . . . . . . . 

9. Crude male death rate for lung cancer in 1950 and per capita 

consumption of cigarettes in 1930 in various countries . . 

10. Percentage of persons who have never smoked, by sex and 

age, United States, 1955 . . . . . . . . . . . . . . . 

Page 

228 

228 

229 

229 

229 

233 

233 

234 

234 

235 

235 

128 

129 

130 

131 

132 

136 

137 

138 

139 

176 

178 

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 current smokers of cigarettes only for selected cancer sites, all 

sites, and all causes of death; each prospective study and 

all studies . . . . . . . . . . . . . . . . . . . . . 

2. Outline of methods used in retrospective studies of smoking 

in relation to lung cancer . . . . . . . . . . . . . . 

3. Group characteristics in retrospective studies on lung cancer 

and tobacco use . . . . . . . . . . . . . . . . . . 

4. Relative risks of lung cancer for smokers from retrospective 

studies . . . . . . . . . . . . , . . . . . . . . . 

5. Mortality ratios for lung cancer by smoking status, type of 

smoking, and amount smoked, from seven prospective 

studies . . . . . . . . . . . . . . . . . . . . . . 

6. Percent of slides with selected lesions, by smoking status and 

presence of lung cancer . . . . . . . . . . . . . . . 

7. Changes in bronchial epithelium in matched triads of male 

non-smokers and smokers of different types of tobacco . . 

8. Relation between WHO and Kreyberg classifications of lung 

tumors . . . . . . . . . . . . . . . . . . . . . . 

9. Mortality ratios for cancer of the lung by smoking class and 

by type of tumor, U.S. Veterans Study . . . . . . . . 

10. Outline of retrospective studies of tobacco use and cancer 

of the oral cavity . . . . . . . . . . . . . . . . . . 

10A. Summary of results of retrospective studies of smoking and 

detailed sites of the oral cavity by type of smoking . . . 

11. O&line of retrospective studies of tobacco use and cancer of 

the larynx . . . . . . . . . . . . . . . . . . . . . 

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 

and cancer of the esophagus . . . . . . . . . . . . . 

14. Summary of methods used in retrospective studies of smoking 

and cancer of the bladder . . . . . . . . . . . . . . 

15. Summary of results of retrospective studies of smoking and 

cancer of the bladder . . . . . . . . . . . . . . . . 

15A. Summary of results of retrospective studies of cigarette 

smoking and cancer of the bladder in males . . . . . . 

16. Summary of methods used in retrospective studies of 

smoking and cancer of the stomach . . . . . . . . . . 

17. Summary of results of retrospective studies of smoking 

and cancer of the stomach . . . . . . . . . . . . . . 

149 

152 

156 

161 

164 

168 

171 

174 

175 

198 

201 

206 

214 

216 

220 

221 

222 

226 

227 

126 
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 Columbia 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 growth of 

the population and the part due to increase in life expectancy or aging of 

the population, there is still a residual increase of significant 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 information, 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). Mortality statistics, cancer register data, and 

collected series of pathological specimens are in general agreement in identifying 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 United 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 on diagnosed cases in Connecticut (136) 

upstate New York (112) and California (37), and the morbidity surveys 

conducted in ten metropolitan areas in 1937-39 and 194748 (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 

7 14-422 o-s4- lo 127 
MORTALITY FROM CANCER (All sites), U.S. DEATH 

REGISTRATION AREA (‘1 OF 1900, 1900-1960 

FIGURE 1. 

Includes Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, Connecticut, 

New York, New Jersey, Michigan, Indiana, District of Columbia. 

Sources: a. United States Census of Population: 1940, 1950, 1960. 

b. Vital Statistics of the United States, Part I, 1940; Vol. III, 1950; Vol. II, Part B, 1960. 

c. Gover, Mary. Cancer Mortality in the United States, Part I, Public Health Bulletin 

248, 1939. 

cancer sites can be regarded as good (91, 247), so that the problems in 

interpretation are less formidable than those arising in studies of cardiovascular 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. “) 

RATE PER 100,000 

SWITZERLAND 

FRANCE 

GERMANY FR 

DENMARK 

NETHERLANDS 

UNITED STATES 

AUSTRALIA 

CANADA 

JAPAN 

ITALY 

IRELAND 

NORWAY 

SWEDEN 

ISRAEL 

DENMARK 

AUSTRIA 

GERMANY FR 

NETHERLANDS 

SWITZERLAHD 

ISRAEL I 

I I 

1 

M .LE 

ENGLAND 6 WALES 

CANADA 

FINLAND 

IRELAND 

SWEDEN 

UNITED STATES 

FRANCE 

NORWAY I 

AUSTRALIA 

I 

ITALY 

I I 

JAPAN 

1 I 

I I 

FIGURE 2. 

If..% data age-adjusted to total population of the continental United States, 1950. 

Source: Calculated from Segi, M., and Kurihara, M. (317). 

FEMALE 

I 

ad New York have been in operation long enough to provide reliable data 

on incidence trends over the past two decades. The morbidity surveys for 

1X7-48 produced a comprehensive report on cancer incidence in large 

cities with very good medical care facilities, but this information has not 

been updated by resurveys. 

129 
AGE-ADJUSTED MORTALITY RATES FOR CANCER OF 

6 SITES IN 6 SELECTED COUNTRIES - MALES”) 

EHCLAND 

FINLAND 

UNITED STATES 

CANADA 

NORWAY 

JAPAN 

JAPAN 

FINLAND 

NORWAY 

ENGLAND 

CANADA 

UNITED STATES 

UNITED STATES 

ENGLAND 

CANADA 

FINLAND 

NORWAY 

JAPAN 

FINLAND 

JAPAN 

ENGLAND 

UNITED STATES 

CANADA 

NORWAY 

ENGLAND 

UNITED STATES 

CANADA 

FINLAND 

NORWAY 

JAPAN 

FINLAND 

ENGLAND 

UNITED STATES 

CANADA 

JAPAN 

NORWAY 

RATE PER 100,000 POPULATION 

UUCCAL CAVITY A 

PHARYNX 

n n n n A LARYNX 

FIGURE 3A. 

U.S. data age-adjusted to the total population of the continental United States, 1950. 

Source: Calculated from Segi, M., and Kurihara, M. (317). 

The deficiencies in any single set of data should not be overstressed. Comparisons 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”1 

ENGLAND 

UNITED STATES 

FINLAND 

CANADA 

JAPAN 

NORWAY 

JAPAN 

FINLAND 

NORWAY 

ENGLAND 

CANADA 

UNITED STATES 

FINLAND 

ENGLAND 

NORWAY 

UNITED STATES 

CANADA 

JAPAN 

FINLAND 

JAPAN 

ENGLAND 

CANADA 

UNITED STATES 

NORWAY 

ENGLAND 

UNITEDSTATES 

CANADA 

NORWAY 

FINLAND 

JAPAN 

ENGLAND 

JAPAN 

FINLAND 

CANADA 

UNITED STATES 

NORWAY 

RATE PER 100,000 POPULATION 

8 , . t : L a * 

! 

1 I 

I 

! 

LUNG, BRONCHUS 8 TRACHEA 

FIGURE 3B. 

U.S. data age-adjusted to the total population of the continental United States 1950. 

Source: Calculated from Segi, M., and Kurihara, M. (317). 

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 favorable prognosis-oral cavity, prostate, and urinary bladder. These differ. 

ences are compatible with existing information on the survival experience 

of cancer patients. 

131 
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. 

Lung and bronchus 

Lsophagus 

Stomach 

Buccal cavity 

and pharynx 

Bladder and other 

urinary organs, 

excluding kidnoy 

larynx 

MALES 

zz 

FEMALES 

m MORTALITY, UNITED STATES WHITE POPULATION, 1959-1961 

m INCIDENCE, UPPER NEW YORK STATE, 1958- 1960 

m INCIDENCE, CONNECTICUT, 1959 

FIGURE 4. 

Sources: Vital Statistics of the United States, annual volumes; Ferber, B. et al (112). 

Eisenberg, H., personal communication to the Surgeon General’s Advisory Committee 

on Smoking 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 (U.S., 195961) (252) 

from cancer for the six sites common to both sexes are given below: 

Male/Female Ratio Male/Female Ratio 

Whites 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 malefemale 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 intervening 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, and gastric 

cancer is encountered less frequently in the South than in other parts of the 

country. Within regions, some cities are known to display exceptional 

incidence of certain types of cancer (91). 

URBAN-RURAL GRADIENTS 

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. metropolitan areas in 19474 (91). 

133 
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 lung 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 incidence 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 topic. Incidence of bladder cancer was not related to income 

class for either males or females. 

OCCUPATION 

From unpublished tabulations of deaths for 1950 according to occupation 

and industry prepared by the National Vital Statistics Division of the Public 

Health Service (252), it is possible to select certain occupations with unusually 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 being 

about double those for all males of comparable age. Similar findings have 

been reported by the Registrar-General 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 molders, 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 occupational 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 mortality 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 much greater. This dilution occurs because data from a 

number of industries and occupations, including many in which no particular bladder cancer hazards 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 recorded 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 oral 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 United States. Laryngeal cancer has not been systematically 

studied from this point of view (1422). 

134 
The several ethnic groups in the United States display their own characteristic patterns of excesses and deficits in risk by site. Men and women 

horn in Ireland have high death rates for oral and esophageal cancers. The 

Polish-born Americans have pronounced excess mortality for esophageal 

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) and a striking excess risk for esophageal 

cancer among women. The English-b orn American men and women have 

above-average lung cancer risks. 

TRENDS 

Figure 5 describes the divergent behavior in mortality trends for cancer, 

all sites, among men and women since 1930. The age-adjusted 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. Th’ IS f orm of cancer was responsible for the deaths of approximately 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 sMft 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 

heen certified as stomach cancer. Detailed examination of the data on 

possible compensatory effects by country, sex, age and other variables conclusively rules out diagnostic artifacts of this type as a poss?ble explanation. 

The Connecticut and New York State registers (112, 136) and the ten-city 

surveys (91) confirm the decline in gastric cancer and the absence of important 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 195%60, and 

the Connecticut experience revealed a similar displacement. A possible 

reason for this increase in case reports of prostatic cancer to registers may 

he found in more careful examination by pathologists of prostates removed 

135 
TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR 

CANCER BY SEX - ALL SITES AND RESPIRATORY SYSTEM 

IN THE UNITED STATES, 1930-1960. ") ‘0.. -... . 

7 

FEMA 

.***** CANCER, ALL SITES 

v CANCER, EXCLUDING RESPIRATORY SYSTEM 

- CANCER, RESPIRATORY SYSTEM ONLY 

FIGURE 5. 

Age-adjusted to the total population of the continental United States. 1950. 

Source: Vital Statistics of the United States, annual volumes. 

surgically, which would result in discovery and reporting of more asymptomatic prostatic carcinomas. Th e 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 gradually thereafter. Incidence data from cancer registers 

provide a close parallel (112). 

136 
TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR 

SELECTED CANCER SITES BY SEX 

IN THE UNITED STATES, 1930-1960. 1” 

.a 

.a 

,’ 

-... 

. 

.-- 

._ 

111 

- 

-- 

-- 

--r--TFEMALES 

. . ‘. ‘. 

. . . . 

_-- 

- 

I 

‘\ 

l ***‘* LUNG AND BRONCHUS 

----- STOMACH 

- ESOPHAGUS 

v BUCCAL CAVITY AND PHARYNX 

c.oo~-o BLADDER AND OTHER URINARY ORGANS 1-1 LARYNX 

(EXCLUDING KIDNEY) 

---- KIDNEY 

- - - PROSTATE 

FIGURE 6. 

Data are for the white popukion, age-adjusted to the total population of the continental 

United States, 1950. 

Sources: Gordon T., et al. (130) ; and unpublished calculations of the Biometry Branch, 

National Cancer Institute, U.S. Public Health Service. 

However, when any separate cohort (a group of persons born during the 

same ten-year period) is scrutinized over successive decades, the seeming 

downturn of mortality rates after age 70 oan be seen to be an artifact due 

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. “1 

lb39- 7.P~ _~~~ ---.- 

1930- 

1914 

-41 

'32 

AGE 

FIGURE 7. 

Data are for the white population. 

Sources: Darn, H. F., and Cutler, S. J. (91). 

Unpublished calculations of the Biometry Branch, National Cancer Institute, U.S. Pnhfic 

Health Service. 

to the admixture of cohorts with differing mortality experiences. W-hen 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 

bold-line curve shows the mortality rates of the cohort in 1914 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, in 1949-50 when they 

were about 70 years old, and in 1959-61 when they were about 80 years old. 

The new series of curves, representing the mortality experience of the 

individual cohorts, reveal 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 
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, 1959-61.1’) 

1959-61 

\%ba 

1949-50 

,05Q 

1939-41 

1930-32 

AGE 

FIGURE 8. 

Sources: Dorn, H. F., and Cutler, S. J. (91). 

Unpublished calculations of the Biometry Branch, National Cancer Institute, U.S. 

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. Th e 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 population 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 CHANGES IN LUNG CANCER DIAGNOSIS ON TIME TRENDS 

The cause of death is at times difficult to establish accurately from clinical findings alone, and the incidence and mortality rates recorded for lung 

139 
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 lung 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). The proportion of lung cancer 

certifications in the 1920’s and 1930’s based on comparable diagnostic evidence is unknown, but the figure was certainly much lower. 

Gilliam (128) has attempted to evaluate the possible effects of diagnostic 

changes on the published lung cancer mortality statistics. He calculated 

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 down from 26- to 8-fold for males and 

from 7-fold to 1.3-fold for 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 conceded, 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 statistics from past years can yield only rough qualitative judgments (267)) and 

we must rely on the composite evidence from several sources. 

The following 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 

(c) The magnitude of the increase in mortality in recent years 

To this we would add that the question can be resolved by reference to the 

contemporary experience of large, population-based cancer registers for 

which a high percentage of the cases reported have microscopic confirmation. 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. D ia g nostic comparability is a far less important 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 

annual 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 contribute 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 real increase in lung cancer. Institutions 

such as the University of Minnesota Hospitals (Minneapolis) (350)) Presby 

140 
terian Hospital (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 bronchogenic carcinoma, 11 males and 6 females, were diagnosed in 5,300 

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 to 1961 

(autopsy rate of 68 percent). 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) 

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 from 1900 on. 

The Copenhagen Tuberculosis Station data, reviewed by Clemmesen et al. 

i56), present an unusual opportunity for evaluating the effect of improvement 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 well 

documented. The increasing frequency of lung cancer found at necropsy 

from 1930 onward, while of itself not decisive, when considered 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 contain a complex mixture of hundreds of 

different chemical components among which are (a) numerous polycyclic 

aromatic hydrocarbons and (b) inorganic compounds. Many of these compounds 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 

effect of these components of tobacco and tobacco smoke, it may be helpful 

to review briefly some basic pririciples of carcinogenesis. 

F~~NDAMENTAL PROBLEMS IN CARCINOGENESIS IN RELATION TO 

INDUCTION OF NEOPLASTIC 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 sensitivity 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 

substances, 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 introduced 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 material, 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 compound in one species does not prove that the test compound would be 

carcinogenic in another species under similar circumstances. Therefore, 

tests for carcinogenicity in animals can provide only supporting evidence 

for the carcinogenicity of a given compound or material in man. Nevertheless, 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) (44j, 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 presented in another section of 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 which 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 the formation of white patches of thickened squamous 

epithelium-leukoplakia-a 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 identified 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 demonstrated the presence of substances in 

tobacco and smoke which themselves are not carcinogenic, but can promote 

142 
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 consideration. The smallest concentration of benzo (a) pyrene known to induce carcinoma 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 controversial at the present time. Th e evidence for the existence of a threshold 

has been summarized by Brues (43). When pulmonary tumors were induced in mice with dibenzanthracene and urethan by Heston et al. (172,232 j : 

a linear response was demonstrated at higher doses but a curvilinear re- 

$ponse appeared at lower doses. At extremely low dosage, the possible effect 

of the agent became obscured by the incidence of spontaneous pulmonary 

tumors. In the case of induction of cancer by ionizing radiation, it has been 

claimed that there is no threshold (210). It is conceivable that there is 

no threshold for certain neoplasms, whereas there may be one for others. 

Neither the available epidemiologic nor the experimental data are adequate 

to fix a safe dosage of chemical carcinogens below 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, 105, 132, 

139,263, 296, 297, 338, 372, 373, 382,383) that tobacco smoke condensates 

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 

of such complex mixtures. The relatively high susceptibility of 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 Pulmonary Carcinogenesis. 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 b e 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 the 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. 

M my investigators have shown that the application of tobacco tar to the 

skin of mice and rabbits induces papillomas and carcinomas (31, 42, 92, 93, 

7 14-422 O-64- I I 143 
105, 132, 139, 263, 296, 297, 338, 372, 373, 382, 383). 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 papillomss (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 (I54 262, 267, 

268) encountered in the literature. Extracts of tobacco usually have weaker 

carcinogenic activity than do the condensates of cigarette smoke (93, 390). 

Crellhorn (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) f ound that the tobacco smoke condensate ap 

peared to accelerate the transformation of papillomas to carcinomas. Anticarcinogens have also been reported in condensates of cigarette smoke (107). 

Nicotine is not usually considered a carcinogen on the basis of animal 

experiments (346, 391) . 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 products. 

Subcutaneous Tissue 

Druckrey (92) found that cigarette smoke condensates or alcoholic extracts of cigarette tobacco regularly induced sarcomas in rats at the site of 

subcutaneous injections. The material was injected once weekly for 58 

weeks, the total 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 experiments with benzo (a) pyrene and found that the amount of this polycyclic 

aromatic hydrocarbon in smoke condensates 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 condensates and the carcinogenic potency of the condensates has been reported 

by several investigators using the mouse skin test (92, 93, 126, 372, 390). 

Mechanism of the Carcinogenicity of Tobacco Smoke Condensate 

Tobacco smoke contains many carcinogenic polycyclic aromatic hydrocarbons (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 ~8s 

unanticipated. Both Druckrey (92) and Wynder (372) emphasized that 

14.4 
the benzo(a)pyrene concentration of various tobacco and smoke preparations 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 

(If the carcinogenic hydrocarbons so as to account for the biological activity 

of the tobacco products. Further, possible synergism between low levels of 

the several known carcinogens in the tobacco condensates and extracts may 

also enhance the carcinogenic potency. 

Other Materials of Possible Importance in Carcinogenicity 

PESTICIDES 

Pesticides currently used in the husbandry of tobacco in the United States 

include DDT, TDE, aldrin, dieldrin, endrin, chlordane, heptachlor, malathion 

and occasionally parathion (see Chapter 6). 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), and 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 C3HeB/Fe 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) and 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 on Pesticides) . 

LACTONES 

The lactones have been suggested as contributors to the carcinogenic 

effects of tobacco. Attention was focused on these compounds by the discovery (74,74A, 291,292, 362) that /3-propiolactone, used as a sterilant and 

preservative, is carcinogenic for mice. Coumarin, a S-lactone, has been used 

as a common flavoring in tobacco. Hydroxy- and methoxy-coumarins are 

constituents of the leaf itself and are carried over in the smoke. Also the 

ylactone, ,%levantenolide, is present in both tobacco and smoke (354). The 

following lactones (not suggested to be present in tobacco) have been found 

to be carcinogenic for animals: y-Iactones (patulin, penicillic acid, methyl 

protoanemonin) and I-lactones (parasorbic acid lactone and aflatoxins) . 

RADIOACTIVE COMPONENTS 

potassium 40, a p-emitter, 

in cigarette smoke. 

has been reported to be a source of radioactivity 

The amounts of this activity taken into the lung, even by 

the heavy smoker, are minute when compared with the daily uptake of K 1u1 

from the diet. Furthermore this material is highly soluble and it is rapidly 

eliminated from the lung tissue thereby preventing any local build-up (300a). 

The a-particle activity due to the radium and thorium content of tobacco 

smoke, even for the heavy smoker, is less than one percent of the atmospheric 

radon.and thoron inhaled daily by any individual (347a) . A recent but still 

\lnpublished report holds that PO 210 is the major source of radioactivity in 

cigarette smoke. The amounts calculated to be absorbed are high 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 radioactive constituents from fall-out (e.g., Strontium 90 and Cesium 137). 

Summary 

Condensates of tobacco smoke are carcinogenic when tested by applica. 

tion to the skin of mice and of rabbits, by subcutaneous injection in rats, 

and by painting the bronchial epithelium of dogs. The amount of known 

carcinogens in cigarette smoke is too small to account for their carcino. 

genie activity. Promoting agents have also been found in tobacco smoke 

but the biological action of mixtures of the known carcinogens and promoters 

over a long period of time is not understood. 

CARCINOGENESIS IN MAN 

Despite the many uncertainties in the application to man of research 

results in animals, the animal data serve a purpose in indicating potential 

carcinogenicity. 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 tobacco smoke 

fall into this category in that they are carcinogenic for most animal species 

tested. Since the response of most human tissues to exogenous factors is 

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. 

i108). 

Polycyclic Aromatic Hydrocarbons 

Cancer induction in man by the application of “pure” polycyclic aromatic hydrocarbons has not been reported. Klar (188) reported an epithelial tumor on his left forearm that appeared three months after 

termination of an experiment in which mice were painted with 0.25 percent 

benzo(a) pyrene in benzene. Cottini and Mazzone (63) applied 1.0 percent 

benzo (a) pyrene in benzene to the skin of 26 volunteers in daily doses and 

observed the sequential development of erythema, pigmentation, desquamation, 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) described 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 exposure to carcinogens. Cancer of the skin of the fingers has not been reported in cigarette smokers, despite the intense discoloration so often seen 

at this site (212). However, spontaneous cancer of the skin of the fingers 

is very rare. 

146 
Industrial Products 

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 cancers ( 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 neoplasms usually occurred 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 nou? working in industries 

involving exposure to “carbon black” is being debated (108). The chemical and physical properties of “carbon black” vary widely (109, 110). 

As early as 1922, Passey (266) f ound that cancer of the skin could be 

produced experimentally by extracts of soots. More recently, Falk et al. 

1111) showed that polycyclic hydrocarbons in the “carbon black” were 

present in processed rubber, and rubber extracts were found to be carcinogenic for the skin of mice. Also Falk and Steiner (109, 110) found fumacetype black rich in pyrene, fluoranthene, benzo ( a) pyrene, benzo (e) pyrene, 

anthanthrene, benzo( g, h, i)perylene, and coronene in particles having an 

average diameter of 80 rnp 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 I892 described cancer of the skin as an occupational 

hazard in the coal tar industry. The distillation of coal tar yields many 

different organic compounds with 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 attributed to exposure 

to tar and pitch, the remainder to mineral oils. The latent period for induction 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). Bonnet 

(32) reported an interesting case of pulmonary cancer in a workman exposed 

to hot tar containing three percent benzo (a) pyrene. He estimated that 320 

rug. of the carcinogenic hydrocarbon could have been inhaled hourly. Carcinogenicity of both creosote oil and anthracene oil for the skin of workmen 

has been documented (18,39,259). 

MINERAL OILS 

So-called paraffin cancer is not caused by paraffin 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 

atraction of carcinogenic hydrocarbons with sulfuric acid (164). Bioassay 

Of mineral oils indicates that their content of carcinogens varies with their 

147 
geographic origin (348). 

mineral oil increases as 

Animal tests show that the carcinogenici of 

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. hlle 

fractions presumably free from benzo(a)pyrene have nevertheless been 

found to be carcinogenic. Coal t ar contains 0.3 to 0.8 percent benzo(a). 

pyrene, soot 0.03 percent, and American shale oil 0.003 to 0.004 percent 

(51). 

SUMMARY 

There is abundant evidence that cancer of the skin can be induced in maa 

by industrial exposure to soots, coal tar and pitch, and mineral oils. AlI 

of these contain various polycyclic aromatic hydrocarbons proven to b 

carcinogenic in many species of animals. Some of these hydrocarbons 

are also present in tobacco smoke. It is reasonable to assume that &m 

can be carcinogenic for man also. 

CANCER BY SITE 

The seven 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 investigators. For these reasons, cancer of the prostate and kidney will not be discussed further at this time. Th’ 1s d ecision does not imply a conclusion that 

the findings must be artifacts, but rather that judgment on these sites should 

be 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 prospective studies is better. In addition, the studies report a stronger association 

of smoking history with stomach ulcer. Clinical impressions of this relation148 
TABLE I.-Expected and observed deaths and mortality ratios of current 

smokers of cigarettes only, for selected cancer sites, all other sites, a& all 

causes of death; each prospective study and a.U studies 

nited Crlli- 

-tab3 fornis 

doctors 1 9 States veterans OCCUPStional 1 

__-__ 

Lung and Observed 129 233 519 138 

bronchus, x-3 2 ;;k&ed 20.2 6423.4 10043.3 12.0 *Si; 

___- 

Expem?n 0. u 1.3 2. 4 0.0 

Ratio -...~ . . . . 13.1 5.5 ._...... 

_______ ~-__ 

OrflK~ity, “,&z,” t.0 22 7. 8 54 5. 1 7. 2 

Ratio _. 2.5 6.6 1.0 

_____ ___. 

Eropha~s, 150 Observed 18 33 4 9 22 

g;T;ted i.3 2. 1 2. 67 65. 64 2 0. 55 71. 58 1 6. 33 8 

---P-P-_____ 

Aladder, 181 faery~~ 12 41 

if.4 

13 

13.9 17.2 2. 2 :.8 z.3 

Ratio 0. 9 2. 4 1.8 6.0 4.0 1. 7 

-___ __I__ __- __5_-__ 

Kidney. 180 Observed 21 34 10 6 13 

Expected i7.0 14.0 23.1 0.0 5.3 9. 5 

Ratio 1.5 1.5 .._. ._.. 0. 7 1. 4 

~__ ~_I______ 

Stnmsch, 151 gher;;~ 31 

28.3 ii.7 

90 24 76 

Rl. 5 31. 4 E.5 41.2 

Ratio 1.1 2.3 1.5 0. 8 1. 2 1.9 

-________--__-~ 

Prostate, 177 ~~% 

ii.0 2. 4 

106 

53.7 i.6 Z.1 

Ratio 

Lz.3 

0. 5 1.6 2.0 0. 5 0.9 1. 5 ~--_____I_-~ 

All Other Sites Observed 116 290 671 141 106 237 

Expected 112.0 223.3 505. 7 109.4 120.6 192.1 

Ratio 1.0 1.3 1.3 1.3 0.9 1.2 --___-_____I_ 

,411 Death. causes of Observed 

F&&d 

1,672 3,781 7,236 1 1.456 1,264 4.001 

1,161.B 1.44 2,227.7 1.70 4,043. 1.79 818.5 1.78 799.4 1.53 2,420.l 1.65 

’ hltdes all ciwette smokers (current and ex-smokers). 

1 W+rnational Statistical Classification number. 

399 

41. 5 

9.6 

23 

6. 3 

3.7 

.- 

33 

3. 6 

9.2 

20 

8.4 

2. 4 

g.8 

2. 2 

28 I24. 1 

1. 2 

91 

68.6 

I1.3 

2.9 l1.0 

-__ 

571 

423.8 

1.3 

,813 a 

,x33.3 1. 

1.63 

Tot nl 

1.833 

170.3 

10.6 

75 

14.0 

5.4 

152 

37. 0 

4. 1 

113 

33.7 

3. 4 

216 

111.6 

1.9 

120 

79.0 

1.5 

413 

285.2 

1.4 

318 

253.0 

1.3 

2.132 

1,692.0 

1.3 

6,223 

5,653.g 

1.68 

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 in recent years, 

simultaneously with the rise in lung cancer. This and the presence of additional evidence from retrospective studies justify reviewing stomach cancer 

in more detail 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 investigators, including Miiller (250) in 1939 and Schairer and Schoeniger (309) 

149 
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 tbe United States were those of Ocbsner 

and DeBakey (258) who were impressed by the probable relationship be. 

tween cigarette smoking and lung cancer. The initial observations prior to 

Miiller’s work were not, however, corroborated by surveys including controls 

without lung cancer. 

As early as 1928, Lombard and Doering (221) in a study of 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 smoking (all types combined) and cancer in general, and between pipe smoking 

and oral cancer in particular. Th e pipe smokers then constituted the bulk 

(73.1 percent) of the heavy smokers. This is of historical interest in relation to the present-day percentage of heavy cigarette smokers. Furthermore, since there were but five lung cancers in Lombard’s test group in an 

era before much of the rise in lung 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 systematically was by Miiller in 1939 (250) who had noted the increase in percentage of primary carcinomas of the lung being diagnosed at autopsy between the years 1918 and 1937 in Cologne, an increase almost entirely in 

males. Although considering other variables as possibly related to the rise 

in lung cancer mortality, such as increases in street dusts, automobile 

exhaust gases, war gas exposure in World War I, increased use of X-rays, 

influenza, trauma, tuberculosis, 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 from shortly before 

and since World War I and selected this variable for study. In what 

appears to be a carefully 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 with 

cancers of other sites reached the literature (280, 309, 363) and from 1950 

to the present time 2.5 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, 83, 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 considerably in design and method. Methodologic variations have occurred in the omission, inclusion, or,treatment of the following: 

150 
METHODOLOGIC VARIABLES 

Subject Selection- Tobacco-use Histories1. 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 Selection1. Age matching vs. age groups 

2. Healthy individuals 

3. Patients hospitalized for other cancers 

4. Patients hospitalized for causes other 

than cancer 

5. Deaths from cancers of other sites 

6. Deaths from other causes than cancer 

7. Samplings of the general population 

Method of Interviewing1. Mailed questionnaires 

2. Personal interviewing of subjects (or 

relatives) and controls 

a) By professional personnel 

b) By non-professional personnel 

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 Studied1. Geographic distribution 

a) Regional 

b) 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 the 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 to all. 

It is indeed striking that every one of the retrospective studies of male 

lung cancer cases showed an association between smoking and lung 

cancer. All have shown that proportionately more heavy smokers are 

found among the lung cancer patients than in the control populations and 

proportionately fewer nonsmokers among the cases than among the controls. 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 statistically significant in all studies but one (236) ; in the latter study, 

although there were fewer non-smokers among lung cancer patients, the 

difference was very small. 

In the studies which dealt with female cases of lung cancer, similar findings 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 authors 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 retrospective studies is enhanced when one considers that these studies exhibit 

considerable diversity in methodologic approach. 

151 
TABLE 2.4utline of methods used in retrospective studies of smoking in relation to lung cancer 

- 

If 

- 

-. 

_. 

-. 

-. 

-. 

-. 

_. 

_. 

_. 

_. 

. . 

- 

-~ 

_. 

_. 

-. 

_. 

-. 

_. 

_. 

_. 

_. 

_- 

_. 

Investigator, year, and 

referenoe 

Number of persons and method of selection 

Country Sex 0 

cases 

Collection of data 

Controls 

86 Healthy men of the same age 

ceses 

86 Lung cancer decedents, Btirger 

Hospital, Cologne. 

M 

M 

___ 

M 

M 

__ 

M 

M 

-. 

-. 

-_ 

-. 

-. 

-. 

-_ 

-. 

-_ 

-_ 

M 

- 

M-F 

- 

M-F 

- 

M-F 

M 

.- 

._ 

__ 

._ 

._ 

._ 

._ 

._ 

._ 

.- 

.- 

._ 

._ 

.- 

._ 

.- 

.- 

._ 

._ 

.- 

.- 

Mtiller 1939 (2501 QWIIX3LlY Cases: Questionnaire sent tc relatives of 

deceased. Controls: Not stated. 

Cases: Questionnaire sent to next of kh 

(195 for lung canrer). 

tionnaire sent to 700. 

Controls: QuesScheirer and Srhoeniuer 

1943 (309). 

93 Cancer decedents sutopsied at Jena 

Pathological Institute, 193+1941. 

270 Men of the city of Jcna ared .53 and 

$.ax?rage ageof lung cancer victims- 7 

1,847 Patients of same group with 

dhqmsss other than CBIICBI. 

(fermany 

Potter and Tully 1945 (280) U.S.A. 43 Male patients aged over 40 in Ma+ 

sachusetts cancer clinics with cancer 

of respiratory tract. 

Cases and controls interviewed in clinics 

Case*: Interviewed in clinic. Controls: 

Not stated. Wmsink 1948 (353) 134 Male clinic patients with lung cancer. 

106 Normal men of same age groups as 

cases. 

Netherlands 

U.S.A. 82 Male lung cancer csses among 5,003 

patients remrded, 1941-48. 

522 Miscellaneous tumors other than 

lung, larynx and pharynx. Schrek et al.. 1950 (311) Smoking habits recorded during routine 

hospital interview. 

Cases: Relatives queried by mall questionnaire or personal visit. Oontrols: 

House-to-house interviews. 

Oases and controls: Routine clinical 

history taken before diagnosis. 

Mills and Porter 1950 (237) 444 Respiratory cancer decedents in 

:$2cirti, 194045 and in Detroit, 

430 Sample of residents matched by age 

in Columbus, Ohio, from ce~lsua tracts 

stratlfied by degree of afr pollution. 

U.8.A. 

U.S.A. 23fl~~~~@tal patients diagnosed 481 Patients in same hospital with noncancer dlagnosas. 

780 Patients of several hospitals with 

diagnoses other than lung cancer. 

Lsvin et al., 19,50 (207) 

U.S.A. 605 Hospital and private lung cancer 

patients in many cities. 

Newly all data by personal interview; a 

few CW~.Y by questionnaire: a few from 

intimate acquaintancea. Some intervfews with knowledge or presumption 

Of dhgnosls, some with none. 

KM Lung veer pptients, unselected, 

hl3&0sp1ts1s m Liverpool area, 

200 Inpatients of same hospitals, 

matched by age and sex, without cancer, 194Grn. 

McConnell et al., 1952 (236) England Personal interviews by the authors of 

be;moea and controls, with few exPersonal interviews of cases and oontrofs 

by almoners. 

Doll and Hill 1952 (82) Great 

Britain. 

1.485 Patients with lung cancer in hospitals of several dtiea. 

1,485 Patients in same hospitals, 

matched by sex and age group; some 

with cancer of other sites, some wfthout cam%r. 

615 Patients In same hospitals with Illnesses other than cancer. 

Sadowsky et al.. 1953 (301) 477 Patients with lung can-r in hwpit&s in 4 statt?a. 

U.&A. 
Wynder and Comflel~ 

1QE.s 079). 

U.8.d. M 133 Phyaldans of same group dying Of 

ranoer of certain other sites. 

81 PhysIclam reported in A.M.A. 

Journal as dying of cancer of the 

lung. 

812 Lung cancer patients dfsgnosed at 

one hospital in 16 years. 

d 

-_ 

-- 

-- 

-- 

1 

-- 

-_ 

, 

-_ 

-- 

I 

-. 

__ 

_. 

_. 

-_ 

_- 

_. 

__ 

__ 

__ 

.- 

.- 

Finlaud M-F 300 Outpatients of same hospital aged 

over 40, living in similar oircumstances. and without caucer, February 

and March 1962. 

Cases and controls quastioned about 

smoking habits when taking oaac 

histories. 

-- 

_- 

_- 

-_ 

-_ 

-_ 

_- 

_- 

_- 

-_ 

-- 

-- 

-_ 

-- 

_- 

M-F 

M-F 

M-F 

M 

246 Lunp cancer patients in * number 

of hospitals and clinics. 

2.002 Sample of persons without cancer 

liViUl( in the snme 8~28 and Of Same sex 

and age rBnge a3 CBS%% 

Personal interviews by staff members of 

cwperatinq hospitals and clinics, 

oorrasponding in time to interviews of 

CS.WS. 

Cases and controls questioned by trained 

interviewers. each matrhed pair by the 

snfn8 person. 

Lickiut 1967 (211) 

Breslow et al., 1954 (33) 

oermsny 

U.S.A. 61R Patients admitted to same hospitals 

about the same time. for mnditions 

other than cancer or chest disease, 

matched for race, sex, and age group. 

518 Lung cancer patients in 11 California hospitals, 194P52 

Watson and Conte 1954 

(305). 

U.S.A. 301 All patients of Thoracic Clinic at 

Memorial Hospital who were disgnosed lung caucer, lQM52. 

135 Men with diagnosis of bronchial 

carcinoma. 

463 All patients of same clinic during 

same period with diagnoses other then 

lung csucer. 

135 Similar hospital patients with diag 

noses other than lung cancer, and of 

the same age. 

The 769 consecutive patients of case and 

control groups were questioned by the 

sane trained interviewer. 

Personal interviews. all by the same 

persotl 

Gel1 1954 (138) Switzerland 

M-F 448 Lung caucer patients in *number 

of West Berlin hospitals, 1952-1991. 

512 Patients with other diagmxxs, 

matched for we. 

Controls were interviewed at about the 

same time as the cases, each casecontrol pair by the same physician. 

Randig 1954 @%I 

St;;oc,aud Campbell 196: (Prelimhmy: see 1057 report below.) 

1,304 Patients at Memorial Center with 

tumors of sites other than respiratory 

or unner alimentary, 1953-1955. 

Caees: Personal interview or questionnaire mailed to close relatives or friends 

Controls: Personal interview. 

Wyuder et al., 1956 (375) 

segl et al., 1957 (316) 

U.S.A. 

J8PflU 

U.S.A. 

England 

F 105 Patients with lung canfer in scv- 

~5~1 New York City hospltals, 195% 

M-F 207 Patients with lung cancer in 33 

hospitals in all parts of the country 

1953-55. 

5,636 Patients free of c*ncer in 420 local 

health centers, selected to approximate the sex and age distributions of 

mws. 

-_ 

‘I 

-- 

__ 

-- 

Cases and controls by personal interriew 

using long questionnaire on ncrupstlonal and medical history and living 

habits. 

Cases: From dwth eartificates, hospital 

records, and close relatives or friends. 

Controls: Personal home visits or telephone rolls, usuelly interviewing 

housewife. 

Mills and Porter 1957 (‘238) M-F 67R Residents of detlned areas dying 01 

respiratory cancer, 1947-55. 

3,310 Population sample approximately 

proportional to cases as regards areas 

;~~$iye, and 10 yews or more in 

ii 

Stocks 1957 (335) M-F 2,356 Patients suffering from or dying 

with lung cancer within certain 

9,362 Unselected patients of the same 

area admitted for conditions other 

than cancer. 

Cases: Histories taken at the hospital or 

from relatives by health visitors. 

Controls: Personal interview in hospital. I areas. 
TABLE 2.-Outline uj methods used in retrospective studies of smoking in relation to lung cancer-Continued 

- T 

__ 

.- 

._ 

-_ 

.- 

.- 

I - 

_. 

-_ 

_. 

-. 

. . 

_. 

_. 

Number of persons and method of selection 

Investigator, year, and 

reference 

aer Of 

cases 

M 

-_- 

F 

M 

M-F 

Country Collection of dots 

-~ 

Fr8LlCe 

U.S.A. 

U.&A. 

Finland 

U.&A. 

Au&alla 

U.S.A. 

7 

CsseS 

602 Patients with bronchopulmonary 

cancer in hospitals in Paris and a 

few other cities. 

Controls 

1,204; 3 groups: patients in same hospitals with other cancer, with nonennw illness. and accident cases, 

matched by age group. 

.- 

._ 

_- 

._ 

.- 

._ 

_- 

- 

8cE3ytz and Denoix 1957 Personal interviews in the hospital; eases 

and controls at about the same time by 

the same interviewer. 

158 Lung cancer patients available for 

interview in 2Q hospitals, 195657. 

339 Patients in .same hospital and service at same time, next older and next 

younger than each case. 

Personal interviews by resident, medical 

social worker, or clinic secretary. 

Haenszel et al.. 1958 (150) 

Lombard and Snegireff 

1959 (222). 

4,238 Controls in 7 groups includina 

volunteers, hospital and clinic patients, random population sample, 

and house-to-house mrvey samules. 

500 Men dying of lung cancer, micro- Personal interviews by trained workers. 

smpleally contied, 1952-53. 

Pemu 1860 (277) 1,RoB Respiratory cancer patients in 4 

hospitals and from cancer registry 

between 1944 and 1958. 

1,773 Cancer-free persons recruited by 

Parish Sisters of 2 institutes in all 

parts of the country. 

Cases: From case histories or mailed 

questionnaires. 

Controls: Questionnaires distributed by 

Parish Sisters. 

Haensz.el et al.. 1862 (147) M 

M 

2,191 Sample of 10 percent of white 

male lung cancer deaths in the U.S. 

in 195% 

31,516 Random sample from Current 

Population Survey used to estimate 

population base. 

Ceas: By mail from certifying physicians and family informants. 

PO ulstion: 

8 

Personal interview by 

ensus enumerators. 

476 Two groups, one with other oaneer 

one with some other diswe, matched 

by sex and age. 

Personal interviews of both cases and 

controls in hospitals. 

Lancaster 1962 (169) 238 Hospital patients with lung eanoer 

Haenszel and Taeuber 

l’X3 ’ (152). 

F 749 &le of 10 percent of white 

female lung cancer deaths in the 

U.S. in 1958 and 1959. 

34339 Random sample from Current 

k%$;t:;; bSzvey wed to estimate 

Cases: By mail from certifying physicians and family informants. 

PO u1ation: 

8 

Personal interview by 

ensus enumerators. 

1 To be published. 
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 of male lung cancer incidence 

derived from the control population, only 10 percent 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 consumption. found a significant association between smoking of any type and lung 

ranter (138, 199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381) ; 16 

studies yielded an even stronger association with cigarettes alone as compared to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236, 237. 

2X8,277,283, 301, 311, 314, 335, 379) when these forms qf smoking were 

ronsidered 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. 

.YvlOUNT 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). 

0~ 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 cautioned 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 

“ass; 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-smokers as well (147, 152, 

*ll? 314) ; in one of these (314)) h 

hY the Cornfield 

w ere relative risks were derived indirectly 

method (61)) and in another by conventional use of standardized mortality ratios (147)) male ex-smokers showed a lower risk than 

155 
TABLE 3.---Group characteristics in retrospective studies on lung cancer and tobacco use 

~- Remarks 

M&S Females 

Percent 

heavy 

makers 

[:I 

13 

c;, 

13 

22.0 

(“) 

11. 1 

0 

(7 

w 

4. 5 

P) 

2. 8 

(9 

3.0 

16. 2 

P) 

4.3 

17. 2 

(3 

14.6 

Control8 

Authors Yea 

- 

1936 

1943 

1945 

1948 

1950 

19x 

1950 

195(1 

1962 

1952 

3953 

19.53 

1953 

1953 

19&i 

1964 

:i: 

:Ei 

1967 

Percent 

heavy 

nnokers 

- - 

‘2 - : 

B 

- _- 

i3” 

43 

134 

4:: 

‘236 

605 

3: 

477 

*E 

L7.l 

265 

136 

416 

3m \y 

166 

434 

101 

CT 

- 

lum her 

- 

(7 

I :j 

(9 

j:] 

(7 

131 

(7 

131 

304 

(“1 

722 

_- 

E; 

1 

.- 

1, 

1. 

1. 

VI 

2, 

1, 

6, 

1, 

- 

1- 1 

8 

-- 

I 

I 

I 

I 

1 

, 

, 

I 

- 

1 E 

-- 

5 

Percent 

JlOIlmnoken 

Ii/ 

i*, 

t:, 

13 

79. 6 

78.6 

54.6 

(7 

I:‘, 

90.4 

Y) 

82.0 

(9 

70.3 

66.0 

w 

73. : 

69.6 

(9 

59. 8 

65. 1 

31.2 

30. 2 

64.8 

18.3 

(“) 

P) 

61.2 

38.6 

25.1 

(“) 

67.0 

K3.9 

:z 

71. 7 

22 

35’G?ov 

(“) 

20.0 

it: 

(9 

,moker 

heavy 

Imokers 

16. 3 

lb. 9 

26. C 

19. 2 

36. 0 

9.3 

230 

19. 2 

23.9 

30.5 

21. 1 

9:2 

(“) 

(“) 

14.6 

6. 6 

4. 6 

13. 2 

19. 1 

23.2 

13. 4 

(“) 

20.0 

18. a 

16.0 

10.3 

29.3 

25.0 

4. R 

42. 7 

9. 7 51. 6 

16. 0 14.0 

6. s 17. 9 

(9 (9 

P) (“) 

27.6 

8.7 

9. n 

(3 

6.3 

22.3 

36.2 

(7 

IlOW 

imoker moken 

;:; 

7. ( 

4.6 

14. t 

7. i 

1.4. 2 

1.3 

5.4 

0. f 

3. a 

4. I 

0. B 

1.8 

3.1 

1.9 

i:: 

feF?a 

P) 

8.4 

1.9 

(4 

‘:; 

I :] 

c:, 

13 

57. b 

67. 1 

37. 0 

(9 

(9 

P’) 

64.0 

(“) 

69.3 

(9 

Il. 6 

56.2 

P) 

83.0 

67. 6 

(9 

Il. 9 

1:; 

[:I 

(:I 

13 

1. 2 

Y) 

0.9 

(7 

{:I 

0. 1 

(“) 

1. 1 

(7 

0 

3.4 

P) 

0. 5 

10.7 

(‘1 

8.2 

MUller --._-l___ -_._-___ 

Schairer & Schoenlpr.. 

Potter & Tully ______. -. 

Wassink _______________ 

16 female cases not analyzed. 

Perhr;$w?s estimated from 

Bchrek et al ______ _ __.__ 

Mills & Porter ______.__ 

Levin et al.. ____ ._- ____ Q;,yetit;, smoked not eonWynder & Graham..wMcCormeil et al ________ 

Doll & Hill _______ . .._ Percentage “heavy” smokers 

understated. 

FJadowsky et al .._.______ “;;~ra~d~t with amount 

Wynder & Cornfield..- 

Koulumirs . ..__.__ _ ____ 

Llckint. __ ______. ______ 

Breslow et al __...__.___, Data include 493 males, 25 

females. 

Watson & come __--___ 

@Jell.- _ ___ _ __. _ __ __. _ __. 

Randig.... __.______. ___ 

Stocks 6r Campbell..-- 

Wynderet al.. _________. 

Bepi et al _______ ________ Quantities smoked stated 88 

averages only. Differences 

am statistically signiecant. 

Percent “heavy” smokers 

understated. Only b9% 

aluwy reaponsa among 

female cam*. 

Mills 6 Porter.. ___ _____ 

Stocks- _ __ __._____.__ ___ 

Schwartz & Denolx.-... 

Haenszel et al ______._. 

1967 

tti.i 
157 
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. 

DURATION OF SMOKING 

Duration of smoking, was considered in 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 in such a way as to permit evaluation 

of the relationship between duration 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 casea and controls, 

but was reluctant to draw any definite conclusions. On the other hand, 

Doll 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 of duration of smoking (236) 

and Doll and Hill, though finding differences between cases and controls, 

could not establish statistical 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 retrospective 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 started. 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 load. Four retrospective investigations were addressed to this 

question. In the earlier Doll and Hill study (821, no difference in the 

proportion 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. 

.4lthough 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 study 

by Schwartz and Denoix (313) 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 did 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) d emonstrated 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 Doll and Hill retrospective study (82), 995 were histologically confirmed (916 males and 79 females). Of the confirmed cases, 85 percent of the 

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 with adenocarcinoma. 

Following the presentation by Kreyberg of a Typing Classification of the 

epidermoid and oat cell or anaplastic types as Group I and the adenocarcinema and bronchiolar or alveolar celI types as Group II, and the suggestion 

of a relationship between Group I and smoking (1%)) 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 relationship between histologic type of lung cancer and smoking. The 1956 

study of female lung cancers by Wynder et al. (375) indicated that adenocarcinomata 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 o-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 1958, Haenszel found relative risk gradients for the several smoking classes for both adenocarcinomas and epidermoid cancers (147). A 

parallel 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 diluted seriously by reporting and classification errors which were definitely known to exist from reinquiry of a sub-sample of deaths (152). (For 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 [A/X]) ? Procedurally, one compares a supposedly representative group of patients with 

disease X, with 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 the 

controls without disease X or who have escaped disease X are a representative 

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 retrospective studies on lung cancer. Doll and Hill (82) made similar calculations and found a linear gradient of deaths from 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 
utilized the data of Wynder and Graham (381) and Doll and Hill (82) for 

calculating similar risk ratios, deriving ratios of 13.6~1 and 13.8:1, respectively. 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:l 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:l. Lombard 

and Snegireff (222) approached their data in a different way, utilizing “lifetime 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 mortality 

as related to residence and smoking histories, calculated relative risk ratios 

of 4.1:1 for one pack or less daily and 16.6:1 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.-Relative risks of lung cancer for smokers from retrospective 

studies 

Author and Reference Year 

_- ___- 

sadowsky et al. (301) 1953 

Doll and Hill (82) 1952 

Wynder and Graham (381) 1950 ’ 

Breslow et al. (38) 1954 

Randig (283) 1954 

khwwtz and Denoix (313) 19.57 

Lombard and Snegireff (222) 1959 

bm.szel (147) 1962 

Haenszel (152) Unpublished 

Sex 

M 

M 

M 

M 

M-F 

! Calculated by Sadowsky et al. (301) from other authors’ data. 

Prospective Studies 

Relative risk-Smokers: 

non-smokers 

4. 6 

13. a 

13. 6 

7.7 ace 5cb59 

4. 6 “ M-69 

17.0 “ e&59 25, 5 ,, 6(t6g > very heavy smokers 

5.1 M 

2.2 F 

8.0 

2.4 light smokers 

34.1 heavy smokers 

4. l<l pack/day 

16.6>1 pack/day 

2.5<1 pack/day 

10.8>1 pack/day 

lt has been pointed out that in retrospective studies the usual approach is 

to determine the frequency of an attribute among cases and controls. This 

measure does not provide estimates of the risks of developing the disease 

161 
among individuals with and without the attribute unless one makes assump. 

tions referred to above. The validity of such assumptions may at times be 

suspect, for the cases may not be representative of the total population with 

the disease nor the controls representative of the population without the 

disease. Thus, some retrospective studies may not truly assess the existent 

risks with reasonable accuracy. However, when aU the cases of a disease in 

an area and a representative sample of the population without the disease am 

included in a study, the estimates of risk bear high validity. 

Despite the criticisms leveled at the retrospective method in general and 

its obvious defects as practiced by some investigators, a number of the retro. 

spective studies on lung cancer have indeed overcome most of the criticisms 

of major import leveled at the method. These criticisms and their implications will be treated specifically below in the section on an Evaluation of the 

Association Between Smoking and Lung Cancer. Suffice it to say at thfs 

point that certain shortcomings of the retrospective survey approach, some 

real and some exaggerated, led several courageous investigators to under. 

take the necessarily protracted, expensive, and difficult prospective approach. 

The first prospective study encompassing total and cause-specific mortality 

in a human population was initiated in October 1951 among British physicians by Doll and Hill (83, 8%). There then followed in rather rapid sue. 

cession, five additional independent studies in the United States and Canada 

(25,87,88,%, 97,157,162,163), all b u t one of which continue to be active. 

The earlier study, by Hammond and Horn, among 187,783 white males aged 

50-69 years, initiated between January and May 1952, was terminated after 

4+% months of follow-up (162, 163). This has been succeeded by the current 

Hammond study which broadened its age-base (35-89 years) and contains 

1,085,OOO persons (in 25 states) of whom 447,831 are males ( 157). 

These studies have been described in detail, analyzed, and evaluated in 

Chapter 8 of this Report where a discussion of differences in total mortality 

between smokers and non-smokers has been presented, and are summarized 

in Table 1 of that chapter. All the prospective studies thus far have shown 

a remarkable consistency in the significantly elevated mortality ratios of 

smokers particularly among the “cigarettes only” smoking class. Of special 

interest is the fact that in a number of the studies the magnitude of the association between cigarette smoking and total death rates has increased as 

the studies have progressed. This has particularly been true for lung cancer. The presently calculated total mortality ratios have been presented in 

Table 2 of Chapter 8 of this Report. 

With reference to the smoking and lung cancer relationship, each of the 

seven prospective studies has thus far revealed an impressively high lung 

cancer mortality ratio for smokers to non-smokers. Examination of Table 

5, which presents in summary form the lung cancer mortality ratios for the 

seven studies by smoking type and amount, derived both from the published 

reports of these studies and current information from the investigators 

wherever available, reveals a range of ratios from 6.0 to 25.2 with a median 

value of 10.7 for all smokers irrespective of type or amount. For smokers 

currently using cigarettes only at the time of enrollment in the studies, the 

ratios range from 4.9 to 20.2 with a mean value of 10.4 as derived from 

a summation of observed and expected values of most recent data. 

162 
Several of the studies have fortunately provided data for a measure of 

the “dose of exposure” relationship (m, 88, 96, 157, 163). It can readily 

be seen from Table 5 that the mortality ratios increase progressively with 

amount of smoking. The pivot level appears to be 20 cigarettes per day. 

Cigar and/or pipe smokers (to the exclusion of cigarettes) manifest ratios 

lower than any of the cigarette smokin, m classes, including combinations of 

cigarettes with pipes and/or cigars (25, 84, 88, 157, 163 1. One study provided data on occasional smokers (163), These have a ratio very close to 

that of non-smokers. Ex-smokers of cigarettes (83, 88, 163) fall into levels 

of risk ratios below those for current smokers of cigarettes depending upon 

the length of the interval since smoking was stopped. In the Doll and Hill 

study (831, the ex-smoker ratio was less than the current smoker ratio 

even when cessation had occurred less than 10 years before entry into the 

study. This, however, was not true for the first Hammond and Horn study 

1163). In this latter study, if smoking had ceased more than 10 years 

before entry, the lung cancer mortality ratios were lower than for current 

smokers at the corresponding daily consumption levels, but if cessation of 

smoking had occurred less than 10 years before entry, the ratios were 

virtually identical to those for current cigarette smokers at the corresponding 

daily consumption levels. The Dorn material 187, 88), currently brought 

up to date (89), provides a measure of relative risk by amounts of smoking 

prior to stopping. The ratios thus elicited are again below those for current 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 crossclassification by these variables, and amount smoked as well, leads to cells 

with small numbers of deaths. Most prospective studies have thus far confined themselves to analyzing the effect of these additional variables on 

deaths from all causes, or in one case (157) from cardiovascular diseases. 

The current Hammond study is concerned with inhalation practices, but 

here also the total number of lung cancer deaths analyzed to date does not 

permit extensive classification by age, type of smoking, amount smoked 

daily, present smoking status, and age when smoking was begun. In the 

studies of total mortality ratios, duration of smoking, obviously immediately 

dependent upon the age of the individual, was in turn dependent upon age 

when smoking (cigarettes) was begun. Age when smoking began was also 

a determinant, not only of the number of cigarettes smoked daily, but of the 

degree of inhalation, with smokers starting at earlier ages very distinctly 

tending to smoke mere and inhale more deeply than those starting to smoke 

at older ages (157). According to Hammond, men who smoke more per 

day also tended to inhale more deeply than those who smoke fewer cigarettes per day. When inhalation and quantity smoked were held constant, 

the total mortality ratios also increased as age at start of smoking decreased. 

The stability of the lung cancer mortality ratios referred to in Table 5 is 

to a great extent dependent upon the number of observed lung cancer deaths 

among non-smokers from which the expected values for the several smoker 

classes are calculated. Referring again to Table 5, in at least two of the 

studies (83, 96), calculation of the expected deaths among smoker classes 

had to be based on extremely small numbers of non-smokers. However, 

163 
- 

- 
the other studies have now yielded significantly greater numbers of nonsmoker lung cancer deaths and in at least three of them (88, 157, 163) these 

are now appreciable. 

Experimental Pulmonary Carcinogenesis 

A’ITEMPTS TO INDUCE LUNG CANCER WITH TOBACCO AND 

TOBACCO SMOKE 

Few attempts have been made to produce bronchogenic carcinoma in 

experimental animals with tobacco extracts, smoke, or smoke condensates. 

With one possible exception (289), none has been successful i 331) . 

Mice rarely develop spontaneous bronchogenic. oral, esophageal. gastric, 

prostatic, laryngeal, or vesical carcinomas, but certain inbred strains have 

a high incidence of spontaneous pulmonary adenomas (6 1. The administration, by any route, of carcinogenic polycyclic hydrocarbons, including 

some found in tobacco tar, increases the incidence and decreases the time 

of occurrence of pulmonary adenomas. These tumors are usually regarded 

as benign, and probably arise from the alveolar epithelium I 4, 5,6, 131, 330) 

rather than the bronchial wall. They have no resemblance to most human 

bronchogenic carcinomas. 

Essenberg (106) and Miihlbock (248) exposed mice to cigarette smoke, 

but their reported results are equivocal. Lorenz et al. (224) and Leuchtenberger et al. (206) did not observe an increase in pulmonary adenomas in 

mice that inhaled cigarette smoke. 

Leuchtenberger et al. (205a.) described a sequence of microscopic changes 

in lungs of mice exposed to cigarette smoke resembling somewhat those 

found by Auerbach et al. in the lungs of human smokers. No dose-response 

effect was reported. The morphologic findings consisted of bronchitis with 

proliferation of the epithelium. Some areas of hyperplasia showed atypical 

changes. However, the changes were reversible when exposure to smoke 

was stopped. The production of bronchogenic carcinomas has not been 

reported by any investigator exposing experimental animals to tobacco 

smoke. 

Most experiments in which tobacco tars were brought into direct contact 

with the lung and tracheobronchial tree of experimental animals have 

yielded negative results (273, 274, 275). Blacklock (29) found one carcinoma when tar from cigarette filters was placed in olive oil together 

with killed tubercle bacilli and injected into the hilum of a small number 

of rats. Rockey et al. (289) painted tobacco tar three to five times each 

week on the trachea of dogs with a tracheocutaneous fistula. Hyperplastic 

changes with squamous metaplasia of the bronchial epithelium were seen 

in seven dogs that survived 178 to 320 days. Carcinoma-in-situ was reported 

to occur in three, and invasive carcinoma in one out of 137 dogs, but this 

work has not yet been confirmed. 

SUMMARY.--Bronchogenic carcinoma has not been produced by the 

application of tobacco extracts, smoke, or condensates to the lung or the 

tracheobronchial tree of experimental animals with the possible exception 

of dogs. 

165 
SUSCEPTIBILITY OF LUNG OF LABORATORY ANIMALS n, 

CARCINOGENS 

POLYCYCLIC AROMATIC HYnnoCARnoNs.--Epidermoid carcinoma has 

been induced in mice by Andervont by the transfixion of the lungs or bronchi 

with a thread coated with a carcinogen (5) and by Kotin and Wiseley (191) 

by treatment with an aerosol of ozonized gasoline plus mouse-adapted 

influenza viruses. 

Kuschner et al. (197, 197a) induced epidermoid carcinomas in the lungs 

of rats by the local application of polycyclic aromatic hydrocarbons, either 

by thread transfixation or pellet implantation. Distant metastases occurred 

from some of the carcinomas. Th e c h anges in 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 tracheobronchial tree of human smokers (9). 

Stanton and Blackwell (324) induced epidermoid carcinoma in the lungs 

of rats that had received 3-methylcholanthrene intravenously. The carcinogen was deposited in areas of pulmonary infarction. 

Saffiotti et al. (302) produced squamous cell bronchogenic carcinomas in 

hamsters by weekly intubation and insufflation of benzoia) pyrene (4 percent) ground with iron oxide (96 percent) resulting in a dust with particles 

smaller than 1.0 micron. A proliferative response followed by metaplasia preceded the appearance of the carcinomas, but was not an invariable antecedent. 

VIttusEs.-Bronchogenic carcinoma has been induced in animals inoculated with polyoma virus by Rabson et al. (282). Carcinogens enhance the 

effect of viruses known to cause cancer in animals (99) and localize the 

neoplastic lesions at the site of inoculation of the virus (98). However, 

no evidence has been forthcoming to date implicating a virus in the etiology 

of cancer in man. 

POSSIBLE INDUSTRIAL CARCINoGE!6.-Vorwald reported that exposure of 

rats to beryllium sulfate aerosol resulted in carcinomas of the lung; 12 percent were epidermoid but most were adenocarcinomas. The tumors usually 

arose from the alveolar or bronchiolar epithelium. He also produced bronchogenie carcinomas in two out of ten rhesus monkeys injected with beryllium 

oxide and in three out of ten exposed to beryllium oxide by inhalation (357). 

Lisco and Finkel in 1949 (217) reported the production of epidermoid 

cancer of the lung in rats with radioactive cerium. Subsequently many 

other investigators have succeeded in producing carcinomas of the lung, 

predominantly of the epidermoid type, in a high percentage of rats and 

mice with other radioactive substances. The various modes of exposure 

included inhalation, intratracheal injection, or insufflation and implantation 

of wire or cylinder. These experiments were reviewed by Gates and Warren 

in 1961 (125). 

Hueper exposed rats and guinea pigs to nickel dust and found metaplastic 

and anaplastic changes in the bronchi (180). Following up earlier work 

in which squamous metaplasia of the bronchial epithelium was found in rats 

exposed to nickel carbonyl (341), S un d erman and Sunderman (342) induced bronchogenic carcinoma in rats by exposure to this compound. This 

166 
group also found 1.59 to 3.07 pg. of nickel per cigarette in the ash and in 

the smoke in several different brands. About three-fourths was contained 

in the ash. Although Hueper and Payne (182, 183) and Payne (270) have 

demonstrated that pure chromium compounds will produce both sarcomas 

and carcinomas in several tissues in rats and mice, bronchogenic carcinomas 

have not been produced by inhalation of chromium compounds in experimental animals. Experiments designed to test the carcinogenicity of arsenical compounds have been either negative or inconclusive. 

Asbestosis can be produced without difficulty in experimental animals by 

inhalation of asbestos fibers (359), but efforts to produce bronchogenic 

carcinoma have been unsuccessful (129, 181, 227, 358). 

SUMMARY.-The lungs of mice, rats, hamsters, and primates have been 

found to be susceptible to the induction of bronchogenic carcinoma by the 

administration of polycyclic aromatic hydrocarbons, certain metals, radioactive substances, and oncogenic viruses. The histopathologic characteristics 

of the tumors produced are similar to those observed in man and are frequently of the squamous variety. 

ROLE OF GENETIC FACTORS IN PULMONARY ADENOMAS IN MICE 

Genetic factors exert a determining influence on the spontaneous development 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 additional evidence of the operation of genetic factors in induced tumors. Linkage between multiple genes for susceptibility to spontaneous and induced 

tumors in mice and specific chromosomes has also been established (47, 

168) and transplantation experiments (171, 173) indicate that the genetic 

susceptibility resides within the pulmonary parenchyma. A number of investigators (36, 47, 124, 131) demonstrated conclusively that these tumors 

usually arise distal to the bronchus and are probably alveogenic. Metastases 

rarely occur. The relative importance of genes for susceptibility to these 

tumors of the lung is indicated by an incidence ranging from a few tumors 

to over 90 percent, depending on the inbred strain examined. 

Spontaneous tumors of the lungs are rare in species of laboratory animals 

other than mice, and the genetics of these neoplasms in other species has 

heen investigated only superficially. 

SUMMARY.PenetiC susceptibility plays a significant role in the develop 

ment of pulmonary adenomas in mice. 

Pathology-Morphology 

RELATIONSHIP OF SMOKING TO HISTOPATHOLOGICAL CHANGES 

IN THE TRACHEOBRONCHIAL TREE . 

In an extensive and controlled blind study of the tracheobronchial tree 

of 402 male patients, Auerbach et al. (11, 13, 15) observed that several 

167 
kinds of changes of the epithelium were much more common in the trachea 

and bronchi of cigarette smokers and subjects with lung cancer than of 

non-smokers and of patients without lung cancer (Table 6). The epithelial 

changes observed were (a) loss of cilia, ib) basal cell hyperplasia (more 

than two layers of basal cells), and (c) presence of atypical cells. The 

atypical cells had hyperchromatic nuclei which varied in size and shape. 

The arrangement of such cells was frequently disorderly (see illustrationa 

below). Hyperplastic changes were also seen in the bronchial glands. 

TABLE 6.-Percent of slides with selected lesions,’ by smoking status aad 

presence of lung cancer 

NUITlber 

slides 

3,324 

3,436 

l,R24 

3,016 

7,062 

1,787 

2.764 

Percent of slides with cilia absent and 

averaging 4 or more cell rows in depth 

No cells Somecells All cells Total 

atypical atypical atypical 2 

-- 

1.0 0.03 ._~ ___.... 1. 1 

3. 5 0.4 0.2 4.1 

0. 2 4.2 0.3 4.7 

7.1 0.8 7.9 

12.6 4.3 169 

.___.-__-. 26.2 11.4 37. 5 

_ 12.5 14.3 26.8 

I In some sections. two or more lesions were found. In such instances. all of the lesions were oounb d and 

are included in both individual columns and in the total column of the table. 

an ulcer were excluded. 

Lesions found at the edge of 

f These lesions may be called carcinoma-in-situ. 

a Of the 63 who died of lung cancer. 55 regularly smoked cigarettes up to the time of diagnosis, 5 regularly 

smoked cigarettes but stopped before diagnosis. 1 smoked cigars. 1 smoked pipe and cigars, 1 was an -. 

sional cigar smoker. 

Each of the three kinds of epithelial changes was found to increase with 

the number of cigarettes smoked (Table 6). In smokers who had no cancers, 

frequency and intensity of these changes correlated with the number of 

EXAMPLES OF NORMAL AND ABNORMAL BRONCHIAL EPITHELIUM 

. 

1. Normal 

168 
2. Basal-cell hyperplasia-replacement of ciliary epilhelium with a thick layer of cells 

resembling stratified squamous epithelium. 

3. Extensive basal-cell hyperphasia with numerous atypical cells. 

Source: Auerbach, Oscar. Special communication to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

cigarettes smoked. Among non-smokers, lesions composed entirely of atypical cells with loss of cilia were uniformly absent, although a few could be 

seen with more than two rows of basal cells containing some atypical cells. 

In contrast, atypical cells were found in all lesions seen in the tracheobronchial tree of patients who smoked two or more packs of cigarettes a day, 

irrespective of the presence of hyperplasia and/or cilia loss or whether the 

patients died of lung cancer. Th e most severe lesion, aside from invasive 

carcinoma, consisted of loss of cilia, and hyperplasia up to five or more cell 

TOWS composed entirely of atypical cells. This lesion was never found 

among men who did not smoke regularly and was found only rarely among 

light smokers. However, it was found in 4.3 percent of sections from men 

169 
who smoked one to two packs a day, in 11.4 percent of sections from those 

who smoked two or more packs a day, and in 14.3 percent of sections from 

smokers who died of lung cancer (15). 

While epithelial changes were found in all portions of the tracheobronchial 

tree, quantitative differences were found between the changes in the trachea 

and those in the bronchi; hyperplastic lesions consisting entirely of atypical 

cells without cilia were found in all regions of the bronchial mucosa but only 

rarely in the trachea. It is notable that cancer rarely occurs in the trachea. 

In 35 children less than 15 years of age, Auerbach et al. (16) found the 

same percent of epithelial changes in the tracheobronchial tree as in the same 

number of adults who had never smoked regularly (16.6 percent of children 

and 16.8 percent of adults). No hyperplasia with atypical cells was seen 

in any section. 

Later, Auerbach et al. (15a.) studied the morphology of the tracheobronchial tree from 302 women and 456 men with respect to additional variablessex, age, pneumonia, and amount smoked. One or more epithelial lesions 

were found in 68.2 percent of sections from men smokers and 68.6 percent 

from women smokers when matched groups were examined. However, on 

further study, hyperplastic lesions composed entirely of atypical cells were 

found in 6.9 percent of the sections from the male group and in 2.5 percent 

of those from females. 

Matched groups of male cigarette smokers of two age groups (averages 

of 37 and 67 years) were compared. Many more lesions, characterized by 

a large number of cells with atypical nuclei, were observed in the older than 

in the younger group. In a parallel study of women who did not smoke 

(average ages of 46 and 76 years), no difference in the number or type of 

lesions was noted. Few changes in the bronchial epithelium were found in 

sections from 27 women non-smokers over 85 years of age. 

Occasional atypical changes were found in women non-smokers (a) who 

died of pneumonia, (b) who died of various other causes but had pneumonia 

at the time of death, and (c) who died with no evidence of pneumonia. 

However, basal cell hyperplasia, loss of cilia, and ulceration were found more 

frequently in sections from women who died with pneumonia than from 

women who had no evidence of pneumonia. These observations are in 

agreement with those of other investigators who found metaplasia of the 

Lronchial epithelium to be more frequent in patients with various nonneoplastic pulmonary diseases than in controls without such disease (256, 

305,352,366). 

Far fewer epithelial lesions were found in non-smokers than in pipe, cigar, 

or cigarette smokers (15a.), the difference being particularly evident in the 

occurrence of atypical cells. However, sections from pipe and cigar smokers 

showed fewer epithelial lesions than did sections from cigarette smokers. 

Cells with atypical nuclei were found far more frequently in cigarette smokers 

than in cigar or pipe smokers (Table 7). 

In 72 male ex-cigarette smokers who had smoked for at least ten years 

and had not smoked for at least five years prior to the time of death, there 

were less hyperplasia, less loss of cilia, and fewer atypical cells than in 

sections from current cigarette smokers (14). An interesting by-product 

of this study was the finding of “cells with disintegrating nuclei” in the 

170 
TABLE 7.--Changes in bronchial epithelium in matched triads of male non-smokers and smokers of different types of tobacc0.l 

Qroup 

Numbe 

of sub. 

jects 

7th set (none vs. pipe vs. cigarette)3 

Non-smokers ___ ___..__.___________ 20 

Pipe smokers.. ____ .___.__ _________._ 

Ciearette smoker/s.. ___-_- ________. 

8th set (none vs. pipe vs. cigarette) 

Non-smokers. _ _ _ .._- .._________ -._ 

Pipe smokers.-...-_-.-......-..--... 

Cigarette srnokers-~~~-.....--.-..~-.- 

9th set (nom vs. cigar vs. cigarette) 

Non-smokers __________.___...__. __ 

Pipe smokers. __._...._._.___..______ 

Cigarette smokers.~ .~ __.__________ -__ 

- 

‘r 

s 

w 

t 

- 

Total Sections with 1 

ectlons or more epithelial 

-ith epi- ISfOIlS 

helium 

-I 

Number Percent 

-- 

Number Percent 

985 214 21.7 110 11.2 

924 3% 1 

914 

ii2 65. 5 352 

96.6 810 88.6 

1,246 22. 9 

1, 164 fi8. 7 

1, 126 96.3 

1,706 467 27.4 

1,733 

I 

1.573 

i 

90.8 

1. 526 1.511 99.0 

3+wll rows with 

cilia present Cilia absent 

167 

451 

999 

216 

1% 

13.4 

38. 7 

88.7 

12. 7 

40.0 

92. 7 

101 10.3 

117 12.7 

116 12. 7 

132 10. 6 

172 14. R 

ml 21. 1 

ii: 

42R 

- 

r 1 

IPercent 

16. 5 

14.3 

28.0 

t. 

_- 

- 

I 

Atypical cells 

Atypical cells 

present with cilir 

present absent 

- 

Jumber Pcroent Numbe 

--~-- 

3: 37. 26 0 3 

870 95. 2 1: 

44: 38. 0. 7 21 

1,008 89. 5 2% 

14 0. R 3 

1,275 73. 6 

1,493 97. a 2; 

-___ 

- 

r 

-. 

Entirely atypical 

c&s with cilia 

absent 2 

qumber Percent 

--- 

0 _ _ _ _ _ _ _ _ 

0 --_-_____ 

35 3.8 

0 __.._. -._ 

0 - _. -. ___ 

70 6.2 

0 __.._-___ 

d 

0.3 

12.8 

1 Modlfled table from Auerbach et al. (15a). 

1 Carcinoma in situ. 

3 Triads were matched for age, occupation, residency and (for smokers) by amount of tobacco used. 
bronchial epithelium of 43 out of 72 ex-smokers. These cells were not 

found in the bronchial epithelium of current cigarette smokers or non. 

smokers. They ‘were considered by Auerbach et al. to be pathognomonic 

of the ex-smoker. 

Many of the histopathologic findings observe-d by Auerbach et al. in the 

bronchial epithelium of smokers have been confirmed by other investigators 

164, 155, 189, 304). 

The significance of the hyperplastic changes in the bronchial epithelium 

for the pathogenesis of lung cancer in smokers is not fully understood. The 

establishment of a link between the hyperplastic changes and the subsequent 

development of lung cancer would relate smoking causally to lung cancer. 

However, the non-specificity of hyperplasia of the bronchial epithelium is 

universally recognized. Furthermore, similar changes are known to be 

reversible. 

On the other hand, evidence from both human and experimental observa. 

tions points strongly to the conclusion that some hyperplastic changes of 

the bronchial epithelium, especially those with many atypical alterations, 

are probably premalignant. 

It is well documented that the bronchial trees of patients with lung cancer 

have areas, sometimes very widespread, of epithelial hyperplasia containing 

many atypical and bizarre cells. This was reported by Lindberg in 1935 

(216) and by many other investigators (10, 12, 28, 52, 134, 265, 285, 349, 

370). Black and Ackerman (28) have carried out an extensive study 

of the relationship between metaplasia and anaplasia and lung cancer in 

human lungs and have presented strong circumstantial evidence for the opinion that the basal cell hyperplasia with advanced atypical changes and 

loss of cilia (the so-called carcinoma in-situ) represent a stage in the development of lung cancer. They also emphasized, as has Auerbach et al. (12), 

the frequent occurrence of atypical basal cell hyperplasia at multiple sites 

in the bronchial tree considerably removed from the site of the lung cancer. 

They have pointed out the similarities between the atypical hyperplasias in 

the tracheobronchial tree and carcinoma in-situ in ather sites, such as the 

cervix, skin, and larynx. 

Lung cancer was induced in animals by radioactive substances (198,217)) 

chemical carcinogens ( 198, 34O), and air pollutants plus influenza virus 

(191). These studies have demonstrated the occurrence of extensive atop 

ical hyperplastic changes in the bronchial epithelium of experimental animals 

preceding the appearance of lung cancer. The changes described are, on 

the whole, similar to those seen by Auerbach et al. in the bronchial epithelium 

of heavy cigarette smokers and by others in patients with lung cancer. The 

hyperplastic lesions in animals do not invariably develop into cancer. This 

appears to be the case also in man (14). 

In view of these observations, it seems probable that some of the lesions 

found in the tracheobronchial tree in cigarette smokers are capable of developing into lung cancer. Thus, these lesions may be a link in the pathogenesis of lung cancer in smokers. 

SuMMA,ttY.---Several types of epithelial changes are much more common 

in the trachea and bronchi of cigarette smokers, with or without lung cancer, 

than of non-smokers and of patients without lung cancer. These epithelial 

172 
changes are (a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance 

of atypical cells with irregular hyperchromatic nuclei. The degree of each 

of the epithelial changes in general increases with the number of cigarettes 

smoked. Extensive atypical changes have been seen most frequently in men 

who smoked two or more packs of cigarettes a day. Hyperplasia without 

atypical changes was seen in the bronchial tree of children under 15 years 

of age and in women non-smokers at all ages who died with pneumonia. 

Women cigarette smokers, in general, have the same epithelial changes as 

do men smokers. However, at given levels of cigarette use, women appear 

to show fewer atypical cells than do men. Older men smokers have many 

more atypical cells than do younger men smokers. Men who smoke pipes 

or cigars have more epithelial changes than do non-smokers, but have fewer 

changes than do cigarette smokers consuming approximately the same amount 

of tobacco. Male ex-cigarette smokers have less hyperplasia and fewer 

atypical cells than do current cigarette smokers. 

CONCLUSION.--It may be concluded on the basis of human and experimental 

evidence that some of the advanced epithelial hyperplastic lesions with many 

atypical cells, seen in the bronchi of some cigarette smokers, are probably 

premalignant. 

TYPING OF LUNG TUMORS 

Historical aspects of the typing of lung tumors in relation to possible 

etiological agents are reviewed in the section on Retrospective Studies, Histologic Types. 

Kreyberg (195, 196i noted that the increase of lung cancer in recent decades seemed to occur for only certain types of lung cancers (his Group I), 

and that other types did not increase (his Group II). Kreyberg’s classification is compared with the World Health Organization classification in 

Table 8. His Group I includes epidermoid carcinomas and small-cell anaplastic carcinomas. His Group II includes adenocarcinomas and a few rare 

tP=. He postulated that a determination of the ratio between Groups I 

and II is a good index of the occurrence and magnitude of an increase in 

lung cancer in a given locality and his epidemiologic studies linked the 

increase almost entirely to the use of cigarettes. His thesis has been accepted by many while disputed by others. 

The results of the study of lung cancer at Los Angeles County General 

Hospital (LACGH) by Herman and Crittenden (167) did not confirm Kreyberg’s conclusions. These investigators, analyzing the autopsy data on lung 

cancer from 1927 to 1957 at LACGH, o b served a marked increase in the 

number of lung cancer cases as had been noted by many other investigators. 

However, the ratio of Kreyberg’s Group I to Group II had not changed perceptibly over this period and was notably lower than in other series studied. 

The Committee on Smoking and Health sponsored a workshop in which 

slides from coded cases of lung cancer from four different institutions in 

three areas of the United States were typed “blind” by Dr. Kreyberg and 

Pathologists from the cooperating institutions.’ There was good agreement 

a~ to typing. Th e 1 ow ratio of Group I to Group II cancers at L:iCGH was 

confirmed. When typing of the reviewed cases was compared with smoking 

‘Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963. 

173 
TABLE 8.-Relation between WHO and Kreyberg classifications of lung tumors 

WHO classification 1 Krwberg classifleation 2 

- -- 

Epidermoid cRrcinomas~~....~........-....~......~.....~~..................-.... 

8. highly differentiated 

b. moderately differentiated 

c. slightly differentiated 

Group I 

2. 

3. 

4. 

:: 

7. 

x. 

9. 

Small-cpllanaplasticcarcinom~ ..- ~~~ . . . . . . . . . ~~.-...~ . . . . . . . . . .._. ~... 

8. with ovalcell structure (“oat-cell” carcinoma) 

Adenocnrcinomas~.~.....~~.~~~..........~.......~......~~.....~.~...~..~~.....~. 

a. acinar (with or without formation of mucus) 

h. papillary (with or without formation of mucus) 

c. tumors with a predominance of “large cells” some of which show formation of glands and/or production 01 mucus. 

Large-rellundifferentiatedcarcinomas .~ . . . . . . . ~~~.~ ~~ ._._. ~~~ .. . .._. ~-._ 

Combined c idermoid and sdenocarcinomas. ~~.~ ~._ ..~ _......__.... 

Bronchiole-a 4 veolar cell carcinomas.. . . . . ~.~ . . . . . . . . . . . ..~ . ..__ ~~ -..... 

Carcinoid tumors (solid. trabecular, slveolar) .~ . . . . . . . . .~- . . .._. . . . . . . . . . _...~. 

Tumorsofmucous glands~~.......-..............~~~...........-........-.-.-...- 

a. cylindroma 

b. muco-epidermoid tumcz~ 

Papillomas of the surface epithelium . . . . . . . . . . . . . . ~~..-- ..-..... . . . .._. ~~.. 

a. epidermoid 

b. epidermoid with goblet cells 

Other 

^ . p.. .~lCO~la8..~~...~.........~.~......~.~~.........~.........~......~.~.-...~~......~.....~ “tt,er 

C. Combined Tumors of Epthelial and Mesemhymal Celk .___... ~. . . . . . . _ ..~. ______ Other 

I). Mesothcliomas ofthe Meura..............................~........~.......~~...~.~.....~ Other 

1. Localized 

2. Diffuse 

E. Tumors Lklasriflcd 

1 Committee on Cancer of the Lung, World Health Organization. 

3 Kreyberg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor. 

wegian Universities Press, 1962. 

3 Types marked “other” are not included in either of Kreyberg groups. 

histories, moreover, it became evident that both Group I and Group II were 

increased among heavy smokers. 

Several factors were recognized to influence Group I/Group II ratios: 

(a) source of material (for example, significant differences in the ratio 

were found between autopsy and surgical materials, and between surgical 

materials obtained by biopsy and by resection during operation for lung 

cancer) ; (b) failure to autopsy certain cases which were judged to be 

inoperable (the patient being sent home as incurable) ; (c) the fact that 

Group I (squamous and oval-cell) carcinomas are more likely to be among 

the operable cases and among those accessible to bronchoscopy, and (d) 

variations in selection of patients in different institutions. 

An independent review of the histopathology of 1,146 lung cancer cases 

from the U.S. veterans study (policyholders) by Dom, Herrold and Haenszel (Table 9) (89) showed high mortality ratios for both Group I and 

Group 11 cancers in current heavy smokers (over 20 cigarettes/day), although Group I bad a higher mortality ratio (31.2) than Group’ II (7.2). 

Another study of Haenszel on white females (152), as well as studies of 

female patients at Massachusetts General Hospital (54)) Roswell Park 

Memorial Institute (133), Presbyterian Hospital (323)) and Washington 

Iiniversity (2601, indicated that adenocarcinoma is also contributing to the 

increment of lung cancer in women. 

CONCLLISION~--(a) The histological typing of lung cancer is reliable. 

However, the use of the ratio of Group I and Group II is an index to the mag 

nitude of increase in lung cancer is of limited value. 

174 
TABLE 9.-Mortality ratios for cancer of the lung by smoking class and 

by type of tumor, .!l.S. veterans study 

oroup I Oroup II 

1.0 1.0 

22 0. R 15. 4 s. 1 

IP. 9 .s. R 

12.9 5. 1 

31.2 1 7. 2 

8.4 1 3.7 

1’; : 2. 5 7 6

’ Inrludes occasional smokers. 

? Include men who were using pipe and/or cigars in addition to ricawttrs. 

Source. Darn, H. F., Haenszel, W. and Herrold. K. (89) (sre Chapter 8 alsol. 

(bl Squamous and oval-cell carcinomas (Group 1) comprise the predominant types associated with the increase-of lung cancer in both males 

and females. In several studies, adenocarcinomas (Group II I hare also 

increased in both sexes although to a lesser degree. 

Evaluation of the Association between Smoking and Lung Cancer 

It is not practical to attempt an experiment in man to test whether a 

causal relationship exists between smoking of tobacco and lung cancer. Such 

an experiment would imply the random selection of very young subjects 

living under environmental conditions as nearly identical as possible, and 

random selection of those who were to be smokers and those who were to 

be the non-smoker controls. Their smoking and other habits would need 

to be held constant for many years. Because of the relatively low incidence 

of lung cancer in the human population, both the test and the control groups 

would have to be very large. 

As such an experiment in man is not feasible, the judgment of causality 

must he made on other grounds. The epidemiologic method, when coupled 

with clinical or laboratory observations, can provide the basis from which 

judgments of causality may be derived. 

INDIRECT MEASURE OF THE ASSOCIATION 

The crudest indicators of an association between lung cancer and smoking 

are certain indirect measures : (a) a correlative increase in lung cancer 

mortality rates and- in per capita tobacco consumption in a number of 

countries (76, 138, 211, 239, 255), and (b) disparities between male and 

female lung cancer mortality rates correlated with corresponding differences 

in smoking habits of men and women, both by amounts smoked and duration 

of smoking (65,151,344). 

Figure 9 shows a correlation of crude male death rates from lung cancer 

iu I1 countries in 1950 with the per capita consumption of cigarettes in these 

countries in 1930 as presented by Doll (76). Assuming a 20-year induction 

Period for the appearance of lung cancer, Doll found a significant correlation 

(0.73-CO.30) between the death rates and cigarette consumption. Since 

virtually all the tobacco consumption in 1930 was among men in the countries 

714-422 O-M-13 175 
500 

400 

300 

200 

100 

0 

CRUDE MALE DEATH RATE FOR LUNG CANCER 

IN 1950 AND PER CAPITA CONSUMPTION OF 

CIGARETTES IN 1930 IN VARIOUS COUNTRIES. 

I 

GREAT BRITAIN 

# 

SWITZERLAND 

# 

U.S.A. 

* NORWAY 

-* 

‘t 

ICELAND 

CIGARETTE CONSUMPTION 

FIGURE 9. 

Source: Doll, R (76) 

represented (Great Britain, Finland, Switzerland, Holland, the United States, 

Australia, Denmark, Canada, Sweden, Norway, and Iceland), it seemed 

reasonable to compare the annual per capita consumption of each country 

with the crude, male lung cancer death rates. 

It will be noted in Figure 9 that the data from the United States show a 

relatively low death rate in relation to cigarette consumption. Doll suggested two explanations: the influence of a higher proportion of young 

176 
people in the U.S. population and the method of smoking, with the U.S. 

smokers consuming less of each cigarette than the British smokers. Since 

Doll’s explanations of the discrepancy. additional information has become 

available. Studies on length of cigarette butts discarded have shown American discards to be significantly longer than British discards; 30.9 mm 

(156) and 18.7 mm (85) respectively. Also, there is a significantly greater 

percentage of smokers in Great Britain than in the United States in the age 

groups in which lung cancer occurs at high rates (52.6 percent in 60+ 

year age group and 29.2 percent in 65+ year age group respectively). 

Strictly comparable data do not exist on inhalation practices for the two 

countries. Such information would aid in explaining this discrepancy as 

well as a similar disparity between Holland and Great Britain. In Holland 

I 156) the length of the cigarette butts was almost the same as in Great Britain 

(19.7 mm), but the crude male lung cancer death rate in Holland was 

significantly lower than in Great Britain. This correlates well, as shown 

in Figure 9, with the annual per capita consumption of cigarettes in Holland 

which has been much lower than in Great Britain. 

It should be mentioned that differences in intensity of air pollution and 

industrial exposures in these countries have not been taken into account. 

However, for reasons given below, these latter factors do not account for 

the magnitude of the difference in incidence of lung cancer nearly as well 

as the amount of each cigarette smoked and the degree of inhalation. 

Finally, the varying composition of the tobacco in the several countries was 

not considered in these studies. 

An elaboration of the disparities between male and female lung cancer 

mortality rates and their correlation with differences in smoking patterns 

is also in order, for the sex disparity has also been posed as contradictory 

to the smoking-lung cancer hypothesis. Although the opponents of the 

hypothesis, pointing to the sex disparity (116, 229), have minimized the 

differences in smoking habits, the fact remains that the magnitudes of the 

differences are quite large. In a representative cross-sectional survey of 

smoking habits coupled with the Current Population Survey of the Bureau 

of the Census in 1955, Haenszel, et al. (151) f ound the following disparities 

between male and female smoking patterns: 

1. Whereas only 22.9 percent of males had never smoked, 67.5 percent 

of females had not. 

2. Males showed relatively little variation among the component age 

groups in percentage not smoking, whereas females after age 

25-38 showed a consistently increasing percentage of non-smokers 

in successively higher age groups (Figure 10). 

3. Sixty-five percent of males smoked cigarettes as compared with 32 

percent of females. 

4. Cohort analyses revealed the adoption of cigarette smoking late in 

life for both males and females among cohorts born before 1890; 

but male cohorts born after 1900 successively began to smoke 

earlier in life. Large-scale adoption of cigarette smoking by 

women did not occur until the decades of the 1920’s and 1930’s. 

177 
PERCENTAGE OF PERSONS WHO HAVE NEVER SMOKE1 

BY SEX AND AGE, UNITED STATES, 1955 

Age (in years) 

18-24 

25-34 

35-44 

55-64 

65 and over 

45-54 

PERCENT NEVER SMOKED 

= MALES g@gj FEMALES 

FICCHE 10. 

Source: Harnszel, W. M. et al. (151) 

5. The median age at which males started smoking has remained fairly 

stable for the several age cohorts: from 19.3 years for ages 65 and 

over to 17.9 years for age 25-34; the median age that females 

started smoking has dropped dramatically from 39.9 years for 

the age group 65 and over to 20.0 years for age 25-34. 

6. Males in all age groups smoked considerably more cigarettes per 

day than did females.. In ages 55 and over, 6.9 percent of the 

178 
males smoked more than a pack a day, compared with only 0.6 

percent of the females. Although urban-rural and geographic regional differences were noted, significant disparities between male 

and female smoking were maintained throughout. Thus it can 

readily be deduced that these findings are consistent not only with 

the sex disparity in lung cancer mortality but also with the slower 

but nevertheless continuing rise in female lung cancer mortality. 

Rritish studies (344) also revealed that females, especially before World 

War II, consumed much less tobacco than did males. A correction for the 

marked disparity in smoking habits of males and females reduced the obser\:ed 5-fold excess of male lung cancer deaths to a 1.4-fold excess as of 

1953 1149). Supporting this finding are the data from two retrospective 

studies (147, 152) in which the age-adjusted lung cancer death rates in 195% 

59 among male and female non-smokers were 12.5 and 9.4 respectively for a 

ratio of 1.33 (145). This residual ratio implies that there may be other 

factors operating to produce a portion of. the sex differential in mortality. 

DIRECT MEASURE OF THE ASSOCIATI0i-V 

For a direct measure of the association between lung cancer and smoking 

it is, of course, essential that both variables or attributes be measured in the 

same populations. The 29 retrospective studies, described earlier, consider 

smoking (usually kind, amount, and duration) and non-smoking among cases 

of lung cancer and individuals without lung cancer. The seven prospective 

studies consider the occurrence or lack of occurrence of lung cancer among 

smokers and non-smokers. 

ESTABLISHMENT OF ASSOCIATION.-A number of investigators, though accepting the existence of an association, have questioned its significance 

in terms of a causal hypothesis (58, 102, 114, 115, 116, 117, 141, 178, 

218, 219, 287, 288, 298, 299). Some of these doubts have been on the 

basis of a possible genetic underlay which might determine both smoking and 

lung cancer (114, 115, 116, 117). Some have followed contradictory observations in the dissenter’s own work (58, 102, 141), incorrectly assessed evidence 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 attributed either to improvements in diagnosis and reporting, (218, 219, 287, 

288, 298, 299) or to the aging of the population. In the latter explanation 

they ignore the fact that aging of the population does not affect age-specific 

mortality rates which, for lung cancer, are also rising with the passage of 

time. Still others express doubt on the basis of the lack of a concomitant 

rise in cancers of the oral cavity (178, 298) or of the skin of the fingers 

(178). Finally, some doubts have been based on supposed incongruencies 

between the cigarette-smoking hypothesis and urban-rural as well as sex differences in lung cancer mortality (116, 178, 229). There are a few investigators who maintain that the association may be spurious or that it has not 

heen proved (22,23, 24, 228,229, 230). 

A number of these objections have been assessed in earlier discussions in 

this section; others will be evaluated below. These latter criticisms have 

revolved about defects inherent in the retrospective or the prospective 

179 
methods of approach, biases of selection in either method, biases of non. 

response. the validity of the results in the early phases of a prospective study. 

and the misclassification of both variables: smoking habits and lung cancer. 

It should be noted that the Current Population Survey of 1955 yielded 

results highly consistent with data on tobacco production and taxation 

(151 I ; that classification errors in terms of amount of smoking were relatively minor in a reliability study by Finkner (113) ; and that, in at least 

three prospective studies, in which subjects were requestioned on smoking 

habits at intervals of at least two years, the replies were closely reproducible 

(87, 88, 157, 159, 162, 163) ? particularly if no illness had intervened (159). 

With regard to the retrospective studies, it has also been suggested that 

knowledge of the illness might have introduced bias in relation to histories 

of smoking habits (158, 229). In at least one retrospective study, both 

patient and interviewer were unaware of the diagnosis of lung cancer. 

the smoking histories having been obtained before the diagnosis was made 

(207). Furthermore. patients initially believed to have lung cancer who, 

after interview: were found .not to have the disease, reported smoking histories similar to the control groups and not the lung cancer groups (84). 

Finally, this bias cannot have influenced the findings of several studies in 

which a significantly greater proportion of cigarette smokers and heavy 

cigarette smokers were associated with epidermoid cancers than with adenocarcinoma (86, 150, 163, 313, 375). Th e reliability of response to smoking 

history would thus appear to be markedly above the critical level for the 

firm establishment of an association by the retrospective method. In prospective studies, this factor is less of a problem. 

In retrospective studies the investigator can confine himself to cases with 

accurate diagnoses. In the prospective approach, accuracy of diagnosis 

may not always be attainable, but all cases must be included. In assessing 

the results of the prospective studies it must be kept in mind that all deaths 

from any cause were involved in the calculations, with the cigarette smoker 

rates higher than those for non-smokers and with a gradient by amount of 

smoking demonstrated in all of the studies. Evidence that the specific 

estimates of risk for lung cancer among smokers actually might have been 

underestimated has been presented by Hammond and Horn (162, 163), who 

found higher relative risk ratios among smokers for confirmed cases than 

for those with less well-established diagnoses. Most of the prospective 

studies yield relative risks of lung cancer by various smoking categories 

which approximate those found in the Doll and Hill physician study (83) 

where, obviously, diagnostic evidence would be more readily available than 

in the general population. It would thus appear that in the data from retrospective and prospective studies, diagnostic accuracy was not a critical 

factor in the establishment of an association between smoking and lung 

cancer. 

The question of selection bias is, of course, a more complicated problem. 

Several criticisms have been leveled at both the retrospective and prospective 

methods. Although in retrospective studies the selection of a control group 

may pose a more serious problem, even the selection of the case material 

may interject difficulties. It has been claimed by Berkson 124) that the 

selection of hospitalized cases may lead to bias if smokers with lung cancer 

180 
were more often hospitalized than non-smokers with the disease. However, 

nearly all lung cancer cases are hospitalized, a point which, he concedes, 

would thus minimize this bias. Furthermore, several retrospective studies 

have surveyed all the cases in the area regardless of hospitalization (238, 

335)) or all deaths regardless of cause or hospitalization 1379). 

Another criticism of patient selection in retrospective studies deals with 

the danger that, in studies highly cross-sectional in time. if smokers live longer 

than non-smokers, there would obviously be more smokers in the disease 

group, and thus a spurious association of disease with smoking would result 

(254). There is no evidence for this basic assumption. Furthermore. it 

is inapplicable because almost all the retrospective studies were actually 

hased on newly diagnosed cases collected serially- over an interval of time 

long enough to remove this bias. 

Control groups pose a problem in retrospectiv-e studies. In 2T of the 29 

retrospective studies (exceptions are references 11’7 and 152 ) the controls 

were subjects without lung cancer, such as patients with other cancers. with 

diseases other than cancer. or so-called normals selected from the population. 

Analysis of the prospective studies proved that the biases interjected by the 

selection of sick controls in the retrospective studies actually operated to 

produce an underestimation of the association. for it has been shown that a 

number of other diseases are also associated with smoking. Furthermore, 

several studies have. in addition to controls with other diseases. selected a 

second set of random controls from the general population (82, 150. 222’1, 

only to find that the association utilizin g sick controls, significant tholrgh it 

proved to be, was intermediate to the association utilizing random population 

controls. 

The problem of selection bias in prospective studies is much more subtle, 

since there may be self-selection on the basis of illness existing at the time 

the study begins. This is essentially a problem of non-response which has 

been handled in detail in Chapter 8. The character of this non-response 

presents at least two nuances: a combination of self-selection and operator 

selection, as in the volunteer studies of Hammond and Horn ( 162) and Hammond (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 overrepresentation of sick smokers or well non-smokers or both in a prospective 

study, with the passage of time more deaths of sick persons would occur 

(without regard to the independent variable of smoking). Thus the death 

rates of smokers would tend to approach the death rate of non-smokers, 

removing the original selection bias and providing greater confidence in the 

residual association of the death rate with smoking if it persisted. In two 

of the studies (157, 162, 163) exclusion of ill persons on entry did take place. 

Further, in the studies that provide this comparison, the high lung cancer 

mortality ratio of cigarette smokers was maintained with the passage of time. 

In the D orn study the mortality ratio was 9.9 after three years experience 

and 12.0 after six years experience; the Hammond study gave 9.0 after 10.5 

months (157) and.9.6 after 22 months, while Doll and Hill (84) showed that 

the gradient ‘of increase in lung cancer death rate with increasing amount 

smoked appeared consistently in each of the first four years of their study. 

181 
This also weakens the criticism by Mainland and Herrera (230) of the uw 

of non-professional volunteer workers for subject selection. 

Thus it would appear that an association between cigarette smoking and 

lung cancer does indeed exist. 

CAUSAL SIGSIFICANCE OF ~1-1~ ASSOCIATION.-AS already stated, statistical 

methods cannot establish proof of a causal relationship in an association. 

The causal significance of an association is a matter of judgment which goes 

beyond any statement of statistical probability. To judge or evaluate the 

causal significance of the association between cigarette smoking and lung 

cancer a number of criteria must be utilized, no one of which by itself is 

pathognomonic or a sine qua non for judgment. These criteria include: 

ia) The consistency of the association 

(b) The strength of the association 

(c) The specificity of the association 

(d) The temporal relationship of the association 

(e) The coherence of the association. 

THE CONSISTENCY OF THE AssocrATIoN.-This criterion implies that diverse methods of approach in the study of an association will provide similar 

conclusions. It is noteworthy that all 29 retrospective studies found an association between cigarette smoking and lung cancer. The very nature of 

the criticisms leveled against these retrospective studies indicates a diversity of characteristics of approach and, for that matter, marked differences 

in shortcomings which have been discussed in detail above. It is indeed 

remarkable that no reasonably well designed restrospective study has found 

results to the contrary. Seven prospective studies have also revealed highly 

significant associations. Where relative risks could be calculated on the 

basis of some reasonable assumptions in some of the retrospective studies, 

a consistency not only among them (38, 82, 147, 152, 222, 283, 301, 313, 

381) but also with the prospective studies could be demonstrated. Such 

a situation would prevail if the association were either causal, or spurious 

on the basis of an unknown source of bias. It is difficult to conceive of a 

universally acting bias in all the diverse approaches unless it be a constitutional genetic characteristic or one acquired early in life, which will be 

discussed later in the section, Constitutional Hypothesis+ 

Two studies of tobacco workers (58, 141) have been cited as inconsistent 

with the 29 retrospective and particularly the 7 prospective studies cited in 

detail in the early portions of this section. Both these studies can be dismissed because of major defects in methodology and concept. The heavier 

smoking among the tobacco workers in these studies was considered, but no 

comparison of observed-to-expected rates was made on the basis of smoking 

classes within this population. Furthermore their conclusions are based on 

expectancies in the general population without regard to the fact that persons 

with acute, chronic, or disabling illness are initially excluded from employ 

ment and that those developing permanent illness are lost to employee rolls. 

THE STRENGTH OF THE AssocrATroN.-The most direct measure of the 

strength of the association between smoking and lung cancer is the ratio of 

lung cancer rates for smokers to the rates for non-smokers, provided these two 

rates have been adjusted for the age characteristics of each group. Another way of expressing this is the ratio of the number of observed cases 

182 
in the smoker group to the expected number calculated by applying the 

non-smoker rate to the population of smokers. This provides us with a 

measure of relative risk which can yield a judgment on the sire of the e,fect 

of a factor on a disease and which, e\en in the presence of another agent 

without causal effect, but correlated with the causal agent. will not be 

obscured by the presence of the non-c.ausal agent. Cornfield et al. (62 1 have 

uot only provided us with a detailed anal! sis of the applic,atiotls of hoth 

absolute and relative measures of risk, but have also demonstrated the useful. 

ness of the relative risk measure in judgin, m causal and non-causal effects 

with mathematical proof of their statements. 

An absolute measure of difference in prevalence of a disease between 

populations with or without the agent I e.g., cigarette smoke‘) _ where the 

agent may be causal in its effect on several diseases. can provide us with the 

means of appraising the public health significance of the disease. i.e. the 

size of the problem, in relation to other diseases. It is less effecti\-e for 

appraising the non-causal nature of agent5 having apparent effects. the 

importance of one agent with respect to other agents. or the effects of rrfinement of disease classification. This, Cornfield and his co-authors / 62 1 hare 

demonstrated. 

In essence, then: a relative risk ratio measurin g the strength of an aeoociation provides for an evaluation of whether this factor is important in the 

production of a disease. In the data of the nine retrospective studies for 

which relative risks of lung canrer among smokers and non-smokers were 

calculated, the ratios were not only high in all of the studies but showed a 

remarkable similarity in magnitude. More important: in the se\‘en prospective studies which inherently can reveal direct estimates of risks among 

smokers and non-smokers, the relative risk ratios for lung cancer were uniformly high and. again, remarkably close in magnitude. Furthermorr, the 

retrospective and prospective studies yielded quite similar ratios. 

Important to the strength as well as to the coherence of the association is 

the dose-effect phenomenon. In every prospective study that provided this 

information, the dose-effect was apparent, with the relative risk ratio increasing as the amount of tobacco (84) or of cigarettes (25, 88, 96, 97, 163) 

smoked per day increased (Table 51. Even the retrospective studies for 

which relative risks were calculated by amount smoked (38. 147. 1.52: 222) 

showed similar increases in risks with amount smoked (Table 4i. 

It may be estimated from the data in the prospective studies that. in comllarison with non-smokers, average smokers of cigarettes have a 9- to lo-fold 

risk of developin g lung cancer, and heavy smokers, at least a 20-fold risk. 

Thus it would appear that the strength of the association between cigarette 

smoking and lung cancer must be judged to be high. 

THE SPECIFICITY OF THE AssocI.~TIoN.-This concept cannot be entirely 

dissociated from the concept inherent in the strength of the association. It 

implies the precision with which one component of an associated pair can 

be utilized to predict the occurrence of the other, i.e., how frequently the 

presence of one variable (e.g.. lung cancer‘) will predict. in the same individual, the presence of another (e.g.. cigarette smokillg) . 

In a discussion of the specificity of the relationship between any factor 

possibly causal in character and a disease it may produce, it must be rec183 
opnized that rarely. if ever. in our biologic universe, does the presence of 

an agent invariably predict the occurrence of a disease. Second, but not 

less important. is our growing recognition that a given disease may have 

multiple causes. The ideal state in which smoking or smoking of cigarettes 

and every case of lung cancer was correlated one-to-one would pose much 

less difficulty in a judgment of causality, but the existence of lung cancer in 

non-smokers does indeed complicate matters somewhat. It is evident that 

the greater the number of causal agents producing a given disease the less 

strong and the less specific will be the association between any one of them 

and the total load of the disease. But this could not be posed as a contradiction to a causal hypothesis for any one of them even though the predictive 

value of any one of them might be small. For example, the pathologist who 

examines a lung at autopsy and finds tubercle formation and caseation 

necrosis would almost invariably be able to predict the coexistence of tubercle bacilli. Experience has shown that the lesions are highly specific for 

Mycohacteriurn tuberculosis. On the other hand, a clinician may encounter 

a combination of signs and symptoms including stiff neck, stiff back, fever, 

nausea, vomiting, and lymphocytes in the spinal fluid. Experience has revealed that any one of a number of organisms may be associated with this 

syndrome: polio virus, ECHO viruses, Coxsackie viruses and Leptospirae, 

to name but a few-. The predictability of the coexistence of polio virus 

per se is rather low. In other words, the syndrome as noted is not very 

specific for polio virus. Th ic .: may well be the condition which prevails in 

coronary heart disease where the mortality ratio is between 1.6 and 1.8 or a 

60 to 80 percent excess among smokers of cigarettes. If this ratio is applicable to the entire population from which the sample data are derived, another 

w-ay of expressing this relationship is that. of the total load of coronary heart 

disease mortality among males only 61 to 64 percent is associated with cigarette smoking. The large residual among non-cigarette smokers implies 

either other causes in addition to smoking or, as a somewhat greater possibility, factors actually causally related to coronary heart disease and frequently, but not invariably, associated with smoking. 

However, in lung cancer, we are dealing with relative risk ratios averaging 

9.0 to 10.0 for cigarette smokers compared to non-smokers. This is an 

excess of 900 to 1,000 percent among smokers of cigarettes. Similarly, 

this means that of the total load of lung cancer in males about 90 percent is 

associated with cigarette smoking. In order to account for risk ratios of 

this magnitude as due to an association of smoking history with still another 

causative factor X t hormonal, constitutional: or other), a necessary condition would be that factor X be present at least nine times more frequently 

among smokers than non-smokers. No such factors with such high relative 

prevalence among smokers ha\,e yet been demonstrated. 

Another aspect of specificity requires some insight. Several cr%tics 

of the causal hypothesis have ‘questioned the significance of the association 

on the grounds that the existence of an association with such a wide variety 

of diseases, as elicited in the prospective studies, detracts from specificity 

for any one of them (22, 7). In a sense, this viewpoint is an exaggeration, 

for not all the specific disease mortality ratios in excess of 1.0 are large 
enough to warrant secure judgments of the strength of the association and 

of causal significance. A detailed discussion of this latter point has been 

presented in Chapter 8. The number of diseases in which the ratios remain 

significantly high, after consideration of the non-response bias, is not so 

great as to cast serious doubt on the causal hypothesis. Even if we were 

dealing with a single pure substance in the environment, the production of a 

number of disease entities does not contradict the hypothesis. It is well 

known that a single substance may have several modes of action on the 

several organ systems and that neither inhalation nor ingestion implies 

action restricted to the respiratory or digestive tracts, respectively. In 

tobacco we encounter a complex of substances whose additive and synergistic 

characteristics before and after combustion remain inadequately explored. 

It w-ould not be surprising to find that the diverse substances in tobacco smoke 

could produce more than a single disease. 

Actually, the finding that an excess risk for smokers does not occur for 

every one of the cauSes of death reinforces the specificity of the excess risk 

for those causes where the excess is significant. 

Thus, it is reasonable to conclude that the association between cigarette 

smoking and lung cancer has a high degree of specificity. 

TEMPORAL RELATIONSHIP OF ASSOCI.~TED VARIAm.Es.-In chronic diseases, 

insidious onset and ignorance of precise induction periods automatically 

present problems on which came first-the suspected agent or the 

disease. In any evaluation of the significance of an association, exposure 

to an agent presumed to be causal must precede, temporally, the onset of a disease which it is purported to produce. The early exposure to tobacco smoke 

and late manifestation of lung cancer among smokers, seem, at least 

superficially, to fulfill this condition. This does not, however, preclude the 

possibility that such patient? who, many years after the initiation of smoking 

are diagnosed as having lung cancer, may have had the primitive cellular 

changes or anlage (as postulated by Cohnheim) before the advent of their 

smoking. However, no evidence has thus far been brought forth to indicate 

that the initiation of the carcinomatous process in a smoker who developed 

lung cancer antedated the onset of smoking. 

COHERENCE OF THE A~SOCMTION.-A final criterion for the appraisal 

of causal significance of an association is its coherence with known facts in 

the natural history and biology of the disease. In the lung cancer-cigarette 

smoking relationship the following should be noted : 

(1.) Rise in Lung Cancer Mortality.-The increases in per capita consumption of cigarettes (76, 138, 211, 239, 2551 and the age-cohort patterns of 

smoking among males and females (lS1) are highly compatible with a real 

increase in lung cancer mortality. 

(2.) Sex Differential in Mortality.-The current sex differences in tobacco 

use (151, 160), the pronuonced differences in ape-cohort patterns between 

males and females, particularly in the older age groups-over 55 (1.51) 

and over 50 (160) -and the more recent adoption of cigarette smoking by 

women (151, 344) are all compatible with the high male-to-female ratio 

of lung cancer mortality and also with the lower ratios of 30 years ago 

(130). Haenzel and Shimkin (149) developed a statistical model for 

determining whether the results of the retrospective and prospective studies 

185 
%ere compatible with the information on distribution of lung cancer and 

thus valid for generalization to larger populations.” Applying their model 

of scheduled relative risks to data on cigarette consumption by age and sex 

derived from the Current Population Survey of 1955, their predicted male/ 

female ratio came quite close to the observed ratio in the general population. 

(3.1 Urban-Rural Differences in Lung Cancer Mortality.-A number of 

sources in this country (90, 136, 148, 175, 238, 252) and overseas (82, 199, 

335 ) have firmly established this existence of an urban excess in lung cancer 

mortality. Because of the possible implication of an air pollution effect, 

this urban lung cancer mortality excess has been cited as either being incompatible w-ith the smoking-lung cancer hypothesis (178, 229) or minimizing 

its significance I 69, 70, 71, 101., 190). The data of the studies of a number 

of authors have clearly shown, however, that although adjustment for 

smoking history does not equalize the urban-rural lung cancer mortality ratio 

(149). control on the urban-rural residence factor nevertheless leaves a 

large mortality risk difference between smokers and non-smokers. Haenszel 

has demonstrated this fact in his two population sample studies on males 

and females (147, 1521. Mills and Porter (238) demonstrated a much 

greater effect of smoking on lung cancer mortality than the urban-rural 

factor. Stocks (335) also demonstrated that though smoking is not the 

sole factor, as manifested by a rural-urban gradient among non-smokers, it 

represented a much more preponderant factor in accounting for the lung 

cancer mortality than did presumed air pollution or at least urbanization. 

He noted that his regression lines on amount smoked were parallel for the 

different areas in England and North Wales and that the urban-rural mortality ratios declined from 2.3 among non-smokers and 2.5 among light 

cigarette smokers to unitv among heavy smokers. The first prospective 

study of Hammond and Horn 1162) also showed higher lung cancer mortality rates irrespective of residence. In Dean’s second study in South 

Africa (70), in which he corrected the critical defect in his first study of 

not studying the smoking habits of the test populations, he continued to 

emphasize urbanization or air pollution as the major factor in lung cancer. 

.A perusal of his data. however. shows that by controlling on smoking, the 

lung cancer mortality rates arv doubled by the factor of country of origin: whereas. \+.ith country of origin controlled, the lung cancer risk increases 

from 3 to 20 times as the amount of cigarette smoking increases. After 

smoking patterns are controlled, the residuals in the urban over rural excess 

imply other factors, although the smoking factor preponderates in the urbanrural differences in lung cancer mortality in all of these studies. Thus the 

urban excess of lung cancer mortality is not incompatible with the smokinglung cancer hypothesis. 

(4.) Socio-Economic Differentials in Lung Cancer Mortality.-Distinct 

socio-economic differentials have been demonstrated convincingly in the 

epidemiology of lung cancer. Cohart (57) found a 40-percent excess of 

lung cancer incidence among the lowest economic class (both sexes) in the 

New Haven population, and the morbidity survey by Dorn and Cutler (90) 

demonstrated a distinct gradient by income class among white males, with 

the highest rates among the lowest income groups. In Denmark, Clemmesen 

and Nielsen, utilizing data derived from the Danish Cancer Registry, aIs0 

186 
found a much higher incidence of lung cancer among males in the lower 

rental groups (55) . In relation to the contribution which smoking makes to 

this differential, there is evidence that cigarette smoking may be inversely 

related to socio-economic status. The components of socio-economic status 

are, at best, difficult to define, compartmentalize, and measure. Direct 

inquiries of family income are rare and, when made, are subject to considerable error. Studies based on rental values. as in the Danish studies. 

express more adequately socio-economic status. 

Another high correlate of income is educational achievement. which has 

been considered by Hammond in his current prospective study I 161) in 

relation to smoking habits. Among males, the highest proportion of cigarette smokers (past or present) and the highest proportion of those smoking 

20 or more cigarettes per day (past or present) w-ere found in the group 

classified as “some high school education I but not high school graduates ) )” 

whereas the lowest proportion was found among college graduates. The 

highest proportion of ex-cigarette smokers (as of 1961-62) was among 

college graduates. Although the relation of smoking and educational le\-el 

in women is more complicated, the group which had been to college also had 

the highest proportion of ex-smokers. Finally. college graduates had the 

next to the lowest proportion of heavy cigarette smokers. NolIe of the 

female gradients was a sharp as those for the men. 

Occupation has also been utilized as a measure of socio-economic status, 

but this measure obviously has severe limitations. No definitive study has 

been reported in which lung cancer has been correlated with occupation 

and smoking class; the current Hammond I 1571 and Dorn 188) prospective studies may ultimately yield definitive findings in this regard. However. 

some indirect evidence of a partial correlation between the observed higher 

lung cancer death rates in lower socio-economic groups may be found in 

Table 26 of the Survey of Tobacco Smoking Patterns in the United States 

I, 151). Keeping in mind that type of occupation is not a critical index of 

income, it will nevertheless be noted that the professional and farmer and 

farm manager groups had higher proportions of non-smokers among them 

than did the laborers and craftsmen. This finding is in the proper direction for compatibility with the socio-economic differential in lung cancer mortality but the disparity does not appear to be sufficient to provide a satisfying 

correction. In fact, in this U.S. study, analyses by amount of cigarettes 

smoked tended to obscure the ordering by social class. In Great Britain, 

however, the inverse relationship of socio-economic class to heavy cigarette 

smoking remained apparent (174). In the U.S. study, classification by 

industry showed the highest proportions of non-smokers to be in the professional 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 important factor in lung cancer, then the risk should be related to the amount 

smoked, amount inhaled, duration of smoking, age when started smoking, 

discontinuance of smoking, time since discontinuance, and amount smoked 

prior to discontinuance. Herein lies the.greatest coherence with the known 

facts of the disease. In almost every study for which data were adequate 

187 
and which was directed to amount of smoking, duration of smoking and age 

when smoking was begun, the associations or calculated relative risks (direct 

or indirect) revealed gradients in the direction of supporting a true dose 

effect. Where discontinuance, time since discontinuance, and amount 

smoked prior to discontinuance were considered in either retrospective 

studies or. with more detail, in prospective studies, these all showed lower 

risks for ex-smokers, still lower risks as the length of time since diseontinuance increased, and lower risks among ex-smokers if they had been light 

smokers. These findings have been described in detail in the section on 

Retrospective Studies. 

Some contradictory information has been presented in regard to inhalation 

of tobacco smoke. This is the lack of association between inhalation and 

lung cancer as noted by Doll and Hill (82) alluded to earlier. These authors 

have begun collecting data (iu their prospective study) on inhalation for the 

mortality experience since 1958. These data are not presently available (80) . 

However, until the current ongoing prospective studies will have yielded information on this point in regard to lung cancer, four retrospective studies 

provide information on inhalation contrary to the Doll and Hill early negative findings ( 38, 211, 222, 313). In two of these (222, 313) inhalation and 

amount of smoking were considered and led to the provocative finding that 

with increase in daily amounts of cigarettes smoked the differences in risks 

between inhalers and noninh,ders diminished. There is no immediate explanation for this apparent discrepancy. 

Hammond has studied the smoking habits of the men and women in his 

current prospective study quite intensively ( 160). He has observed that the 

majority of men (92.9 percent) who smoke cigarettes inhale, and of these 

the majority inhale “moderately” to “deeply.” Pipe or cigar smokers inhale 

rarely. Combination smokers i i.e., cigarettes in combination with pipes and/’ 

or cigars) inhale in proportions intermediate to these. These findings become 

compatible with the hypothesis that the degree of inhalation accounts for a 

gradient of lung cancer risks, high to low, for smokers of cigarettes only. 

combination smokers, and pipe or cigar smokers (Table 5). An explanation of the diminishing differences in risks between “inhalers” and “noninhalers” with increase in amount smoked might be obtained if a more 

objective measure of inhalation were available. 

(6.) Localization of Cancer in Relation to Type of Smoking.-Although 

historically a relationship between cancer and smoking was suspected by 

Holland ( 176) and Soemmerring (322) with reference to the lower lip, it was 

not until the systematic, controlled study of lung, lip, pharynx, esophagus. 

colon and rectum cancers in relation to types of smoking by Levin in 1950 

that significantly distinctive associations between localization of the cancer 

and type of smoking were ehcited (207). Levin noted that statistical significance was achieved for cigarette smoking and lung cancer and for pipe 

smoking and lip cancer and stated, “It is somewhat surprising that type of 

smoking is the associated factor, rather than the actual use of tobacco.” 

Since then other studies have pointed up the relationship between type of 

smoking and localization of ca.ncer. Sadowsky I 301) in relative risk estimations of types of smoking and cancer site, also noted the highest significant 

values for cigarettes with lung, larynx and esophagus; for pipes with lip. 

188 
tongue and oral cavity; and for cigars with tongue and oral cavity. The 

complexities involved in a rational explanation for these phenomena are 

legion. especially since critics of the smoking-lung cancer hypothesis would 

point to no phenomenal rise of laryngeal cancer (onl?- a slight rise for whites 

between 1930 and 1955i in the face of increased cigarette consumption. 

Although among cigarette smokers, the relative risk of mortalit!- from lung 

cancer is presently greater than the relative risk for laryngeal cancer, the 

reverse seems to be true among cigar and pipe smokers I Chapter 8, Tables 

19 and 24). Furthermore. the per capita riae in cigarette consumption has 

been accompanied by a concomitant decline in consumption of pipe and 

cigar tobacco, the smoke of which was not deeply inhaled. It is thus conceivable that the increase in cigarette consumption ( and decline in cigar and 

pipe smoking) could affect an increase in lung cancer more significantly 

than in laryngeal cancer. 

Finally. there is no reason to assume that the susreptibility of the larynx 

to cancer equals that of the bronchus. Thus. a reasonable explanation for 

the difference in localization and relative risk is apparent. especially when 

it is known that in certain industrial exposures in which the irritant is inhaled and lung cancer is associated with such inhalation ~chromatesi, 

laryngeal and tracheal cancer is rare. It is. on the other hand. easier to 

visualize a mode of action for pipe and cicar tobacco in production of lip and 

ton,- and other oral cavity cancers. Thus, none of these considerations detract from the coherence of the association between cigarette smoking and 

!ung cancer. 

HISTOPATHOLOGIC EVIDEIVCE 

In earlier -mtions of this Chapter it has been noted that the application 

of tobacco extracts, smoke or condensates to the lung or tracheobronchial 

tree of experimental animals has failed to produce bronchogenic carcinoma, 

except possibly in dogs ( 289 I . I n addition, no animal experiments have thus 

far been devised to duplicate precisely the act of smoking as it is practiced by 

man. However, that the lungs of experimental animals are susceptible to carcinogens, particularly polycyclic aromatic hydrocarbons isolated from tobacco smoke. has been demonstrated by a number of workers (5, 197, 302). 

Of immediate import to the smoking-lun g cancer relationship is the observation that the histopathologic characteristics of the cancers thus produced are 

similar to those observed in man and are predominantly squatnous in type. 

Furthermore. certain bronchial epithelial changes, sequentially observed 

prior to the malignant changes in animals exposed to these carcinogens are 

similar to those in the bronchial epithelium of human smokers (9). In 

this latter extensive and well-controlled study, these changes were rarely 

seen among non-smokers, but increased in frequency and intensity with the 

number bf cigarettes smoked daily by individuals without lung cancer and 

were most frequent and intense in patients dying of lung cancer (Table 6 

of this Chapter). Ex-cigarette smokers and pipe and cigar smokers yielded 

a higher frequency of such cellular changes than non-smokers but less than 

did current cigarette smokers. Thus. the histopathologic evidence derived 

from laboratory and clinical material supljort the cigarette smoking-lung 

cancer hypothesis. 

189 
CONSTITUTIONAL HYPOTHESIS 

GESETIC CoNsrDERATloPs.--Thus far in the evaluation, the Committee has 

considered whether the al-ailable data are consistent with the hypothesis 

that smoking causes cancer of the lung. The analysis must consider with 

equal attention the alternative hypothesis that both the smoking of cigarettes 

and cancer of the lung hare a common cause which determines both that an 

individual shall become a smoker and also that he shall be predisposed to 

lung cancer. This h as often heen called the constitutional hypothesis. However. one should distinguish between the morphologic and physiologic characteristics of any individual due to a given environment and those characteristics (phenotyie~ that are due to an interaction of hereditary susceptibility 

and the environment. 

The characteristics of individuals studied in relation to smoking have been 

numerous and varied. Some of them have been physical attributes such as 

physique or somatotype, height and weight and their ratios, masculinity, 

anthropometric variables, physiologic variables (heart rate, pulsk pressure, 

blood pressure, cholesterol le\-els), and physical activity; others have been 

psychosocial iincluding persoqalitv-i in character (Chapter 14). Cigarette 

smokers have been described as consuming more alcohol, drinking more 

black coffee. being more neurotic. engaging more often in athletics: and as 

being more likelv to have at ltaast one parent with hypertension or coronar!- 

dieeasr i 1.X. 214. 235). Many studies have been poorly designed and 

controlled. others have yielded contradictory findings: and still others. 1)~. 

admission of their authors. have included characteristics that could either 

have heen acquired or have heen produced by smoking. None of these 

constitutional attributes have been included in a prospective study of mortality front Lund cancer fulfilling satisfactory epidemiological criteiia. except 

for a breakdo\\n h! longeviti of parents.and grandparents in one study 

( 1.59 I. Thr penrtics of the c%haracteristics themselves has not been determined. and adequate anal!si; of common genetic determinants in relation 

to the hahit of smoking has not been attempted. No environmental determinant.< that ~vould uni\-rrsall7; induce smoking and also produce the characteristics are evident I 02 I or have been proposed. 

Fisher I 11:: I bar: hem forelnost in calling attention to the possibility that 

cancer of the lung and the habit of smoking may be due to a common genotype. Selection of smokers then would automatically provide a population 

in I( hich I)uln~onarv canrer would appear on the basis of genetic susceptihilit)-. Studies on the concordance of smoking in twins (122. 127,281. 3561 

were used to supl)ort the hvljothesis, since more monozypotic pairs haye 

similar smoking hahits than.do dizygotic pairs. Although the data on the 

smoking hahits of identical and fraternal twins raised apart are compatible 

with this h!-pothesis. the histor Y of cancer in twins whose smoking habits are 

knorin has ne\-er been documented sufficiently to be useful in helping to 

resolyp the question of whether the concept of the constitutional hypothesis 

is valid. Also information about the habits and medical history of other 

siblings. offspring. and parents is singularly scanty, and efforts to separate 

genetic factors from influences of the environment in such studies have been 

only rudimentary. 

190 
Although single genes may be involved in a few exceptional neoplastic and 

preneoplastic states such as retinoblastoma and precancerous colonic polyposis, 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 numerous coincidences with small probabilities. Also, in order to adhere to a consistent argument in explainin g the reduced incidence of cancer of the lung in 

this group, it would be necessary to postulate another common genotype for 

those who smoke and subsequently terminate the habit. The argument 

becomes even more labored when multiple examples of identical genotypes 

for susceptibility to smoking and respective specific types of cancer are required by the hypothesis to explain the multiple types of cancer associated 

writh smoking. 

Since cancer of the lung occurs in both men and women who do not 

smoke, susceptibility genes acting alone or in combination with extrinsic 

or additional intrinsic factors can be effective without exposure to tobacco 

smoke. The occurrence of the disease, therefore, is not invariably linked to 

hypothetical genes responsible for the habit of smoking. Since susceptibility 

to cancer may be due to multiple genes with variable penetrance, and since 

the expression of these genes may change with environmental conditions, a 

minor portion of the cases of pulmonary cancer can be explained as the 

expression of genetic susceptibility in an environment excluding the habit 

of smoking. 

Smoking then mav add an extrinsic determinant which can increase the 

incidence of cancer of the lung beyond that which would otherwise prevail 

in the same population. 

It should be emphasized that comparisons of lung cancer mortality in 

smokers, non-smokers and ex-smokers have been made on different populations. 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 incidence in both men and women has occurred in recent decades. This points 

either to a change in the genie pool, or to the introduction of an agent into 

the environment, or a quantitative increase of an agent or agents capable of 

inducing this type of cancer. The genetic factors in man were evidently not 

strong enough to cause the development of many cases of lung cancer under 

environmental conditions which existed half a century ago. In terms of 

what is known about rates, pressures, and equilibria of human mutations the 

asumption that the genome of man could have changed gradually, simultaneously and identically in many countries during this century is almost 

inconceivable. 

714-422 O-64-14 191 
Smoking may be placed more properly in the role of an environmental 

determinant than as part of the phenotype of the pluripotential gene or 

genes, interacting with the environment and resulting in cancer of the lung. 

Current evidence is compatible with the opinion that genetic factors play 

a minor role compared to thse contribution of the smoking habit in the 

etiology of lung cancer today. 

EPIDEMIOLOGICAL CoivsmER,\TIoi%-Although evidences for the constitutional hypothesis are, at present, either tenuous or actually lacking, the 

basic philosophical and logical prerequisites for this hypothesis are contradicted by a number of well-established observations (62) : 

( 1.) Lung Cancer Mortality.-Lung cancer mortality has been increasing 

in the last SO years and much more in males than females. This increase could be due to either an environmental change or a mutation. 

Since an unchanging constitutional makeup cannot of itself explain the increase, we must postulate either that there are genetic differences which make 

some individuals sensitive to a new environmental factor (not tobacco), or 

that differences in constitution,al makeup ire not genetic but the result of 

differential exposure to some new factor that predisposes to lung cancer and 

creates the desire to smoke, or that the mutation has produced an increased 

susceptibility and a desire to smoke. For the first two postulates a new,environmental factor, other than tobacco, is required. Such a factor, it must, 

be remembered, must be correlated with lung cancer as highly as are cigarettes and also highly correlated with cigarette consumption. None has yet 

been found. In order to account for the magnitude of the lung cancer 

mortality increase, the third postulate would require a mutation rate which 

far exceeds any observed. 

(2.) Tobacco Tars.-Tobacco tars have been found to be carcinogenic for 

experimental animals. AlthouiFh carcinogenicity of tobacco tars has not 

been demonstrated in man, the constitutional hypothesis would require that 

they are not, and that the association with lung cancer in man of substances 

found to be carcinogenic for experimental animals is a coincidence. 

(3.) Pipe and Cigar Smoking.-Pipe and cigar smoking appears to have a 

higher correlation with laryngeal and oral cancer than with lung cancer. 

The constitutional hypothesis would require that there shall be two constitutional makeups, one predispos.ing to cigarette smoking but not to pipe and 

cigar smoking and also to cancer of the lung; the other predisposing to tobacco consumption in any form and to cancer of the larynx and oral cavity 

but not to cancer of the lung. The alternative within this hypothesis would 

require that the special constitut.ional makeup predisposes to cigarette smoking 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-cancer mortality and a gradient is noted by length of time smoking has been discontinued 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 be192 
tween smoking and lung cancer, but recognizes differences, defined or ill 

defined, between smokers and non-smokers may be stated as follows: There 

are factors in the individual acquired early (or genetic I which predispose to 

cigarette smoking, and cigarette smoking by direct action of smoke on the 

bronchial epithelium is a major factor in producing lung cancer in susceptible 

individuals. 

A detailed discussion of the significances of the data on psycho-social, 

constitutional, and physical characteristics of smokers and non-smokers 

is presented later in this report (Chapters 14 and 15). The role of the 

genetic factor in carcinogenesis has been discussed earlier in this Chapter. 

OTHER ETIOLOGIC FACTORS Ah’D CONFOUNDING F’ARIABLES 

Throughout this evaluation. it has been recognized that a causal hvpothesis 

for the cigarette smoking-lun g cancer relationship does not exclude other 

factors. This is attested to by the fact that a small but not insignificant 

percentage of cases of lung cancer does occur among non-smokers. Some 

estimates in retrospective studies and most of the prospective studies indicate that approximately 10 percent of the lung cancer cases are in nonsmokers. Doll (78) h as p rovided a higher estimate of 20 percent. Furthermore, the inability to account for the higher lung-cancer incidence in the 

lower economic classes entirely by disparities in smoking habits, which 

do exist, does imply other causal factors. 

Several other possible etiologic factors which have been explored merit 

discussion. These include occupational hazards, urbanization or industrialization and air pollution, and previous illness. 

(1.) Occupational Hazards.-In an extensive review of the literature on 

lung cancer in chromium and nickel workers and in uranium miners, Seltser 

(318j found the evidence for an excess of lung cancer mortality among chromate workers highly consistent. However, because of the smallness of the 

numbers involved, caution must be exercised in any calculation of the magnitude of the risk. Furthermore no evidence has been presented either for or 

against an excess risk of lung cancer among workers exposed to other 

chromium products or chromium mining. The evidence for an excess risk 

among nickel processing workers in refineries was even more consistent than 

for chromate workers. The lung cancer risk was five times greater among 

nickel processing workers than in other occupational groups in the same area 

(the risk for nasal cancer was 150 times higher). Among uranium miners 

an excess risk is apparent (3601, and is greater than in certain other miners 

of similar ores without the high radioactivity component (361). Although 

the induction of lung cancer by radio nuclides is probable in man, the evidence is not as firm as in animals. 

In addition, Doll has found a significant excess of lung cancer deaths 

among coal gas workers i81) and asbestos workers (77 i . In another review 

article, Doll (79) has added arsenic and hematite as suspects to the list, with 

isopropyl oil, beryllium, copper. and printing ink as possible risks. 

The evidence for the possible role of arsenic as a factor in the etiology of 

lung cancer has been summarized by Hueper (178), and I{uechley (45) has 

193 
recently suggested that it merits epidemiological investigation. The chief 

points of evidence cited include 1) the universality of arsenic in many ores 

and in the atmospheres in and near smelters; 2) the widespread use of 

ar-s&c as an insecticide and rthe consequent exposure of workers in insecticide manufacture, agricultura.1 workers, and those handling or consuming 

crops with arsenic residues; and 3) reports of a relatively high incidence of 

lung cancers in people living around smelters processing arsenic-containing 

ores, and also in vineyard workers exposed to large amounts of arsenical 

pesticides and consuming large amounts of arsenic-contaminated beverages. 

It is noteworthy that for the nickel and chromate material the lung cancer 

mortality is referrable to a high exposure period in the respective industries, 

a situation which probably does not prevail today. Of greater importance is 

the regrettable fact that in none of these occupational hazard studies were 

smoking histories obtained. Thus the contribution which smoking, as a 

contributory or etiologic factor, may have made to the lung cancer picture 

in these risk situations is unknown. However, the series of cases in nonsmoking 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 population exposed to industrial carcinogens is relatively small and that these 

agents cannot account for th’e increasing lung cancer risk in the general 

population. 

(2.) Urbanization. Industrialization, and Air Pollution.-The urban-rural 

differences in lung cancer mortality risk, though small and accounted for in 

part by differences in smoking habits (see section entitled Coherence of 

Association) ) nevertheless may have a residual which implies other etiolopic 

factors in an urban environment. This has been the explanation offered in 

the studies by Stocks and Campbell (337) and Stocks (335) who noted a 

gradient among non-smokers, light cigarette smokers and pipe smokers by 

density of population but who found no gradient among heavy smokers. 

Less direct evidence was derived by Eastcott (101) and Dean (69, 71 j who 

found higher lung cancer rates among migrants from Great Britain to New 

Zealand. South Africa and Australia, respectively. Their inferences were 

that these immigrants had had significant exposure to air pollution in England prior to coming to the Commonwealth countries. Unfortunately, these 

interpretations were untenable for there was no individual case-control information on tobacco consumption. A correction of method by Dean in a 

later study (70) did elicit smoking histories and revealed a marked influence 

of cigarette smoking but a significant though lesser factor of urbanization. 

Doll’s study of non-smoking lung cancer cases (78) revealed no differences 

in risk among men and women and in residents of areas of different population density. His findings cannot be considered to be conclusive of a negative 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 Occupational Histories and Mortality from Cancer of the Lung in Two Cities. Inter-regional 

Symposium on Criteria for Air Quality and Methods of Measurement, W.H.O., Geneva, 

Switzerland, August 6-12, 1963. 

194 
mathematical model embodying amount of smoking, age, air pollution 

measurements by specific carcinogenic constituents, proportion of life spent 

in country and town, and lung cancer mortality was applied to the data derived from Belfast and Dublin. The lung cancer death rates were found to 

be compatible with an hypothesis that in Belfast about two-thirds of the deaths 

of men resulted from cigarette smoking and one-third from air pollution by 

smoke and, in Dublin, 75 percent from cigarette smoking and 25 percent from 

air pollution. These data are not offered as proof but represent the approaches necessary for future research in the area of proportional contributions to lung cancer mortality. Such appl ica t ions may be useful in determining the role of air pollution in such disparate lung cancer mortality rates 

between, for example, the United States and Great Britain when adjustments 

in smoking habits still do not eliminate the difference completely. 

Two studies (147, 152 ) have also indicated that migration of rural people 

into urban areas subjects them to lun g cancer risks greater than for lifetime urban residents. This effect is noted among non-smokers as well. The 

least that can be said is that the intensity of urbanization or industrialization 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 infections, on the development of lung cancer. 

Winternitz (371) called attention in 1920 to proliferative changes in cases 

of post-influenza] pneumonia similar to those seen in invasive, malignant 

neoplasms of the lung but this report stimulated relatively few epidemiologic 

observations. In the retrospective study of the smoking-lung cancer relationship by Doll and Hill (82) inquiry into a history of previous respiratory 

infections led to finding a significant excess of antecedent chronic bronchitis 

and pneumonia among lung cancer patients even when smoking class was 

controlled. However, because a collateral comparison with another control 

group of patients, for whom a lung cancer diagnosis was subsequently found 

to be in error, failed to reveal a difference, Doll and Hill concluded that 

either “chronic bronchitis and pneumonia predispose to a whole group of 

respiratory disorders . . . or that patients with respiratory disorders recall 

previous chronic bronchitis and pneumonia more readily than do patients 

with diseases with other symptoms.” However, almost simultaneously 

Beebe (20) investigated the relationship between mustard gas exposure, 

chronic bronchitis, pneumonia and influenza and lung cancer, and Case and 

Lea (53) between mustard gas exposure and/or chronic bronchitis and lung 

cancer. Smoking histories were controlled in these studies. Beebe found 

no evidence of an increased lung cancer risk with an antecedent history of 

influenza] pneumonia and primary pneumonia but there did appear a highly 

suggestive association between mustard gas exposure and lung cancer. No 

relationship between chronic bronchitis and lung cancer was noted. Case 

and Lea, however, interpreted their findings to mean a sequential relation-. 

ship between mustard gas exposure, chronic bronchitis, and lung cancer. 

The lung cancer risk was doubled by pre-existing chronic bronchitis. Doll, 

195 
in a later review (76), however, indicated that since the smoking-lung cancer 

relationship is stronger than the chronic bronchitis-lung cancer relationship, 

chronic bronchitis is not a necessary intermediate pathogenetic process. The 

failure of the Beebk study to affirm the Case and Lea findings in regard to 

chronic bronchitis may lie in the problem of differences in British and 

American diagnoses of chronic bronchitis. 

In an epidemiologic approach to other factors in lung cancer risks, Denoix 

et al. (72) studied 160 characteristics. Among other factors, much less 

strongly associated with lun,g cancer than smoking of cigarettes, they 

found a history of exposure to war gas and chronic bronchitis to predispose 

to lung cancer. The war gas component was strong enough to double the risk 

of lung cancer even with control on smoking class. 

Thus, the observations on previous respiratory illness are too few in 

number to place any degree of assurance on a relationship, but the studies 

hy Case and Lea and by Denoix et al. remain interesting. 

(4.) Other Factors.-Numerous other factors, such as coffee drinking, 

alcohol consumption, nutritional status, and beer drinking, have been studied 

and some associations with lung cancer have been found, but none of them 

does more than double the risk (and sometimes these are noted to be associated with lung cancer via the smoking component’) as compared to the 

9- to lo-fold risk in average cigarette smokers and the 20 + fold risk in heavy 

smokers. 

Conclusions 

1. Cigarette smoking is carnally related to lung cancer in men; the magnitude 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 discontinuing 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 insufficient to warrant a conclusion for each group individually. 

ORAL CANCER 

Epidemiologic& Evidence 

The suspicion of an association between use of tobacco and oral cancer 

dates back to the early 18th Century when Holland ( 176) first noted cancer 

of the lip among users of toba.cco. In 1795, Soemmering (322) made the 

same observation. In the pre;ent era. additional clinical observations have 

been recorded. The investigators noted the proportions of users of the 

1% 
various forms of tobacco among the various cases of oral cancer and found 

clues to a relationship. These observations lacked controls. Notable 

among these reports are the review by Haase (142) emphasizing location of 

the cancer of the lip and mouth according to where the pipe was held; the 

analysis by Ahlbom (1) by specific type of tobacco use in relation to site; 

and the work of Potter and Tully (280) which indicated an increase in risk 

of oral cancer with increax in smoking. From the first two studies mentioned 

(1, 142)) it is immediately apparent that any reasonably meaningful study 

of the relationship between tobacco and oral cancer must take into account 

ndt only the specific sites (lip, cheek. gingiva, tongue, oropharynx, etc.) 

hut also the precise form of tobacco u-se (pipes, cigars, cigarettes, chewing 

tobacco. snuff, etc.). 

Of additional interest is the specialized use of tobacco as a component of 

hetel nut quids in certain areas of the world: several observations suggest an 

association with oral cancer (66, 67. 269. 319). In contrast. observations 

of populations using betel nut quid s without tobacco (104. 234. 367) in 

certain other areas of the world show no association of betel nut with oral 

cavity cancer. 

More formalized case-control or retrospective studies varying in specific approach, in suitability of controls and in sample size have appeared 

between 1920 and the present (26,41,103,202,207,221,237,245,272.301, 

306, 314, 326, 355, 369, 385, 387, 388: 398 I. These studies are described 

in Table 10 which includes general smoking data, for the most part, on combinations of specific sites of orat cancer. A number of these investigations 

either did not separate the several sites of the oral cavity because of the small 

number of cases for each site or. upon separation into such sites, found the 

smoking classes too numerous for testing of significance (26,221, 237, 388). 

Since associations with form of tobacco use varied according to smoking 

classes and, wherever possible, to specific sites (Table lOA), in this summary table, a statistically significant positive association is designated by 

a plus sign, whereas the lack of such an association is designated by a minus 

sign. A plus-minus sign indicates that there was some evidence of an association which was not, however, statistically significant. 

It will immediately be noted that in 10 of 17 studies all oral sites were 

combined in an attempt to elicit an association with forms of tobacco-use 

(26, 202, 221, 237, 245, 272, 306, 314, 326, 388). Although eight of these 

showed positive association, they were so scattered among the several forms 

of tobacco use that little can be derived from them. Furthermore, distinctly 

specific site associations may be masked by such combinations. In examining the data for specific site localizations and forms of tobacco use, several 

associations become clarified. 

It would appear that pipe smokin g is associated with lip cancer in all six 

studies in which this site and form of tobacco use was analyzed (41,103,207, 

301,378,385). 

In one additional study (237) an association with pipe and cigars com197 
TABLE lo.--Outline of retrospective studies of tobacco use and cancer of the oral cavity 

Co”trols T 

__- 

Method of selectlo” 

Investlgetor and yen, HerW”Cl 

Collection of data 

Numba 

500 

V U”llR 

526 

II 

.__ 

217 

Method of selcctio” 

,’ 

-- 

‘r 

-_ 

(41: 

(“21: 

Series of elimc patients without 

epithelion~n of the lip. 

7s. 6% tobacco users 

75.2% xnokers 

44.4% rigarettes 

13.4%, chew 

ZS.G% pipes 

44.0% cigars 

Apparently by interview in the 

clinic. 

U.S.A. M 

F 

Series 01 rlinir patients with epithclioma of the lip. 

80.6% tobacco users 

75.1’% sl”okers 

0.9% +arettes 

24.0% chew 

59.0% pipes 

38.57, cigars 

Clinic patients with cancer of 

vsriou sites. Site breakdown 

md smoking data not rlpar. 

Lonlhanl and Doering lW%. 

217 Clinir pnticnts without cancer, 

“Wched by sex and age. Smok. in7 ,,?,+* .,,>* “I”“. 

. ..* ““%.. ..1(1 \.Y‘.L. 

Personal interview by investigators 

in clinics. 

1J.S.A. M-F 

__ 

Bigelow and 

Lorrlbnrd, 1933. 

(27: 

(103) 

(? 

439 

33 

143 

Patients without ca”cer, in eomparable “u”lbers. 

26.5% “on-users 

24.07:. excessive users (Table 111). 

-__-- 

Sweden M 

F 

) Clinic and hospital patients, apparently several hundred. 

14.2% “on-USXS. 

36.4% exessive users (Table 111). 

-___ 

Clinic patients with cxncer of the 

tin 

Personal interview in hospitals and 

clinics. 

/- Not defined. 

68.7% tobacco “sers. M 

1 to 2 701 tobacco users, F 

22.9% pipes, M 

60.7% chew OT use snuff, M 

32.5% cigars and cigarettes, M 

Ebenius 1943 

_.,. 

79.7% tobncro users, M 

57.6% tobacco user+, F (all pipes) 

61.8% pipes, M 

47.4% chew OT “se snuff, M 

12.9% rigars and cigarettes, M 

- 

Canrer institute patients with 

cancer of the lip. 

84.5% smokers 

45.3% cigarettes 

48.1% pipes 

26.5% cigars 

Levi” et al. 1950 m7) 1J.S.A. 1 M Csnrer institute patients with Rolltine clinic interview. 

non-cancer diseases of same site. 

74.0% snlokers 

43.00/, cigarettes 

30.7% pipes 

34.9% cigars 

Mills and Porter 1950 (237) M 124 185 Sn”lple of population of Columbus. Ohio, and in same proportion 

of valor, sex, and age as in CRSW. 

32.4% cigarettes only 

‘29i;~;sPipes, rlgers. or combinaFrom next of kin of deceased by 

rnsil questionnaire or by personal 

interview. Controls by houseto-house interview. 

Deaths from canrcr oi oral cavity 

ill Cincinnntl and Detroit, 1940- 

45 and 1942-46, rcspectivcly. 

35.5% eiearettes only 

54i~~XXs”prs, clpirrs. or combina- 

_- - 
Moore et al. 1953 (245) U.S.A. M 112 Patients OYer M yrs. old since 1961 

with ca”cer of oral cavity. 38 Patients of same age groups with 

53.0% chew 

be”irn oral lesions or benign 

Personal IntervIew of contmls; fool 

cases, next-of-kin were visited or 

42.0% pipes 

surgical amditions. 

38.4% cigars and cigarettes 31.6% chew 

contacted by letter. 

47.4% pipes 

52.6% cigars and cigarettes ____^.____ 

Sadowsky et al., 1953 (301) IJ.9.A. 

Smghvl et al., 1955 

-- 

(306) India M 

F 

136 Hospital patients with oral and 

pharyngeal cancer, 193M& 

42.3% cigarettes only 

4.0% cigars only 

6.57 

31 

17.3% pipes only 

23.2’% mixed 

IIospibl patients with cancer of M 

oral cavity and pharynx. F 

3~3.87~ smoke and chew, M; 3.7% F 

46.7% smoke only, M; 6.2y0 F 

11.7% chew only, M; 64.2% F 

2.7y0 neither, M; 25.9% F 

(Smoking is of bidis among both 

cases and controls.) 

615 Pntients with illrlrss other than Ily trained lay interviewers, 

cmccr. 

53.3% cigarettes only 

3.4% cigars only 

7.0% pipes ouly 

23.1% mixed 

Hospital patients witb disetlses 

other thxn cancer. 

24.0% smoke and chew, M; 0% F 

50.0% smoke only, M; 6.3% F 

8.7% chrw only, M; 23.2% F 

17.376 neither, M; 70.5% F 

Personal history interview in hospital. 

Ledermenn 1955 

Wynder et al., 1957 

(202) France M 

(373) U.9.A. y240 Patients with cancer of oral cavity 62 

& pharynx. 

Patients with cancer of ski”, bone, 

FIYlSCk. 

4.6% non-smokers 17.2% “on-smokers 

23.4%>20 cigarettes per day 18.6%>20 cigarettes per day 

543 Patients with cancer of oral cavity M 207 Patients with cancer of other sites Personal Interviews tn hospltsl or 

116 1 

3% non-users, M; 4770 F 

20% cigars, M 

11% pipes, M 

3% mixed, M 

17% chew, M 

57% cigarettes, M: 53% F 

29%>35 cigarettes per day, 

34%>16 cigarettes per day, 

W;;l$ns and Vogler (369) U.S.A. $f 37 Clinic ad hospital patients with NO”e 

44 cancer of gingiva. 

327’ chew or chew and smoke, M 

20?& smokers, M 

52% use snuff, F 

9% smokers, F 

and benlg” disexes. 

10% non-users, M; 70% F 1~37~ cigars, M 

6Y0 pipes, M 

8% mixed. M 

Sal0 chrw, M 

clinic. 

63% cigarettes, M: 307, F 

17%>35 cigarvttcs per day, M 

110/,>16 cigarettes per day, F 

Clinic and hospital histories. 

pt;tir;ts with “on-cancer Questioned about the swne time 

wcident CLLSCS, by the same interviewer. 
TABLE lO.-Outline of retrospective studies of tobacco use and cancer of the oral cavity-Continued 

Investigator and yea 

‘le 

Refrem 

Country T sex 

F 

P 

i-i-- 

F 

M 

GF 

CmS T C0*tr01s 

Nunbe] 

- 

I 

. . 

!r 

-- 

Method of xlectlon 

Collectlo” of data 

Method of selection 

Wynder et al. 1957 (388: , Cuba Hospital clinic patients with 

mncer of oral cavity and 

pharynx. 

Personal questiontng in clinic, all 

by 2 interviewers. 

4% “on-smokers, M; 24y0 F 

45% cigarettes predom., M; 62% F 

33% cigars predom.. M; 12% F 

- 

-- 

-- 

Wynder et al. 1967 Sweden 

-- 

rumbe 

178 

34 

115 

140 

---ii 

al 

383 

Hospital patients with cancer of 

oral cavity and pharynx. 

-- 

-- 

-- 

_- 

_- 

M 116 

F 166 

Patients in same hospital with 

center of sites other than oral, 

pharynx, larynx, lung, esophagus and breast. 

36% cigarettes, M 

9% cigara, M 

16% pipes, M 

13% mixed, M 

Personal interview in hospital; and 

medical histories. 

3&S?& cigarettes, M 

i3.0yo oijara, M 

12.2% @pes, M 

15.7% mixed. M 

Peacock et al. 191% m: 

__-- 

U.S.A. Hospital patients with oral cancer 

“F :: Persons1 interviews. 

66.67o chewed or used snuff over 

20 years. 

Patients in same hospital without 

oral wwer and 117 male and 

100 female randomly selected 

outpatients. 

32.6?0 of Arst nroup, 

43.30/, of second group chewed or 

used snuff over 20 years. 

Staszewski ,880 (3271 Poland Male patients with oral cancer 912 

-- 

-_ 

Male patients with other cancer 

a”d “on-cancerous conditions. 

17.3% non-smokers 

49.0% “heavy” smoking index aO..5% cigarettes only 

11.1% pipes and/or cigars 

Personal interviews. 

5.7% non-smokers 

72.8% “heavy” smoking tnder 

72.3% cigarettes only 

12.3% pipes and/or cigars 

Vogler et al. IQ62 (35.51 J:S.A. 133 

92 

Clinic patients with cancer of lip 

and oral cavity. 

M 521 

F 1,064 

Patients of same clinic with other 

cancer or non-ma&want mnditions. 

6.1% snuff dippers, F 2 

5670 totwco users, M + F 

‘erwnal interviews in clinic. 

32.Wo chewers, M 2 

22.9% excessive chewers, M 

72.07, snuff dippers, F 

41.3% excessive snuff dippers, F 

905% tobacco users, M + F 

- 

’ Estimate of prevalence o “se. 

f Due to varying tabular treatment of the data, the percentages of tobacco wars are not all based on the same numbers of cases. 
Investigator and reference Cigarettes 

Broders (41). ..~ .~ . . . . . . 

Lombard and DoerIng 

wzl). 

Bigelow and Lombard (26) 

Ebenius (103) ____._.... ~.. 

Levin et al. (207).-..~ . . . . . 

Mills and Porter (237). 

(Lip)- *.. .~~.-.- ____._.. ~. (Lip)+ ____ ~.__~.._~ . . . .._.__ 

(Lip)- _.__..__._.. ~.~~~ . . . . . (Lip)+-...-- . . .._ _ ._._.... 

(Oral)*.. ~~.~...~ . . . . . .._.. ..__._._._._._....._ ~.~ . . . . . . 

(Lip, mouth)- z..- ~... (Lip, mouth)-.... -~_~ 

(Lip, tongue, other oral, (Lip, tongue, other oral)+.. pharynx)-. 

(Oropharynx)+ 3 ___._.._.... . . . . . . . . . . .._.__.___..... ~... 

(Oral)+. 

fhl, +F (Floor of mouth)-. (Each site except tongue)+. 

(Pharynx)+ ’ . . . . . .._____... 

My2n;p+ (Oral and phnrCO+)-. (LIP)+- .____.. ~~ ._..____.... 

y&afPnx)+, (Other ...-~.~.~~~ . . . . . ..-.......... 

Moore et 81. (245)m . . . .._ 

Sadowsky et al. (301)... 

Sarlghvi et al. (306) _______ 

Ledermarm (2w.. __~. 

Wynder et al. (378) ._____. 

Schwa&et al. (314)m.... 

Wyndrr et al. (338) .. . . . . 

Wynder et al. (385) ~~. ~~ 

Peacock et al. (272). _. 

Staszrwski (326). _..~-..~ 

Vogler et RI. (355) .. . .._.. 

TABLE lOA.-Smmry of results of retrospective studies of smoking by type and oral cancer of detailed sites ’ 

Pipes cigars 

(Lip) - .___. ___ _. . -.. 

Chewing 

(Lip)+. 

- 

Miscellsneous 

--~-___ 

(Lip,oralcavity)+ __.. ~..~ . .._.............. . . . . . . -._ 

(UP)*. 

(Tongue, other oral)+. 

(Each site)+ . . . . . ..__... 

My+,‘,)r‘+ (oral and phar- 

(Tongue, gingiva, phsryox)t. 

:/- (Lip)-. 

~~. 1 (All forms combined-oral)+ 

(Pipes and cigars combinedoral)+. 

(Lip, mouth)+ ______.... (SnuR-lip, mouth)+. 

(Or++ __..._......_.... (If smoke and chew-base of 

tongue, hypopharynx)+. 

((+ingivs, lip)*. 

. .._ (Pipes, and cigars combined -tongue)+. 

(Or3l)f be-.-.- . . . . ..___ (s!lu~-oral)+.~ 

..~. (Pipes and cigars combinedlip, oral cavity)*. 

._._ (.411 terms combined)+, 

Ff (snuff -flip and buccal 

cavity in both cases). 

-Ilf=Significant association. 

- =Association ahsent or not signiflcaot. 

* = Association of doubtful qignlficsnce. 

* Cigarettes and cigars. 

3 Hidis. 

1 Includes cigarettes and other. 

1 Only in individuals oi low economic status and over 60 years old. 
bined was noted. Among four studies of lip cancer the chewing of tobacco 

and/or snuff was found to be associated in two of them (41,245). 

There is some indication of an association of tongue cancer with cigar 

smoking in three studies (301, 378, 385) and in one of these (385) with pipe 

and cigar smoking combined. In two studies an association of gingival 

cancer with cigar smoking was demonstrated (378, 385) ; in one of these 

(378) an association also noted with pipe smoking, and a suggestion of an 

association with chewing of tobacco. 

Pharyngeal cancer was considered as a separate site in four studies (301, 

306, 378, 385). An association with cigarette smoking was noted in two out 

of three (306, 385) ; with cigars in two (378, 385) ; and with pipe in one 

(378). 

Among the better studies in which the sample sizes were large and controls 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 tobacco in pipes and cigars combined, and for other oral cavity cancers by 

number of pipefuls. IVo I gradient by amount smoked was noted for cigarettes. 

The seven prospective studies have yielded 152 cases of oral cavity cancer 

associated with cigarette smoking, with an adjusted expectancy of 37.0 cases 

giving a weighted mean mortality ratio of 4.1. This is the third highest 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. 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 smokers of one pack or less. Estimates of gradients by amount of smoking of 

pipes and/or cigars, by duration of smoking and by discontinuance are not yet 

available, because of the relatively smaller number of deaths from oral cancer. 

Inasmuch as the incidence of female oral cancer is markedly lower than 

in males, data on these variables for the female, to be derived from the current Hammond study, will require an inordinately prolonged observation 

period. 

Carcinogenesis 

Cigarette smoke and cigarette smoke condensates have failed to produce 

cancer when applied to the oral cavity of mice (75, 177, 240 I and rabbits 

(312) or to the palate of hamsters (194, 303). Exposure of the hamster 

cheek pouch to cigarette tar, snuff, or tobacco also failed to induce cancer 

202 
(95, 194, 243, 244, 245, 246, 271, 272, 303, 303a). Leukoplakia was reported to have been induced by the injection of tobacco smoke condensates 

into the gingiva of rabbits (296). 

The oral mucosa appears to be resistant in general to cancer induction 

even when highly active carcinogens such as benzo(a )pyrene (95, 194, 209, 

243,244.245,246,271,272.2%, 303) are applied. Mechanical factors, such 

as secretion of saliva, interfere with the retention of carcinogenic agents. 

Saliva may also play a chemical role in modifying the action of carcinogenic 

agents on the tissues of the oral cavity and the pharynx. The only positive 

results with carcinogens have been obtained with benzoiaipyrene, 20.methylcholanthrene, 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 histopathologic examination. It is difficult to distinguish clinically between 

hyperplasia of the surface epithelium with keratinization (termed pachydermn 

or&) and “true” ZeukopEakia, which resembles microscopically senile keratosis, a preneoplastic lesion of the skin, showing atypical changes and mitotic 

figures, in addition to hyperplasia. 

In a study of the tissue changes in the palate of women in a part of India 

where the burning end of a cigar is held inside the mouth, Reddy and Rao 

(284) found ulceration, increased pigmentation of the epithelium of the 

palate and leukoplakia. Many of these women develop cancer at the same 

site. The carcinomas found are epidermoid and are frequently surrounded 

by an area of leukoplakia which sometimes shows changes characteristic of 

carcinoma-in-situ. Leukoplakia is a common finding in patients with multiple 

oral carcinomas, the majority of whom use tobacco (241). A histopathologic 

study of lesions in the oral mucosa in betel nut-tobacco chewers in Malaya 

showed frequent epithelial hyperplasia with atypical changes and papilloma 

formation (233). These lesions were considered to be frequent sites for the 

subsequent development of cancer. An association between leukoplakia and 

oral cancer has been noted by other investigators in studies on individuals 

with the habit of dipping snuff (179, 200). 

nlthough these results do not warrant any conclusion by themselves, 

they are consistent with the suggestion that oral cancer is frequently preceded by characteristic premalignant changes and that these have a relationship to the use of tobacco. 

Evaluation, 

Because of the diversity of sites involved in the category oral cancer 

and the need to delineate forms of tobacco use in each of them, the number 

of retrospective studies is inadequate to furnish sufficient material for a 

203 
judgment of consisted of the association except for cancer of the lip ad 

pipe smoking. 

Inasmuch as only one retrospective study (301) had large enough numbers 

of cases to derive the relative risks for specific site associations, reliance 

for strength of the association must be placed on the prospective studies. 

Since, in turn, the numbers of deaths from cancer of these sites so far have 

been small, only a combination of such sites could be analyzed for relative 

risk determinations. Five of the seven studies show reasonably high relative 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 localization 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 necessarily incompatible with a strong association between cancer of the lip and 

pipe smoking. 

Furthermore, other probable factors in the production of oral cavity cancer 

such as mouth hygiene, nutrition, and particularly alcohol consumption have 

not remained stable. In two studies (314, 378) alcohol consumption is 

clearly also associated with oral cancer and in one (378) evidence is 

presented for independent operation of this factor. 

The problem of heat from burning tobacco has not been investigated, as 

far as could be determined. It is of interest that cancer of the palate has been 

associated with smoking of cigars with the lighted end in the mouth (186). 

The heat factor should be kept in mind with respect to the excess of lip 

cancers among the cigar and pipe smokers. 

Although cancer of the oral cavity has not been produced experimentally 

by the exposure of animals to tobacco smoke, it has occurred following 

repeated applications of henzo(a)pyrene and other hydrocarbons to the 

cheek pouch of the hamster. 

The relationship of leukoplakia to tobacco use has been described earlier 

Conclusions 

1. The causal relationship of the smoking of pipes to the development 0’ 

cancer of the lip appears to be established. 

204 
2. Although there are suggestions of relationships between cancer of other 

. . specific sites of the oral cavity and the several forms of tobacco use, their 

causal implications cannot at present be stated.. 

LARYNGEAL CANCER 

Epidemiologic Euidencp 

RETROSPECTIVE STUDIES 

The possible association between tobacco smoking and laryngeal cancer 

received some attention in studies as early as 1937 ( 1. 185). Ahlbom noted 

a marked association between cigar and cigarette smoking and cancers of the 

pharynx. larynx and esophagus, but because of the small sample size, the 

three sites as defined were grouped together i I). The Kerrnaways calculated 

standardized mortality ratios for various occupational Froups (against the 

age-specific mortality rates for the general population of England and Wales 

for 1921-32‘1 and found barmen, cellarmen. and tobacconists to have significantly higher ratios (185). This latter study was repeated in 1947 and 

again the tobacconists and their assistants were noted to have an excess mortality for cancer of the larynx (184). It is difficult to attach much importance to these studies though they contain clues which should be investigated. 

The earliest controlled study, retrospective in approach, was that of Schrek 

and co-workers (311) in 1950. Their very carefully analyzed data showed 

an association between smoking and cancer of the larynx but the evidence 

is not firm, for the association was found in only one out of four age groups, 

perhaps because of the small number of cases in the study sample. There 

then followed nine additional retrospective studies, two more in the United 

States (301, 376) and one each in Czechoslovakia (353), Germany (30), 

France (3141, Sweden (385), Cuba (388), India (loo), and Poland (327) 

(Table 11 I. These were stimulated in part by the retrospective studies of 

lung cancer and the general prospective studies. 

Most of the studies (30, 100, 301, 311, 314, 327, 376, 385, 3881 show a 

stronger association between cigarette smoking and laryngeal cancer than for 

other forms of tobacco use but one of the studies shows a borderline relationship with cigar smoking (385). Wynder et al. (376) also distinguished between 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 demonstrated in two studies (301, 376) and suggested in four others (30, 311, 314, 

327). In the study by Sadowsky et al., this gradient was noted not only 

for cigarette smokers but for pipe smokers and combination smokers as 

Well. 

205 
TABLE 1 I.--Outline of retrospective studies of tobacco USC and cancer of the larynx 

i cases 

Coun try 

. -_ _- 

U.S.A. 

._ 

, 

.- 

Cl.ChO 

SlOW 

-- 

,- 

.kia. 

-- 

U.S.A. 

-- 

-- 

w 

-- 

Qerma 

U.6.A 

- 

M 

- 

M 

- 

M 

kfernu? 

- 

:311) 

sex 

__ 

M 

M-F 

IN 

I 

_- 

“Ill 

leer 

- 

73 

G 

273 

- 

241 

oe 

- 

Schrek et al. 1950 

Valko 1962 

Sadowsky et al. (1953) 

Bliimlein 1955 

Wynder et al. 1956 

Collection of data 

NIlIllher 

622 

108 

Method of selection Method of selection 

Referrals from V.A. hospitals in 

“entire mldwest” to V.A. Can. 

cer Center, Nines, Illinois, during 1942-44: patients with larynx- 

% hsrynr tumors clinically or 

lstologicelly diagnosed. 

13.7% non-smokers 

79.5% cigarettes 

3.7% cigars 

6.8% pipes 

From same set of referrals, patients 

with tumors other than lip, lung, 

larynx-pharynx. 

Random sample of 5003 admissions; 

questionnaires from Hines refermls for 1942-S; records lneluded smoking history. 

23.9% non-smokers 

59.2% cigarettes 

10.0% cigars 

11.5% pipes 

Clinic patients with cancer of the Clinic patients of same age group 

with other diagnoses. 

Medical history and questionnaire 

in clinic. 

22.2% non-smokers 

litrym. 

83.2% cigarettes 

4.4% cigars 

10.6% pipes 

7.5% non-smokers 

Admissions to hospitals in N.Y.C. 

Missouri. New Orleans, Chicago: patients with diagnosed 

laryngeal tumors, 1933-1943. 

4.0% non-smokers 

EQ.l% cigarettes only 

2.2% cigars only 

4.3% Pipe only 23.9% some combination 

.- 

From same set of admlssions: 

patients with illnesses other 

Sample of 2605 out of 2347 interthan cnocer. 

views (including smoking hlstory) by trained lay interviewers. 

615 

13.2% non-smokers 

53.3y0 cigarettes only 

3.4oJ, cigars only 

7.0% pipe only 

23.1% some combination 

ml 

203 

Patients with no laryngeal disease. Personal history taken in clinic. 

13.0% non-smokers 

4.3% heavy smokers 

17.0% inbalers 

Clinic patients with cancer of the 

larynx. 

0.8% non-smokers 

79.3% heavy smokers 

95.0% inhalers 

Inpatients Memorial Cancer Re. 

search Center during 1952 to 

1954, with be&-n or malignant 

epldermold tumors of larynx. 

0.5% non-smokers 

36.0% cigeiettes 

7.5?& cigars 

5.0% pipes 

Patients with other than e ldermold cancer, indlvl 2 ually 

matched controls in same instltutions. 

10.5% non-smokers 

73.7% cigarettes 

10.17~ cigars 

f.t,C pipe .i..._-,..i_ 

Trained lay interviewers. 
M 

- 

M 

M-F 

F” 

132 Laryngeal cancer petlents at Tata 

Memorial Hospital, 1952-1954. 

13.60/o non-smokers 

78.8% bidis 

5.3% cigarettes 

1.5% hooksh 

0.8% chilum 

Controls individually matctwl as for TJ.S.A. data abow. 

30.3% non-smokers 

S2.1% bidis 

4.5% cigarettes 

0.8% hookah 

2.39; chilum 

India 

Sweden 

132 Interviews for smoking and medical histories. 

-- 

-- 

_. 

-- 

-- 

, 

-- 

-- 

-- 

-- 

Schwartz et al. 1957. 121 

-ii 

Patients hospitalized from 1954 

through 1956 with laryngeal cancer, in Paris and other large 

cities. 9SYo smokers 

58Yo inhalers 

440/, roll their own cigarettes 

242 

.-- 

271 

lame time and sources; patients 

hospitalized for non-canremus 

conditions or trauma. 

84% smokers 

47% inhalers 

31% roll their own rigarrttcs 

Cases and controls individually 

matched withtn institutions; 

each member of a set questioned 

tgt;?, same trained lay interPatients at Rsdiumhemrrxt with 

squamous-cell cancer of larynx, 

from 1952 through 195n5. 

Males: 

5% non-smokers 

47% cigarettes 

17% ciears 

15”iu p;pes 

17% mixed 

Patients from same source and 

time, with cancer other than 

squamouscell of larynx. hfslrs: 

24% non-smokers 

36% cigarettes 

9% cigars 

16% pipes 

137, mixed 

By trained lay interViewers in 

hospital. 

Wynder et al. 1957-e 

Wynder et al. 1958. Cuba 

--- 

India 

-- 

‘2 Clinic patients in Havana during 1956, 57, with histologically diagnosed epidermoid cancer of 

larynx. 

1% non-smokers, M; 13% F 

62% cigarettes, M; 72% F 

20% cigars, M; 6% F 

1% pipes. M 16% nixed, M; 9% F 

M22-3 

F 214 

Same source and time; apparently Intxrview of patients in ctintc. 

patients with cancers other than 

larynx, lung, or oral cavity, 

matched for age. 

18% non-smokers, M; 6670 1’ 

45% cigarettes, M; 27% F 22% cigars, M; 6% F 

1% pipes, M lG% mirad, M; 0% F 

-~_ 

Not specified. 

- 

- 

--___- 

Tobacco histories obtained during 

1951-54, apparently by interview. 

Dutta-Choudhuri et 

al. 1959. 

M-F 582 

- 

Patients in Calcutta cancer hospital during 195(t54, with laryngeal tumor diagnosed and confirn cd by biopsy or smear. 

14.1% non-users 

77.8% cigarettes or bidi 

3.1% chew 

5.0% both 

41.7% non-users 

SZ.lY, cigarettes or bldi 

3.8% chew 

2.4% both 

-___.~ - 
TABLE ll.--Out&ne of retrospective studies of tobacco we and cancer of the larynx-Continued 

I I I I 

RefInvesti@xx and year erems 

co”ntry sex Num 

her 

-- 

Stasrawski 1960. w7) Polmd F 207 13

cases Controls 

Method of selection Numher 

Method of selection 

Patients admitted to chronic die.- M 912 Patients admitted during 1957 & 

ease hospital during 1957 & F 1813 1958 to chronic disease center 

1968 with histologfeally eon- for cmce~ous and non-caucerous 

5rmed squamous-cell carcinoma conditions presumably not reof the larynx. 

0.6% non-smokers 

lated to tobaoco consumption. 

17.3% nonanokers 

87.9% cigarettes only @4X5% cigarettes only 

1.9% pipes and/or cigars 

88.4%“hesvy smokers” 

11.1% pipes and/or cigars 

49.0%“ heavy smokers” 

96.1% inhalers 66.80/, inhalers 

30.8% smoke, F 8.4% smoke, F 

I 

Collection of data 

Author interviewed patients SW 

petted of lung cancer for smoking 

history and backgtound. 
A combination group of lung and laryngeal cancer cases was also included 

by Wynder et al. (376) and relative risks for lung cancer as well as laryngeal 

cancer among the several smoking categories were calculated. It is of interest that the risks attending the several categories of amounts of cigarettes 

smoked were similar for both lung and laryngeal cancer, but the risk of 

laryngeal cancer among cigar and pipe smokers was 2.5 times that for 

lung cancer. 

Four of the retrospective studies concerned themselves with inhalation 

practices and a significant association between inhalation of cigarette smoke 

and laryngeal cancer was noted in three of them (30, 314. 327). The 

fourth study by Wynder et al. (376) f ound an association with inhalation 

among light cigarette smokers and among pipe and cigar smokers. 

For both whites and non-whites the male-to-female age-adjusted sex ratios 

in laryngeal cancer are higher than for any other site common to both sexes 

(130). Despite the fact that the female case material is exceedingly sparse, 

at least two studies concerned themselves with laryngeal cancer in the female 

(377,388). The material in one study was adequate to establish an association 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 admission to a hospital and that this type of cancer was very infrequent among 

all cancer admissions. Smoking and drinking among adherents of this 

religious sect are uncommon. 

PROSPECTIVE STUDIES 

In the seven prospective studies previously described, laryngeal cancer has 

in each one of them been observed among smokers in frequencies in excess 

of the expected. Although in four of these studies (25, 84, 96, 97) the 

number of observed cases is so small as to weaken the stability of any calculable ratios, in the three major studies, the number of observed cases among 

cigarette smokers is reasonably large and yields ratios of 3.7 [current Hammond study (157) 1, 5.8 [Dorn (88) 1, and 13.1 [Hammond and Horn 

(163) 1. A summation of all seven studies yields a mean mortality ratio of 

5.4 (Table 1) for cigarette smokers. For five studies in which laryngeal 

cancer cases were associated with cigar and pipe smoking, the mean mortality ratio was 2.8. However, this was calculated from only nine cases 

observed and 3.2 expected (Table 24, Chapter 8). 

None of the studies currently in progress has yielded a sufficient number 

of cases of laryngeal cancer to permit analysis of smoking class categories 

by inhalation practices, duration of smoking, and age started smoking. 

However, the recently calculated material from six prospective studies (Table 

23, Chapter 8) shows a gradient of risk ratios from 5.3 for smokers of one 

pack or less of cigarettes per day to 7.5 for smokers of more than a pack 

per day. Because of the relatively low yield of cancers of this site. the 

current prospective studies (25, 84, 88, 96, 97, 157) will have to continue 

for a considerable length of time to provide answers to the other components 

of the problem. 

209 
Carcinogenesis 

So far as known, no attempts to induce carcinoma of the larynx. by to. 

bacco smoke or smoke condensates have been reported. 

Pathology 

For information about histological changes in the larynx of smokers, see 

Chapter 10, Non-Neoplastic Respiratory Diseases. 

Evaluation of the Evidence 

The 10 retrospective studies have a high degree of consistency despite the 

weakness of the control selections in one or two of them. A sufficient 

number of these studies have an adequate sample size for categorization of 

type of smoking and these all show consistency in designating cigarette 

smoking as the significant associative class. The fact that each of the 

prospective studies yielded an excess of cases among cigarette smokere 

over the number expected from the incidence among non-smokers adds to 

the level of consistency noted. Th e calculations for cigarette smoking alone. 

as well as for the combination of cigarettes, pipes, and cigars, were almost 

identical to those in the prospective studies. 

The relative strength of the association as measured by the specific mortality 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 section on lung cancer, the implication of a lower relative risk is that other 

factors of etiologic significance may be independently associated with the 

disease. That this may be true for laryngeal cancer, as it seems to be for 

oral cancer, is reasonable because alcohol consumption, though frequently 

associated with heavy smoking, appears to be associated with laryngeal 

cancer independently from smoking (376, 377). 

As with lung cancer a dose-effect of smoking is also demonstrable. The 

majority of the retrospective studies have shown a greater association 

with heavy smoking and in two of them gradients with increasing amounts of 

tobacco consumed have been elicited. The prospective studies (Chapter 8. 

Table 21) also suggest a gradient although the numbers of deaths are small. 

Inhalation, a crude indicator of exposure, has also been noted as being asssociated with laryngeal cancer in each of the studies in which such analyses were 

attempted. The parallelism with lung cancer, though not as complete because of a smaller amount of material, is remarkable. 

In an assessment of the coherence of the association between smoking 

and laryngeal cancer with the facts of the natural history and biology of 

the disease an approach similar to that utilized in the lung cancer analysis 

can be helpful. 

TIME TRENDS 

Although laryngeal cancer mortality has increased somewhat over the 

past three decades, the increase has been much less than that for lung cancer 

210 
mortality. In this regard it has also been mentioned that in at least one detailed study (376) the laryngeal cancer risk for cigarette smokers, irrespective 

of amount smoked, seems to be equal to that for pipe and cigar smokers i as a 

combined group i . Furthermore, while the per capita consumption of 

cigarettes has risen, the consumption of pipe and cigar tobacco has declined. 

In addition, there is no evidence or reason to assume that the susceptibility 

of the larynx for cancer is equal to that of the bronchus. Finally, evidence 

has also been presented (stemming from the implications of lower mortality 

ratios of smokers to non-smokers) that othe; factors may play a significant 

role in the production of laryngeal cancer, such as alcohol and inadequate 

nutrition (376 1. Thus a diminution of such other factors in time could 

well have counterbalanced. in great part. a rise which could have attended 

increased cigarette consumption. 

Tobacco chewing has also declined to such a great extent in this country 

that adequate case material among chewers is not available for analysis. 

However, evidence derived from studies amonp betel nut chewers in India 

indicates that even among smokers of cigarettes. cigars, pipes or bidis l 

the addition of tobacco to the material chetied is associated with an even 

greater risk of laryngeal cancer ( 100. 376). The evidence from the retrospective and prospective studies is compatible with the small rise in laryngeal 

c’ancer incidence observed. 

SEX DIFFERENTIAL IN MORTALITY 

As has been noted in the discussion of lung cancer, the much later advent 

of cigarette smoking among females wzould be compatible with their lower 

laryngeal cancer mortality rates. Furthermore. the negligible degree of pipe 

and cigar smoking and tobacco chewing among females would not only be 

compatible with a significantly lower risk of cancer of the larynx among 

them today as compared to males IWM: WF-- 10.8) but also with a lower 

sex ratio 30 years ago IWM: WF=6.3) (130). Assuming a reasonable 

induction period, the mortality rates 30 k-ears ago could have been a reflection of the much lower consumption of iobacco even among males between 

19OO-1910 (239). 

One cannot overlook the role of alcohol consumption in this differential. 

The greater alcohol consumption among males and a strong association between laryngeal cancer and alcohol consumption (376, 377) must be considered as contributing to the excess ratio of male to female laryngeal cancer 

mortality. 

The role of inherent sex differences (e.g.. hormonal, laryngeal anatomy) 

as determinants in the difference in mortality related to smoking cannot 

he fully evaluated from the limited information available. 

LOCALIZATION OF LESIONS 

TWO studies have dealt analytically with laryngeal cancer from the standpoint of specific localization, i.e., extrinsic vs. intrinsic laryngeal cancer 

1327, 376). (Most laryngeal cancers designated as extrinsic arise in the 

larynx proper; about 30 percent designated as extrinsic arise in adjacent 

‘Bidi (variant of biri)-a locally made cigarette of tobacco flakes rolled in the dried 

leaf of a variety of bauhinia (306). 

211 
structures such as the epiglottis, its valleculae and on the arytenoid folds.) 

In only one of these studies (376) were the data analyzed in sufficient detail to 

permit tentative interpretation. It should first be noted that intrinsic 

laryngeal cancer was more often associated with cigarette smoking, whereas 

a higher percentage of pipe and/or cigar smokers was found among extrinsic 

than among intrinsic cancers. Secondly, in both the United States and the 

Indian data referred to by Wynder, chewing of tobacco seems to be associated 

with a higher risk for the extrinsic type, implying that tobacco juice makes 

contact readily with such extrinsic structures as the epiglottis (37.6 percent 

of the extrinsic cancers were in this location). Finally, males predominate 

in intrinsic cancers of the larynx, whereas the ratio for extrinsic cancers, 

though lower, still shows an excess for the male. Thus far, the tobacco 

smoking and chewing patterns of males vs. females are compatible with 

the data on localization differences between the sexes. Extrinsic laryngeal 

cancer is relatively more common among rural than urban females. This 

evidence was presented by Wynder as indicating that some other factor 

which does not influence intrinsic lesions is operating. From some suggestive 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 unconscious inhaling, at least to the level of the larynx. Furthermore, the more 

common findings of pipe and cigar smoking among cases of extrinsic 

laryngeal cancer are compatible with exposure to tobacco juice from this 

form of smoking. And, finally, the obvious exposure to such juice from 

tobacco chewing is compatible with the preponderance of extrinsic types 

among such users of tobacco. 

Conclusion 

Evaluation of the evidence leads to the judgment that cigarette smoking 

is a significant factor in the causation of laryngeal cancer in the male. 

ESOPHAGEAL CANCER 

Epidemiologic Evidence 

RETROSPECTIVE STUDIF,S 

As with cancers of other sites, clinical impressions of an association between smoking and esophageal cancer led to more or less controlled studies 

of the two variables as early as in 1937. Ahlbom (1) studied a group of 

patients with cancers of the pharynx, larynx, and esophagus and found an 

excess frequency of cigarette and cigar smokers among the combined group. 

The first controlled retrospective study directed specifically to the esophagus was by Sadowsky et al. (301) published in 1953, the data for which 

were collected in the period 1938-43. These investigators found associa212 
tions with cigarette and with cigar smoking but only the cigarette smoking 

relationship was noted to be statistically significant. 

Since then there have been six other retrospective studies (306, 315, 325, 

329, 374, 385) (Tables 12 and 13). It should be noted, however, that one 

of these (3291 is an autopsy series with no reliable data on smoking histories. Among the five remaining studies with better data collection methods. 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 portion 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 between tobacco smoking and esophageal cancer was observed. 

The remaining study in this group is that of Sanghvi et al. (306) who 

found no significant associations with tobacco chewing alone and with cigarette and bidi smoking alone, but found a significant association for the 

combination of smoking and tobacco chewing. 

Several of the studies were concerned with the amounts of tobacco smoked. 

The Swedish study by Wynder and co-workers (385) which had demonetrated excess frequencies of cigarette and cigar smokers among the esophageal cancer cases not to be statistically significant, showed a significant excess 

of amount of tobacco smoked among the cancer cases. A later study by 

Wynder and Bross (374) found significant excesses of heavy smokers among 

both male and female esophageal cancer cases. Staszewski (325) found a 

highly significant excess of heavy smokers among the cases in his Polish study. 

Schwartz and his co-workers (315) in the most extensive study of all, found 

significantlv more smokers among cases than among controls. However, 

the differen’ce in daily amount of cigarettes smoked was not significant. 

A refinement of the data in two studies (301, 374) by classes of number of 

cigarettes smoked daily showed a gradient of increasing risks for esophageal 

cancer in both. 

Inhalation practices were explored in two of the retrospective studies (315, 

325). In neither of them was a significant difference found in percentage of 

inhalers between cases and controls. 

Relative risk ratios were calculated from the data available in each of the 

retrospective studies (Table 13). The relative risks for all smokers in these 

studies ranged from 2.1 to 4.0 for American males and 2.0 to 4.1 for American females. Data were available for calculation of relative risks with regard 

to heavy smoking in only two of the studies (32.5, 374). The Polish data 

revealed a relative risk ratio of 16:l for heavy smokers as compared with 

non-smokers, whereas the latest Wynder study revealed ratios paradoxically 

lower for heavy smokers than for the category “all smokers.” 

In view of previous studies which had revealed an association between 

esophageal cancer and alcohol consumption, Wynder and Brass (374) tested 

213 
N TABLE 12.~-Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus 

Controls 

Investigator, yew, and 

rcferfxlce 

CaSeS 

Collection of data ;‘ountrv sex 

- 

M 

- 

N 

-- 

-- 

-- 

-- 

-- 

‘urn 

her 

- 

104 

Method of wlrotion Method of selection 

White patients admitted during 

1938-43 to selected hospitals in 

N.Y. City Missouri, New Or. 

leans, and Chicago. 

ber 

615 

(1) 288 

(2) 107 

464 

115 

912 

_- 

_- 

_~ 

_- 

.- 

White patients with illnesses other 

than cancer admitted to same 

group of hospitals during same 

period. 

(1) Obtained by 4 especially trained 

lay interviewers. 

(2) 242 records out of a total of 2,847 

excluded because of incomplete or 

questionable smoking histories. 

Sadowsky et al. 1953 (301) U.S.A. 

Sanghvi et al. 1955 (306) India 

-- 

-- 

-- 

-- 

, 

, 

-- 

_- 

M 73 Consecutive cllulc admissions to 

Tata Memorial Eospital, Bombay. 

Consecutive cllnlc admissions of 

patients without cancer. 

Consecutive admissions of patients 

with cancers other than intraoral 

By meaus of ‘detailed questionary’. 

No other details given. 

U.S.A. 

or esophagus. 

Btelner 1958 (329) “F+ 

M 

116 Consecutive cases studied at autopsy In University of Chicago 

Dept. of Pathology during lSOl1954. 

Autopsy cases comprising: 

116stomach cancer 

116 lung caner 

116 mallguant lymphatic dis. 

ll;e;z&;ithout any malignant 

Matched by sge, sex. race and year 

of autopsy. 

Not clear how smoking histories were 

obtained-from hospital records, 

probably, which indicates they 

may be inadequate. 

Wynder et al. 1957 (365) Sweden 39 

- 

24 

- 

362 

Patients admitted to Radlumhemmet, Stockholm during 1952-1955. 

Patients admitted to same hospital 

with cancer of skin, and head and 

neck region other than squamous 

cell cancer, leukemia, colon, other 

sites. No matchinn. 

No details given on method of data 

collection. No age adjustment or 

matching. Avcmge age of ranter 

patients=60.5 and of wntrols=53. 

M 

M 

Patients admitted to Oncologlcal 

Institute during 1957-59. 

Other patients sent to Institute with 

symptoms probably not etiologitally connected either with smoking or with diseases of esophagus, 

stomach or duodenum. 

Staszewskl1960 (326,327) Poland 

Schwartzet al. 1961 (315) France 362 

---- 

Interviewed by team of special interviewers who iuterviewrd the 

largest proportion possible of al: 

caucer patients. Cases and 

matched controls inturviwved by 

same per.wn. 

Realthy individuals admitted to 

same hospital because of work or traffic accidents--matched by 5 

yr. age group and time of admission. 

Admisions to hospitals in Paris and 

a few large provincial cities since 

1954. 
215 
- 

- 

- 

216 
this independent variable. Since a relationship between alcohol consumption 

and tobacco use is known to exist, these investigators analyzed the relationship between tobacco consumption and esophageal cancer after adjusting for 

alcohol intake. Of extreme interest is their observation that in the absence 

of alcohol consumption there was no association with tobacco consumption, 

but in the presence of alcohol consumption an increasing relative risk with 

increasing number of cigarettes smoked was apparent. In the presence of 

alcohol consumption, a high association between esophageal cancer and cigar 

and pipe smoking was also noted. 

PROSPECTIVE STUDIES 

In the seven prospective studies (Table 1 of this Chapter I some deaths 

from esophageal cancer have been accumulated to date. The mortality ratios 

range from 0.7 in the California Occupational study to 6.6 in the Dorn study. 

Combining the observed deaths from this cause for all seven studies yields 

a total mortality ratio of 3.4. The stability of the ratios for three of the 

studies (84, 96, 97) is of low order, for they are based on only 7, 4 and 9 

cases respectively. The mean mortality ratio for cancer of the esophagus in 

cigar and pipe smokers is 3.2, second only to that for cancer of the oral 

cavity, 3.4 (Table 24, Chapter 8). This ratio is based on 33 cases of esophageal cancer in cigar and pipe smokers in five studies. 

Recently calculated data from six prospective studies (Table 23, Chapter 

8) reveal a gradient of risk ratios from 3.0 for smokers of one pack or less 

of cigarettes per day to 4.9 for smokers of more than a pack per day. It is 

obvious that with so few cases to date, further cross-classification by duration 

of smoking, inhalation practices, and discontinued smoking is not feasible 

at the present time. 

Carcinogenesis 

So far as known, no attempts to induce carcinoma of the esophagus by 

tobacco smoke or smoke condensates have been reported. 

A further note, indicative of needed research, is in order. In the recent 

Wynder and Bross study (374) these authors report that injection of ethyl 

alcohol into or painting of ethyl alcohol on the skin of mice promotes the 

carcinogenic activity of cigarette smoke condensate when applied to the skin. 

No data are presented in evidence. 

Evaluation of Evidence 

Five of the seven retrospective and six of the seven prospective studies 

show significant associations between esophageal cancer and tobacco consumption. One prospective study showed a mortality ratio less than unity 

(%) but this is based on only four observed cases among smokers. Although 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 retrospective studies fall within the same range of mortality ratios as in the 

prospective studies. Th is 1 eve 1 o f consistency is not to be ignored although 

few of the studies revealed increasing gradients of risk with amount smoked. 

217 
Here, only two studies (301, 374) and possibly a third retrospective study 

I 385) show such a gradient. Whether this subclass inconsistency is due to 

inadequacy of data because of small sample size cannot be determined at the 

present time. 

The prospective studies have, however, revealed such a gradient for amount 

of cigarette smoking when the data of six studies were combined. Although 

not as marked a gradient as in the lung cancer group, the increase in risk for 

esophageal cancer among smokers of more than a pack a day is greater than 

for laryngeal and oral cancer. 

Inhalation data are extremely sparse but in the two studies in which the 

data were analyzed (315, 325), no correlation could be found. This is compatible with an hypothesis that postulates an action on esophageal mucosa by 

swallowing of tobacco condensates or tars. Evidence for this is lacking, but 

the associations between esophageal cancer and several‘ forms of tobacco use, 

viz., cigarette, cigar and pipe smoking and tcibacco chewing, would support 

such an hypothesis. It is also supported by the fact that the mortality ratio 

for cigar and pipe smokers, though based on a relatively small number of 

cases, is approximately equal to the ratio for cigarette smokers (3.3 vs. 3.0). 

Mortality from esophageal cancer in the United States has shown a tendency to rise slightly among whites in the last 30 years; non-whites show a 

greater rise, but this is usually attributed to improvement and increased 

availability of diagnostic facilities. The smallness of the rise does not negate 

the significance of an association with tobacco use, some forms of which have 

been concurrently rising. This has b een discussed earlier but it should be 

emphasized that declines in other environmental factors may counterbalance 

the otherwise rising influence of the variable under study. Since neither 

prospective nor retrospective studies were executed in the decades of 1910- 

1930, conjectures on such an hypothesis are speculative. Inasmuch as the 

interaction between alcohol and tobacco use is documented in only one 

study, it would at the present time be unwise to attempt any more detailed 

evaluation of the relationship of tobacco use to trends in the incidence and 

mortality of esophageal cancer. Suffice it to say that, if the component of 

tobacco use involves the swallowing of tobacco juice, then the time trends in 

types of tobacco use over the past 50 years are relevant and not incompatible 

with the hypothesis. 

Conclusion 

The evidence on the tobacco-esophageal cancer relationship supports the 

belief that an association exists. However, the data are not adequate to 

decide whether the relationship is causal. 

URINARY BLADDER CANCER 

Epidemiologic Evidence 

RETROSPECTIVE STUDIES 

The experimental work of Holsti and Ermala (177) in 1955 prompted 

the first retrospective study of the relationship between smoking of tobacco 

218 
and cancer of the urinary bladder. After the lips and oral mucosa of albino 

mice of a “mixed known strain” were painted with tobacco tar daily for five 

months, 10 percent of the animals developed malignant papillary carcinomas 

of the urinary bladder. No carcinomatous change was observed in the 

oral cavity. The report of this work led Lilienfeld (215) to undertake a 

study of bladder cancer cases admitted between 1945 and 1955 at Roswell 

Park Memorial Institute. Before being seen by clinicians for diagnosis, all 

patients at this institution are interviewed regarding smoking histories. Lilienfeld found a significant association between cigarette smoking and 

urinary bladder cancer among males but not among females. This study, 

though carefully controlled, was done before much knowledge of cigarette 

smoking relationships to other diseases had accumulated and before the 

results of the earliest prospective study had revealed a relationship of smoking to urinary bladder cancer. Thus, information on amount smoked. age 

at onset of smoking, duration of smoking, and inhalation was either not 

collected or not analyzed. 

Only three additional retrospective studies (220, 315, 389 ) have appeared 

since Lilienfeld’s publication in 1956. The methodology and results of 

these studies are presented in Tables 14 and 15. 

All of these investigators found a significant association between cigarette 

smoking and urinary bladder cancer in males. Three of these studies (215. 

220, 389) concerned themselves with the study of female cases as well. 

Two of them found no relationship between smoking and urinary bladder 

cancer in females, but one study (3891 found the relationship to be 

significant. 

Three of the studies examined other forms of smoking. Schwartz et al. 

(3151, in France where cigar smoking is negligible, separated pipe smokers 

and mixed smokers from cigarette smokers and found only a suggestion 

of an association with pipe smoking, but the number of cases in this category were too few for meaningful inferences. Lockwood (220) found significant associations between both pipe and cigar smoking and urinary 

bladder cancer in the male. Wynder and co-workers i389) found no excess 

frequencies of pipe-only and cigar-only smokers among the urinary bladder 

cases. Here, too, the number of such smokers was even smaller than in the 

Danish study by Lockwood. 

Only two studies (220, 389) are concerned with amount oj smoking. In 

each, a significant excess of heavy smokers was noted among male patients 

with urinary bladder cancer. In the Danish study, female cases and controls had equal proportions of heavy smokers but Wynder found only a 

suggestion of an excess of heavy smokers among the cases (Table 15). 

ln?dztion was examined in two studies, the French and the Danish (220, 

315). Schwartz et al. (315) found a profound effect of inhalation on the 

association between smoking and urinary bladder cancer. When comparisons between cases and controls were made in each of the classes of amount 

smoked, the bladder cancer cases showed a greater frequency of inhalers 

in each class. When inhalation was controlled, the effect of amount of 

cigarette smoking disappeared. Thus the implication is clear that the essential relationship is between inhalation of either cigarette or pipe smoke 

with urinary bladder cancer. Lockwood (220) found statistically signifi219 
TABLE 14-S wnmury of methods used in retrospective studies of smoking and cancer of the bladder 

Lilienfeld et al., 1956 

(215). 

sc;l15ytc et al., 1931 

Lockwood leSl(220). 

W ynder 1963 (389). 

(To be published). 

- 

.- 

I 

.- 

.- 

.- 

1 

- 

lJ.6.A. 

Denmark 

U.S.A. 

&x 

M 

F 

- 

M 

- 

F” 

- 

M 

F 

M 

F 

- 

i 

- 

N 

_- 

-- 

- 

‘urn. 

ber 

- 

321 

116 

- 

214 

- 

% 

- 

200 

60 

100 

20 

- 

. 

.- 

-- 

_- 

_- 

- 

CaSeS I controls 

Method of selectlou Number Method of selection 

AdmIssions to Roswell Park 

Memorial Institute. 1945-55 over 

45 yrs. of age. 

337 No-diseese patients. 

287 Prostate cancer. 

&me as males 

Admissions to hospitals in Paris and 

* few large provincisl cities since 

1954. 

109 Benign bladder mndltions. 

317 Nodisease patients. 

763 Breast cancer 

-- 

214 Healthy individuals admitted to 

same hospital because of work or 

traffic accident-matched by 5 yr. 

age group. & admitted during 

same time to same hospital as I I case8. 

All bladder tumors reported to 

Danish Cancar Roglster during 

1942-1956 and living at time of 

interview in and 

Fredericksburg. 

Copenhagen 

282 A. From election rolls matched with 

37 ca8es according to sex, age, marital 

status, occupation and residence. 

33. Another control group obtained 

from sample of Danish Morbidity 

Survey (1952-53 & 54) compared 

with respect to smoking histories. 

First Phase 

Admission to several hospitals In 

N.Y.C. during January, 1957- 

200 Admission to same hospitals (exDecember, 1960. 60 

;plu” cancer of respiratory sysupper alimentary, tract, 

mydcardial infarction). Matched 

second Phase 

by sex and nge. 

A&nssion to same hospital during 100 &me 85 above. 

20 

- 

Collection of data 

_- 

Interview of pallents by groups of 

interviewers at time of 1st visit to 

Institute hefore seen and diagnosed 

by physicians. 

Cases-59 c8.m interviewed b 

Clemmesen and 310 hy Lockw rxxf 

Election Roll Controls-2 inter: 

viewed by Clemmesen and 367 by 

Lockwood. 

Trained Interviewers. 
TABLE 15.~Summary of results of retrospective studies uf smoking (irrespective oj type) and cancer of the bladder 

Percent non-smokers Percent heavy smokers Percent inhalers among Relative risk: ratio to 

smokers non-smokers 

Investigator, year, and reference sex 

CaSeS Controls CaSeS controls CWZS control3 All smokers Heavy 

smokers 

____ 

Lillenfeldet al., 19% (215) ____________ -.__ _____..____ {f 29 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ _ _ - 

i! 

2.3 ._._....______ 

83 .___________._ . .._..._..__.. ..~_~ . . . . . ..__ ._..______.... 1.4 .._____...___- 

-- -- ~__- ___-- -~--__-.-- 

Schwartz, 1961 (315) ._____.__...._______---.-----.-.- M 11 20 ___- ..._...... ._.__.._..---- 54 37 2.0 __..._..._____ 

-- -- -___ 

Lockwood, 1961 (nO)-- ___.._._..._..._.___..-------- {F 30 15 33 9 2. 1 2.4 

4 . . . .._........ ~__......_.... 

iM G zi 4 

1. 5 1.0 

Cancer cases .____ __..__...___________---.. _.__. g 

11 ______ ___._._ _________...._ . ..__......-.- 24 _ _ _ _ _ _ _ _ . _ _. _ . _ _ _ _ - 

69 _______ __..__ .__________.__ __________.... 14 ..~ . . .._._.... . . .._____ ____ ______... ---__ 

PapillomaCases~-~...................~~~---~..~ F 8 ._.___________ . . . ..-.__....- ._ .-.-- ------- 31 ._............ ..~ .._... .~... . . . . . .._______ 

55 ____._____..__ __._._______.. . . . . . .._ . . . . . 14 .____.._._.._. __......._.... ...~.._...---- 

-- p-p__--__------- -- 

Wynderet al., 1963 (389) (Phase A and B combined). {F 47 23 . . . _ _ _ _ _ _. . 2.9 3.0 

6: ii 6 0 -. _ . . _ . . _ _ _ 3.9 __.__. ..___.. 
cant relationships with inhalation also but, unfortunately, he did not attempt 

cross-classification of inhalation with amount and type of tobacco smoked. 

Schwartz analyzed this even though his numbers were smaller and his sample 

more heterogenous in tobacco habits than Lockwood’s. 

Only one study analyzed data on age at onset of smoking. Lockwood 

(220) found that his patients began smoking larger amounts of tobacco 

at an earlier age than did his controls. 

Other variables were examined in three studies, not only as a check on 

possible biases and influence of confounding variables on the association 

(220, 315) but also as a means of eliciting other environmental factors 

(389). In the latter study by Wynder, which included analysis of occupation, 

an excess of leather workers and shoe repairers was noted among the urinary 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 original 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 

unity 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. 

TARLE ISA.-Summary of results of retrospective stud& of cigarette smoking 

and cancer of the bladder in males 

- 

Perrmt Cigar&r Smokers Relative Risk: 

!nrestieator and Classification of Cigar&t? Smoking __- Ratio of Cigarette Smoker.s 

CtLSfS Controls to Non-Smokerr 

__--- -.__~ ----__ ----- 

I.iiicnfcld (ciparette eG other) (215) 1066 Rl 41 2.0 

- 

Schnartb (ciparrttr only) (315) 1961 <s3 70 2. 1 

Lockwood (Ciearettc is main modr of smoking) (220! l9fil 30 15 24 

Wyndw (ricsrettr .G other) (389) 19+% s5 63 3.3 

PROSPECTIVE STUDIES 

Six of the seven prospective studies showed bladder cancer mortalityratios ranging from 1.7 in the current study by Best et al., in Canada’(25j 

to 6.0 in the California occupational study of Dunn et al. (96). The only 

disparate finding is in the Doll and Hill study 184) where, on the basis of 

12 bladder cancer deaths among the physicians of the study. the mortality 

ratio is 0.9 (Table 1 I. 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, 157, 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 
not presently available. Some information on a gradient for amount of 

cigarette smoking was obtained from previously published data of Dom 

(88) ; 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.‘i5. In the original 

Hammond 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, 3.5). Data for cancer 

of the bladder per se were not then available. In the Dorn study, even at 

the I959 mark in its progress, a distinct gradient was noted. These data 

have recently been augmented by calculations of up-to-date data from six 

of the prospective studies. Th ese 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 the 

ratio for smokers of more than a pack is 3.1 (Chapter 8. Table 23). 

Carcinogenesis 

In a study whose original aim was to determine the effect of tobacco tars 

on the tissues of the oral cavity in mice, Holsti and Ermala (177) 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 classified as carcinomas, though no metastases were observed. Benign papillomatoses were observed in 87.5 percent of the animals. In a similar study, DiPaolo and Moore (75) observed only slight 

hyperplasia of the mucosa, but in one mouLw anaplastic sarcoma of the urinary bladder was encountered. Th e significance of these experiments as well 

as earlier ones reported by Roffo ( 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 urinary bladder in males. Two investigators who studied the dose-eject 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 prospective 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 elicited from 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: will be necessary. Suffice it to say that in the 

714-422 O-62-16 223 
Lilienfeld study, all interviewing for smoking history was done on all admissions for any complaint prior to diagnosis. In the Schwartz study, matched 

healthy controls were utilized, comparisons were made for area of residence, 

family statL:s, and occupation; and these variables were tested for relationship to smokin= 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 

j)robably neutralized. Furthermore, the results of the early phase of the 

study were consistent with the findings in the entire study reported on 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 criteria of malignancy in these tumors exists, it is possible that this type of 

tumor was similar to those diagnosed as cancers in other countries. Nevertheless, Lockwood’s group did analyze the material separately and found 

the smoking relationship to both benign and malignant tumors to be essentially the same. These authors also utilized a second control group derived 

from the Danish Morbidity Survey. Their study control 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 consumption. marital status. housing, history of pyelitis and cystitis, sulfonamide 

consumption. and other variables. 

The Wynder study (389) involved controls matched by age and sex and 

hospital of admission. Variables of comparison included race, marital status, 

religion. place of birth. dietary habits, education, residence, alcohol consumption, weight, oral hygiene, blood group, circumcision status, occupation, and 

genito-urinary diseases. Cases and controls were similar for all variables 

except for occupation and genito-urinary diseases. The excess of leather 

workers and shoe repairers among the bladder cancer cases has been noted 

above. The bladder cancer cases also had a higher frequency 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 cancer in females. This latter association is weakened, however, by the equivocal finding of only a slight excess of heavy smokers among the cases. A 

second inconsistent finding is an 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 characterize them as being different from cigar smokers in the United States. Finally, the urinary bladder cancer mortality ratio in the Doll and Hill prospective 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 cases in a single study (389) is the fact that no association exists 

for women in two other retrospective studies. If cigarette smoking is ac224 
tually associated with male bladder cancer, should not an association be found 

in the female, as with lung. larynx, oral, and possibly esophageal cancer? 

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 “swamping” 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 looked 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 with urinary bladder cancer. 

Little can be said regarding the coherence of the association beyond the 

scanty data on dose-effect. Furthermore, adequate information is lacking 

for an intelligent discussion of the sex differential, which is the lowest for 

any of the cancer sites for which an association. direct or indirect, with smoking has hitherto been suspected. 

An urban-rural differential is virtually non-existent in urinary hladder 

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. DiPaolo 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 forthcoming results on female subjects in the current Hammond prospective study 

will be necessary to provide more nearly adequate data in urinary bladder 

cancer. 

Conclusion 

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. 

STOMACH CANCER 

Epidemiologic Evidence 

RETROSPECTIVE s~uDn3s 

Very little interest in the relationship between smoking and gastric cancer 

seems to exist since only four (94, 193, 315, 325) retrospective studies have 

appeared in the literature since 1946. The methodologv and findings of 

these studies have been summarized in Tables 16 and 17. Of the four studies, 

two (94, 315) failed to find any association between smoking and gastric 

225 
TABLE 16.4 wnmary of methods used in retrospective studies of smoking and cancer of the stomach 

!wntrJ 

--~ 

3.S.A. 

__ 

Sex 

d&F 

- 

I 

_- 

_- 

-- 

-- 

u 

- 

U 

- 

vo. 

- 

4Q 

- 

66 

G 

z-i 

T C%%S Controls 

Method of selection 

investigator, year. and 

reference 

c Collection of data 

-- 

: I 

-- 

1 J.8.A. 

Staszewskl 19fH (327). - Pdmd 

-. 

-. 

h 

-- 

A 

-- 

I 1 

-- 

l E 

- 

?atients admitted to Oncological 

Institute during 1957-59. 

lee TABLE 11 

_- 

1 

-- 

-- 

-- 

-- 

-7- 

Method of selection 

_I_- 

lot clear. Patients fn Dept. of 

Surgery, Univ. of Chicago. 

Vat clear. Patients without gastric 

tumor. 

,dmfssions to Raswell Park Memorid Inst., 11/48-8/51, 25-74 

yews of age. 

-- 

I 

-- 

1 

-- 

, 

Not speciffrd 

Patients admitted to Rowe11 Park 

during same time period in following 4 dfagnostlc groups: 

(1) Digesttve canox other than 

esophagus or stomach. 

(2) Camer+ther than digestive-respiratory, urinary, skin, 

hemat. 

(3) Non-tumor dfag. of digestive 

system other than esophagus or 

Questioned by trained fntervlewen 

sromacn. 

(4) Non-tumor diag. other than 

dlgestfve-respiratory, urinary, 

skin, hemat. 

Each control group matched to 

mncer group by age and populstion size of place of residence. 

See TABLE 11 1 See TA-BFE 11: ‘IJvo-thirds of +a 

I Patients hospitalized from 1964-1956 See TABLE 11 

with gwtrlo cancer in Paris and 

other loge citiar. 

Dunham 6r Bnmwhwb 

1946 (94). 

Krsus et al., 1957 (19% 

Schwartz et al., 1961 (316). FrUlCB 
TABLE 17.~Sm.mary of results of retrospective studies of smoking and cancer of the stomach 

Investigator, reference, and year 

Percent non-smokers Percent heavy smokers Percent inhalers among 

smokers 

---- -- 

CaSeS Controls cases Controls ClLWS Controls 

- 

Dunham and Brunschwig lQ46 (Q4) ____ -- .__.__....__....._ 

-- 

47. b 47.b ~..- . . . ..__.__ .____.____.... __.......... ___....... ~.~~. 

t3tawewski1880(325) ___. -.~...- . .._..._ -.- _...._...__...... 12. 6 13 76.8 59 38 2 30 I_--- ----~- I 

Bchwarte et al. lwI1 (316) _____..........._..._______________ 16 17 Total clgarcttes smoked 37 34 

diiily 

14.6 15.3 

Relative risk: ratio to 

non-smokers 

All Bmokers Heavy 

Smokers 

0 ..~~ . . ..------ 

-- 

1.3 ._._..__._.... 

1.5 I 2.1 
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 

several possible etiological factors (94, 193) ; the other two were specifically 

directed to the role of smoking i315, 325). The relative risks as calculated 

are not significantly different from unity. 

PROSPECTIVE STl’DIES 

The seven prospective studies brought up-to-date (except for the original 

Hammond and Horn study) have yielded a total of 413 deaths from gastric 

cancer. The mean gastric cancer mortality ratio for the seven studies is 

calculated to be 1.4. This is obviously lower than for any of the sites 

described earlier. The individual studies, however, with fairly adequate 

numbers for stability, show a range of mortality ratios from 0.8 in the 

Dunn, Linden, Breslow occupational study (96) to 2.3 in the Hammond 

and Horn study (163) (Table 1 of this chapter). The Hammond and Horn 

ratio is not statistically significant (pzO.12) (163). 

Two of the earlier reports (84,88) provide information on mortality rates 

or mortality ratios for the several cigarette smoking classes by amount 

smoked. In neither of these is any gradient apparent. 

For cigar and pipe smokers the combined studies provide a mean gastric 

cancer mortality ratio of 1.1 (Table 24, Chapter 8). 

Carcinogenesis 

Squamous cell carcinoma has been produced in the forestomach of mice 

by the oral administration of various polycyclic aromatic hydrocarbons (8, 

19, 59, 113a, 223, 276, 308, 334, 364, 368) including benzo (a) pyrene (19, 

59, 276, 364). It should be noted that the forestomach of mice and rats is 

covered with squamous epithelium extending down from the esophagus. The 

incidence of such cancers in mice varies with the strain used. Stewart and 

Lorenz (333) produced the same type of cancer in the forestomach by 

injecting 20-methylcholanthrene intramurally. 

Rats also develop squamous cell tumors in the forestomach after prolonged 

oral administration of carcinogens (249). 

Adenocarcinoma has been produced in the glandular stomach of mice and 

rats by the intramural injection of carcinogenic hydrocarbons (17, 19, 187, 

339) or by inserting a silk thread impregnated with 2-methylcholanthrene 

into the glandular stomach wall between the serosa and mucosa (332, 333). 

Attempts at production of cancer of the stomach with tobacco tars or 

condensates have not been successful (294). 

Eualuation of the Evidence 

Squamous and adeno-carcinomas have been produced experimentally in 

mice with benzo (a) pyrene and dibenz (a,h) anthracene injected directly into 

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 

228 
mortality ratio. In fact, the mean gastric cancer mortality ratio for cigarette 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 CONCI.USIOSS 

Cancer deaths per year increased seven-fold (in the United States death 

registration area of 1900) between 1900 and l%fLfrom 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 lung cancer is attributable to improvements 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 death rate has taken place. About 5,700 women and 33,200 

men died of lung cancer in the United States in 1961; as recently as 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 tenyear period) is scrutinized over successive decades, its lung cancer mortality 

rates vary directly with the recency of the birth of the group: the more recent 

the cohort, the higher the risk of lung cancer throughout life. Within each 

cohort, lung cancer mortality apparently increases unabated to the end of the 

life span. The pattern would suggest 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 themselves, 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 induced 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 applied to the lung or the tracheobronchial tree of experimental 

animals have not been successful, the administration of polycyclic aromatic 

hydrocarbons, certain metals, radioactive substances, and certain viruses have 

been shown to produce such cancers. The characteristics of the tumors produced 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 

man are susceptible to the carcinogenic action of some of the same polycyclic 

aromatic hydrocarbons that produce cancer in experimental animals 

Neither the available epidemiological nor the experimental data is adequate 

to fix a safe dose of chemical carcinogens for men. 

The systematic evidence for the association between smoking and lung 

cancer comes primarily from 29 retrospective studies of groups of persons 

with lung cancer and appropriate “controls” without lung cancer and from 

7 prospective studies (described in Chapter 8). The 29 retrospective studies 

of the association between tobacco smoking and lung cancer (summarized 

in Tables 2 and 3 of Chapter 9) varied considerably in design and method. 

Despite these variations, every one of the retrospective studies showed an 

association between smoking and lung cancer. All showed 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 controls. 

The differences are statistically significant in all the studies. Thirteen 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 asso’ciationbetween smoking and lung cancer increased as the amounts of smoking increased. Ex-smokers generally showed a lower risk than current smokers 

but greater than non-smokers. Relatively few of the retrospective studies 

have dealt with “age started smoking,” but all except one of these studies 

found that male lung cancer patients began to 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, 

from retrospective studies, the relative risks of lung cancer for 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 2.4-to-l for light smokers to as much as 34.1-to-1 

for heavy smokers, with most of the ratios between these two extremes. 

All seven 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 

total lung cancer death rates has increased with the ongoing progrm of 

the studies. Depending on the kind of population studied, the relative risks 

of lung cancer for current cigarette smokers in America compared 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 non230 
smokers. The mortality ratios increase progressively with amount of smoking: the pivot level appears to be 20 cigarettes a day. For those who smoke 

pipes and /or cigars (to the exclusion of ciparettes 1, the lung cancer ratios 

are lower than for any of the cigarette smokir;? classes including combinations of cigarettes with pine and/or ciears. 

In extensive and controlled blind studies of the tracheobronchial tree of 

402 male patients. it h-as 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 non-smokers and patients 

without lung cancer. The epithelial changes ohserved are I 1 i loss of ciliated 

cells, (21 basal cell hyperplasia (more than two layers of basal cells), and (3’1 

presence of atypical cells. Each of the three kinds of epithelial changes was 

found to increase with the number of cigarettes smoked. Extensive atypiral 

c,hanges were seen most frequentlv in men who smoked two or more packs 

of cigarettes a day. Men who smoke pipes or cigarettes have more epithelial 

changes than non-smokers but have fewer changes than cigarette smokers 

consuming approximately the same amoliot of tobacco. It may be concluded. 

on the basis of human and experimental 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 with the increase of lung cancer in 

the male population, and that a significant relationship exists between smoking and the epidermoid and anaplastic types. In several studies, adenocarcinemas 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 crude indirect indicators as well as by the direct measures 

(retrospe:tive and prospective studies) described earlier. Indirect measureS 

include: a parallel increase in lung cancer mortality rates and in per capita 

consumption of tob’acco; disparities between male and female lung cancer 

rates and the corresponding differences between 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 of population. 

Careful analysis of thee studies demonstrates that neither diagnostic errors 

nor classification errors in terms of amount smoked are of sufficient si7e 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 lung 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, 

provide an adequate test: the association is consistent; no prospective study 

and no reasonably designed retrospective study has found results to the contrary. In the nine retrospective studies for 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 
&se 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 with non-smokers. 

average smokers of cigarettes have approximately a 9- to lo-fold risk of 

developing lung cancer and heavy smokers at least a ZO-fold risk. 

An important criterion for the appraisal of causal significance of an association 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 investigated. The probability that genetic influences might underlie both the tendency toward lung cancer and the tendency to smoke were 

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 conditions that existed half a century ago. The assumption that the genetic 

constitution of man could have changed gradually, simultaneously, and 

identically in many countries during this century is most unlikely. Moreover, the risk of developing lung cancer diminishes when smoking is discontinued, although the genetic constitution must be assumed to have 

remained the same. 

It has been recognized that a causal relationship between cigarette smoking and lung cancer does not exclude other factors. Approximately 10 

percent of lung cancer cases occur among non-smokers. The available evidence 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 industries-notably chromate, nickel processing, coal gas, and asbestos-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 differences in lung cancer mortality 

risk, though small and accounted for in part by differences in smoking habits, 

imply that intensity of urbanization 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 relationship with lung cancer. 

Conclusions 

1. 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. 

2. The risk of developing lung cancer increases with duration of smoking 

and the number of cigarettes smoked per day, and is diminished by diicontinuing smoking. 

232 
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 warrant 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. 

In 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 oral cancers by number of pipefuls. No gradient by amount smoked was 

noted for cigarettes. 

The seven prospective studies show that cigarette smokers have proportionately 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 smokers compared with non-smokers, oral cancer has the highest mortality ratio, 

3.3, of all causes of death, exceeding cancer of the esophagus, larynx, and 

lung. 

Cancer of the oral cavity has not been produced experimentally by the exposure of animals to tobacco smoke or to carcinogenic aromatic polycyclic 

hydrocarbons except in the special case of benzo (ai pyrene and other hydrocarbons on the cheek pouch of the hamster. Leukoplakia was reported to 

have been induced by the injection of tobacco smoke condensates into the 

gingiva of rabbits. A strong clinical impression links the occurrence of 

leukoplakia of the mouth with the use of tobacco in its various forms. 

Conclusions 

1. The causal relation of the smoking of pipes to the development of cancer 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 
In each of the seven prospective studies, laryngeal cancer has been observed 

among smokers in frequencies in excess 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 mortality 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 

loads indicate that the real value of the relative risk may approach that for 

lung cancer. As with lung cancer, a dose-effect of smoking is also demonstrable. The majority of the retrospective studies have shown a greater 

association with heavy smoking. 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. 

ESOPHAGUS 

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 3.2, 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 day to 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 animals developed carcinoma of the 

urinary bladder. This experimental work led to four retrospective studies, 

all of w-hich found a significant association between cigarette smoking and 

234 
urinary bladder cancer in males. Two of the studies also found 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 rat&-cigarette smokers to non-smokers-for all 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 association between cigarette smoking and 

urir?ary 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 often than non-smokers, but 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 stomach 

cancer. 

REFERENCES 

1. Ahlbom, H. E. Priidisponierende Faktoren Fiir Plattenepithelkarzinom in Mund, Hals und Speiserchre. Eine Statistische Untersuchung am Material des Radiumhemmets, Stockholm. Acta Radio1 

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 Foundation Symposium on Carcinogenesis. J&A 

Churchill, Ltd., London, 1959. p. 12-25. 

3. Andervont, H. B. Further studies on the susceptibility of hybrid mice 

to induced and spontaneous tumors. J Nat Cancer Inst 1: 135-45, 

1940. 

4. Andervont, H. B. P u 1 monarv tumors in mice. VIII. The induction 

of pulmonary tumors in Lice of strains D, M, C57 brown and C57 

black by 1,2,5,6-dibenzanthracene. Pub Health Rep 51: 1524-9, 

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 (Wash. I 52: 212-21, 1937. 

6. Andervont, H. B. Biological background for experimental work on 

tumors. Canad Cancer Conf 1: 2-24, 1954. 

7. Arkin, H. Relationship between human smoking habits and death 

rates. Current Med Digest 22: 3744, 1955. 

8. Armstrong, E. C.. Bonser, G. M. Squamous carcinoma of the forestomach and other lesions in mice following oral administration of 

3,4,5,6dibenzcarbazole. Brit J Cancer 4: 203-I 1. 1950. 

9. Auerbach, 0. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

10. Auerbach. 0. The pathology of carcinoma of the bronchus. New 

York State J Med 49: 90&7, 1949. 

11. Auerbach, O., 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, O., Gere, J. B., Pawlowski, J. M., Muehsam, G. E., Smolin, 

H. J., Stout, A. P. Carcinoma-in-situ and early invasive carcinoma 

occurring in the tracheobronchial trees in cases of bronchial carcinoma. J Thorac Surg 34: 298309, 1957. 

13. Auerbach, O., 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 report of 41 cases. Cancer 9: 76-83, 1956. 

14. Auerbach, O., Stout, A. P., Hammond, E. C.. Garfinkel, L. Bronchial 

epithelium in former smokers. New Eng J Med 267: 119-25, 1962. 

15. Auerhach, O., Stout, A. P., Hammond, E. C., Garfinkel, L. Change 

in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. New Eng J Med 265: 253-67,1961. 

15a. Auerbach, O., 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, O., Stout, A. P., Hammond, E. C., Garfinkel, L. Microscopic 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 production of cancer by pure hydrocarbons 

part3. Proc Roy Sot [Biol] 117: 31851,1935. 

19. Beck, 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 relation 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 promoting action and its significance in the understanding of the mechanism of carcinogenesis. Cancer Res 14: 471-7, 1954. 

22. Berkson, J. Smoking and lung cancer: Some observations on two 

recent reports. J Amer Stat Ass 53 : 2838,1958. 

23. Berkson, J. The statistical investigation of smoking and cancer of 

the lung. Proc Mayo Clin 34: 20624a, 1959. 

24. Berkson, J. The statistical study- of association between smoking and 

lung cancer. Proc Mayo Clin 30: 31948,1955. 

25. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mortality in relation to smoking habits. A preliminary report. Canad 

J Public Health 52: 99-106. 1961. 

26. Bigelow, G. H., Lombard, H. L. Cancer and other chronic diseases in 

Massachusetts. Boston, Houghton Mifflin Co., 1933. 355 p. 

27. Bittner, J. J. Spontaneous lung carcinoma in mice. Pub Health Rep 

53: 2197-2202, 1938. 

28. Black, H., .4ckerman, L. V. The importance of epidermoid carcinomain-situ in the histogenesis of carcinoma of the lung. Ann Surg 136: 

44-55, 1952. 

29. Blacklock, J. W. S. The production of lung tumors in rats by 3:4 

benzpyrene, methylcholanthrene and the condensate from cigarette 

smoke. Brit J Cancer 11: 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[alpyrene 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. Insecticide 

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 strains of lung 

tumors in mice. Cancer Research 2: 116-124, 1942. 

37. Breslow, L. Special report to the Surgeon General’s Advisory- Committee on Smoking and Health. 

38. Breslow, L.. Hoaglin, L., Rasmussen, G.. Abrams, H. K. Occupations 

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 International Conference on Cancer, London, July, 1928, p. 258-68. 

237 
40. Brill, A. B., Tomonaga, M., Heyssel, R. M. Leukemia in man following exposure to ionizing radiation: A summary of findings in Hiroshima and Nagasaki, and a comparison with other human experience. 

Ann Int Med 56: 590-609, 1962. 

41. Broders, A. C. Squamous-cell epithelioma of the lip. JAMA 74: 656- 

64, 1920. 

42. Brosch, A. Theoretische und experimentelle Untersuchungen zur Pathogenesis und Histogenesis der malignen Geschwiilste. Virchow’s 

Arch Path Anat 162: 32-84, 1900. 

43. 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 cancer of the skin. Gig Tr Prof Zabo16: 38-43,1962. 

45. Buechley, R. W. Epidemiological consequences of an arsenic-lung cancer theory. Amer J Public Health 53: 1229-32, 1963. 

46. Burdette, W. J. Gradient in susceptibility of the bronchopulmonary 

tract to tumors. Surgery 38 I 1) : 27%S6, 1955. 

47. Burdette, W. J. Induced pulmonary tumors. J Thorac Surg 24: 

427-32, 1952. 

48. Burdette, 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 chimneysweeps and others. Brit Med J 1: 1341-6, 1892; 2: l-6, 66-71, 

1892. 

51. Cahnmann, H. Detection and quantitative determination of benzo(a) 

pyrene in American shale oil. J Anal Chem 27: 123M0, 1955. 

52. Carnes, W. H. The respiratory epithelium of patients with lung cancer. 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, University 

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 in the 1914-18 war might be a factor in the production of neoplasia. Brit J Prev Sot Med 9: 62-72, 1955. 

54. Castleman, B. Personal communication to the Surgeon General’s 

Advisory Committee on Smoking and Health. 

55. Clemmesen, J., Nielsen, A. The social distribution of cancer in Copenhagen, 1943-1947. Brit J Cancer 5: 159-77,195l. 

56. Clemmesen, J., Nielsen, A., Jensen, E. Mortality and incidence of cancer of the lung in Denmark and some other countries. Acta Un Int 

Caner 9: 603-36, 1953. 

57. Cohart, E. M. Socioeconomic distribution of cancer of the lung in 

New Haven. Cancer 8: 1126-9,195s. 

58. Cohen, J., Heimann, R. K. Heavy smokers with low mortality. Industr 

Med Surg 31: 115-20, 1962. 
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., Shimkin, M. B., Wynder, E. L. Smoking and lung cancer: recent evidence 

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: l&-95,1939. 

64. Cunningham, G. J., Winstanley, D. P. Hyperplasia and metaplasia 

in the bronchial epithelium. Ann Roy Co11 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: l-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. J., Fitzhugh, 0. G. Tumorogenic potential of aldrin and 

dieldrin for mice. Toxic01 Applied Pharmacol 4: 187-9, 1%2. 

69. Dean, G. Lung cancer among white South Africans. Brit Med J 2: 

852-7, 1959. 

70. Dean, G. Lung cancer among white South Africans. Report on a 

further study. Brit Med J 2: 1599-1605, l%l. 

71. Dean, G. Lung cancer in Australia. Med J Aust 1: 100>6,1%2. 

72. Denoix, P. F., Schwartz, D., Anguera, G. L’enquCte francaise sur 

l’etiologie du cancer broncho-pulmonaire. Analyse detaillee. Bull 

Ass Franc Cancer 45: l-37, 1958. 

73. de Vries, W. M. Pitch cancer in the Netherlands. Rep Int Conf 

Cancer Bristol, 1928. p. 290-Z. 

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 activity of lactones and related substances. Brit J 

Cancer 17: lOO-8,1963. 

75. DiPaolo, J. A., Moore, G. E. Effect on mice of oral painting of cigarette 

smoke condensate. J Nat Cancer Inst 23: 529-34, 1959. 

76. Doll, R. Etiology of lung cancer. Advances Cancer Res 3: l-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, 1953. 

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 O-64-17 239 
81. Doll, R. The causes of death among gas-workers with special reference 

to cancer of the lung. Brit J lndustr Med 9: 180-5, 1952. 

82. Doll, R., Hill, A. B. A study of the aetiolom of carcinoma of the lung. 

Brit Med J 2: 1271&86,1952. 

83. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. 

Brit Med J 2: 1071-81, 1956. 

84. Doll, R., Hill, A. B. The mortality of doctors in relation to their smoking habits; a preliminary report. Brit Med J 1: 1451-5, 1954. 

85. Doll, R., Hill, A. B., Gray, P. G., Parr, E. A. Lung cancer mortalit) 

and the length of cigarette ends; an international comparison. Brit 

Med J 1: 322-5, 1959. 

86. Doll, R., Hill, A. B., Kreyberg. L. The significance of cell type in relation to the aetiology of lung cancer. Brit J Cancer 11: 43-8,1957. 

87. Dorn, H. F. The mortality of smokers and non-smokers. Amer Stat 

Ass Proc Sot Stat Set 33-71, 1958. 

88. Dom, H. F. Tobacco consumption and mortality from cancer and other 

diseases. Public Health Rep 74: 581-93, 1959. 

89. Dorn, H. F., Haenszel, W., Herrold, K. Special Report to the Surgeon 

General’s Advisory Committee on Smoking and Health. 

90. Dorn, H. F., Cutler, S. J. Morbidity from cancer in the United States. 

Public Health Monogr No. 29: l-121, 1955. 

91. Dorn, H. F., Cutler, S. J. Morbidity from cancer in the United States. 

Public Health Monogr No. 56: l-207, 1959. 

92. Druckrey, H. Experimental investigations on the possible carcinogenic 

effects of tobacco smoking. Acta Med Stand Suppl 369: 24-42: 

1961. 

93. Druckery, H., Schmghl, D., Beuthner, H. Vergleichende Priifung von 

Tabakrauch-Kondensaten, Benzpyren und Tabak-Extrakt auf carcinogene Wirkung an Ratten. Naturwissenschaften 47: 605-6, 1960. 

94. Dunham, L. J.: Brunschwig. A. A review of dietary and related habits 

in patients with malignant gastric neoplasms. Gastroentrology 6: 

286-93, 1946. 

95. Dunham, L. J.: Herrold, K. M. Failure to produce tumors in the hamster cheek pouch by exposure to ingredients of beta1 quid; histopathologic changes in the pouch and other organs by exposure to 

k nown carcinogens. J Nat C ancer Inst 29: 104.747. 1%2. 

96. Dunn, J. E., Jr., Linden. G., Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Public 

Health 50: 1475-87. 1960. 

97. Dunn. J. E.: Jr.. Buell, P.. Breslolc. L. California State Dept. of Publir 

Health, Special Report to the Surgeon General’s Advisory Committee 

on Smoking and Health. 

38. Duran-Reynals. M. L. Carcinogenesis in cortisone-treated mice following vaccinia dermal infection and application of methylcholanthrene. 

J Nat Cancer lnst 29: 635-51, 1%2. 

99. Duran-Reynals: F., Bryan, E. Studies on the combined effects of fowl 

pox virus and methylcholanthrene in chickens. Ann N Y Acad Sci 

54: 977-91, 1954. 

241) 
100. Dutta-Choudhuri, R., Roy. H., Gupta, B. K. S. Cancer of the larynx 

and hypopharynz-a clinicopathological study with special reference 

to aetiology. J Indian Med Ass 32: 352-62, 1959. 

101. Eastcott. D. F. The comparative mortality experience from cancer of 

certain sites between the indigenous non-Maori population. and immigrants from Great Britain. Report of the British Empire Cancer 

Campaign (N.Z.‘i $ Branch Cancer Registration Scheme. Department 

of Health. Wellington. New Zealand, 1955. 

102. Eastcott, D. F. The epidemiology of lung cancer in New Zealand. 

Lancet 1: 37-9. 1956. 

103. Ebenius. B. Cancer of the lip: A clinical study of 778 cases with particular regard to predisposing factors and radium theory. Acta 

Radio1 Suppl 48: l-232. 1943. 

104. Eisen, M. J. Betel chewing among natives of the Southwest Pacific 

Islands. Cancer Res 6: 139-41, 1946. 

105. Engelbreth-Holm, J., Ahlmann, J. Production of carcinoma in St ‘Eh 

mice with cigarette tar. Acta Path Microbial Stand 41: 267-72. 

1957. 

106. Essenberp. J. M. Cigarette smoke and the incidence of primary neoplasms of the lung in albino mice. Science 116: 561-2. 1952. 

107. Falk. H.. Kotin. P. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

108. Falk. H. L.. Kotin. P.. Mehler, A. E. Special report to the Surgeon 

General’s Advisory Committee on Smoking and Health. 

109. Falk, H. L.. Steiner. P. E. The absorption of 3.4.henzpyrene and 

pyrcne by carbon blacks. Cancer Res 12 : 4,0-3. 1952. 

110. Falk, H. L., Steiner. P. E. The identification of aromatic polycyclic 

hydrocarbons in carbon blacks. Cancer Res 12: 30-9.1952. 

111. Falk, H. L., Steiner, P. E.. Goldfein, S., Breslow, A., Hykes, R. Carcinogenic hydrocarbons and related compounds in processed rubber. 

Cancer Res 11: 318-Z,%. 1951. 

112. Ferber. B., Handy. V. H.. Gerhardt. P. R.. Solomon. M. Cancer in 

New York State, exclusive of New York City, 1941-1960. A review 

of incidence, mortality. prohability. and survivorship. Bureau of 

Cancer Control, New York State.Department of Health. 1962. 379 p. 

113. Finkner. .4. L., Horvitz. D. G.. Foradori. G. T., Fleischer. J.. Monroe, 

J. An investigation on the measurement of current smoking by individuals. Univ N Carolina lnst Stat Mimeo Series ?To. 177. 1957. 

I13a. Firminger. H. I., Stewart. H. I,. Histopathogenesis of carcinoma of 

the forestomach of mice induced by intramural injection of ZOmethylcholanthrene i Abstract ) . Amer J Path 25: 815. 1939. Also: 

J Nat Cancer lnst 12: ,491-531.1951. 

114. Fisher. R. ,4. Cancer and smoking. Nature. London 182: 596. 1958. 

115. Fisher, R. A. Clparettes. . cancer and statistics. Centennial Rev Arts 

and Sci 2: 151-66. 1958. 

116. Fisher, R. A. Dangers of cigarette-smoking. Brit Med J 2: 297-8, 

1957. 

117. Fisher, R. A. Lung cancer and cigarettes? Nature. London 182: 

108. 1958. 

247 
118. Fisher. R. A. Smoking, the cancer controversy. Some attempts to 

assess the evidence. Oliver and Boyd. London. 2959, pp. 47. 

119. Foulds. L. Progression of carcinogenesis. Acta Un Int Caner 17: 

14856, l%l. 

120. Freedlander. B. L., French. F. A. Absence of co-carcinogenic action 

of oxidation products of nicotine in initiation of pulmonary adenomas 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 dizvgotic twins. Brit Med J 1: 109O-2,1959. 

123. Furth. J. Influence of host factors on the growth of neoplastic cells. 

Cancer Res 23 : 21-34,1963. 

124. Furth. J., Furth. 0. B. Neoplastic diseases produced in mice by general irradiation with x-rays. I. Incidence. Am J Cancer 28: 54 

65, 1936. 

125. Gates. O., Warren, S. The production of bronchial carcinomas in mice. 

Amer J Path 36: 653-71,196O. 

126. Gellhom, A. The cocarcinogenic activity of cigarette tobacco tar. 

Cancer Res 18: 510-7, 1958. 

127. Geminus [It seems to me.] Editorial on article by Sir Ronald Fisher 

(114). New Scientist 4: 440, 1958. 

128. Gilliam. A. G. Trends of mortality attributed to carcinoma of the 

lung: possible effects of faulty certification of deaths to other respiratory diseases. Cancer 8: 1130-6. 1955. 

129. Goldblatt, N. W. Occupational carcinogenesis. Brit Med Bull 14: 

13640: 1958. 

130. Gordon. T., Crittenden, M., Haenszel, W. Can’cer 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. Histogenesis of induced pulmonary 

tumors in strain ,4 mice. Amer J Path 16: 417-32, 1940. 

132. Graham, E. A., Croninger. A. B.. Wynder. E. L. Experimental production of carcinoma with cigarette tar. IV. Successful experiments with rabbits. Cancer Res 17, 105866. 1957. 

133. Graham. Saxon. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

134. Gray, S. H.. Cordonnier. J. Early carcinoma of the lung. Arch Surg 

19: 161826, 1929. 

135. Great Britain General Register Office. The Registrar-General’s Decennial 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. Cancer in 

Connecticut 1935-1951. Hartford. Connecticut State Departmeni 

of Health, 1955. 141 p. 

137. Gross, L. Oncogenic viruses. Oxford, Pergamon, 1961. 393 p. 
138. Gsell, 0. Carcinome bronchique et tabac. Med Hyg 12: 429-31, 

1954. 

139. GuCrin, M., Cuzin, J. L. Action carcinogene du goudron de fumee de 

cigarette sur la peau de souris. Bull Ass Franc Cancer 44: 387-408, 

1957. 

140. GuCrin, M.: Oberling, C. Neoplasies et cancers i virus. Paris, Amedee 

Legrand 1961. 322 p. 

141. Haag, H. B., Hanmer, H. R. Smoking habits and mortality among 

workers in cigarette factories. Industr Med Surg 26: 559-62, 1957. 

142. Haase, G. Zur Kenntnis der Leukoplakia oris und der Lippen- und 

Zungenkrebse bei Rauchern. Deutsch Mschr Zahnk 49: 881-913, 

929-76, 1931. 

143. Haddow, A. The chemical and genetic mechanism of carcinogenesis. 

I. Nature and mode of action. II. Biologic alkylating agents. In: 

Homburger, F.? ed. The physiopathology of cancer. 2 ed. NY, Hoeber, 1959. p. 565-685. 

144. Haenszel, W. Cancer mortality among the foreign-born in the United 

States. J Nat Cancer Inst 26: 37-132, 1961. 

145. Haenszel, W. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

146. Haenszel, W. Mortality and morbidity statistics on all forms of cancer. 

Acta Un Int Caner 17: 837-47,1961. 

147. Haenszel, W., Loveland, D. B., Sirken, M. G. Lung-cancer mortality 

as related to residence and smoking histories. 1. White 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: l-85, 1956. 

149. Haenszel, W., Shimkin, M. B. Smoking patterns and epidemiology of 

lung cancer in the United States. Are they compatible? J Nat 

Cancer Inst 16: 141741, 1956. 

150. Haenszel, W., Shimkin, M. B., Mantel, N. A retrospective study of 

lung cancer in women. J Nat Cancer Inst 21: 82542, 1958. 

151. Haenszel, W., Shimkin, M. B., Miller, H. P. Tobacco smoking patterns in the United States. Pub Health Monogr No. 45: l-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. Morphological changes in smokers’ lungs. Canad Med Ass J 77: 177-82, 

1957. 

156. Hammond, E. C. Lung cancer death rates in England and Wales compared with those in the United States. Brit Med J 2: 649-54, 1958. 

157. H ammond, E. C. Prospective study of 1,085,OOO men and women in 

25 of the United States aged 35-89. Unpublished data. 

243 
158. Hammond. E. C. Smoking in relation to lung cancer. Conn Med J 

18: 3-9. 1954. 

15’). Hammond, E. C. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

If& Hammond. E. C.. Garfinkel, L. Smoking habits of men and women. 

J Nat Cancer Inst 27: 419-42.1961. 

101. Hammond, E. (:., Garfinkel. L. Special report to the Surgeon General’s 

Advisory Committee on Smoking and Health. 

162. Hammond. E. C., Horn, D. S mo k inp and death rates-report on forty. 

four months of follow-up of 187,783 men. I. Total mortality. JAMA 

166: 1159-72, 1958. 

163. Hammond. E. C., Horn, D. Smoking and death rates--report on fortyfour months of follow-up of 187,783 men. II. Death rates by cause. 

JAJl.4 166: 1294-1:10$ 1958. 

163. 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. 4. Occupational cutaneous cancer attributable to certain 

chemicals in industry. Brit Med Bull 4: 389401, 1947. 

167. Herman. D. L.. Crittenden. M. Distribution of primary lung carcinomas in relation to time as determined by histochemical techniques. 

J Nat Cancer Inst 27: 1227-71, 1961. 

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 Internat Genetics Symposia, Cytologia suppl 219: 224. 1957. 

169. Heston. W. E. Genetic analysis of susceptibility to induced pulmonary 

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 F, hosts. J Nat Cancer Inst 5: 1057-71. 1951. 

172. Heston, W. E., Schneiderman, M. A. Analysis of dose-response in rclation to mechanism of pulmonary tumor induction in mice. Science 

117: 109-11, 1953. 

173. Heston, W. E., Steffee. C. H. D eve I opment of tumors in fetal and adult 

lung transplants. J Tat Cancer Inst 18: 779-93,1957. 

174. Hobson. J. W., Henry, H. eds. Pattern of Smoking Habits. Hulton 

research studies of the British social pattern. London. Hulton 

Press, 1948. 

175. Hoffman, E. F., Gilliam, A. G. Lung cancer mortality. Public Health 

Rep 69: 103342, 1954. 

176. Holland. J. J. Dissertatio inaugur. med. chir, sistens Carcinoma labii 

inferioris absque sectione persanatum. In : Wolff, J. 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. 
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 cancer. In: Raven, R. W.. ed.. Cancer. 

180. Hueper, W. C. Experimental studies in metal carrinogenesis. Is. 

Pulmonary lesions in guinea pigs and rats exposed to prolonged inhalation of powdered metallic nickel. AMA Arch Path 65: 600-7, 

1958. 

181. 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 Cancer Inst 15: 113-29, 1951. 

182. Hueper, W. C., Payne. W. W. Experimental cancers in rats produced 

by chromium compounds and their significanre to industry and 

public health. Amer Industr Hyg Ass J 20: 274-80.1959. 

183. Hueper: W. C.. Payne. W. W. Experimental studies in metal carcinogenesis. Chromium, nickel. iron. arsenic. Arch Environ 

Health 5: 445-62. 1962. 

184. Kennaway. E. L.. Kennaway. N. M. A further study of the incidence 

of cancer of the lung and larynx. Cancer 1: “60-98 1917. 

185. Kennaway, N. M.. Kennaway. E. L. A study of the inc;denre of cancer 

of the lung and larynx. J Hyg 36: 23667.1937. 

186. Khanolkar, V. R. Cancer in India in relation to habits and customs. 

In: Raven. R. W., ed. Cancer. London, Butterworth & CO. Ltd. 

1958. Chapter 11, p. 272-80. 

187. Kirby, A. H. M. Attempts to induce stomach tumors. I. The effects 

of cholesterol heated to 300” C. Cancer Res 3: 519-25. 1943. 

188. Klar, E. iiber die Entstehung eines Epithelioms Beim Menschen 

Nach Experimentellen Arbeiten mit Benzpyren. Klin Wschr 17: 

1279-80. 1938. 

189. Knudtson, K. P. The pathologic effects of smoking tobacco on the 

trachea and bronchial mucosa. Amer J Clin Path 33: 310-7: 1960. 

190. Kotin, P. The role of atmospheric pollution in the pathopenesis of 

pulmonary cancer: A review. Cancer Res 16: 375-93, 1956. 

191. Kotin, P., Wisdey. D. V. P ro d UC tion of lung cancer in mice by inhalation exposure to influenza virus and aerosols of hydrocarbons. 

Progr Exp Tumor Res 3: 18&215. 1963. 

192. Koulumies, M. Smoking and pulmonary carcinoma. Acta Radio1 

iStockholm ) 39: 255-60. 1953. 

193. Kraus, A. S., Levin. M. L.. Gerhardt. P. A study of occupational associations with gastric cancer. Amer J Public Health 47: 961-70, 1957. 

194. Kreshover, S. J.. Salley. J. J. Predisposing factors in oral cancer. J 

Amer Dent Ass 54: 509-14.1957. 

195. Kreyberg, L. Histological lung cancer types; a morphological and 

bioIogica1 correlation. Norwegian Universities Press. 1962. 92 p. 

Also: Acta Path Microbial Stand Suppl 157, 1962. 92 p. 

196. Kreyberg, L. The significance of histological typing in the study of 

the epidemiology of primary epithelial lung tumours: a study of 466 

cases. Brit J Cancer 8: 199-208, 1954. 

245 
197. Kuschner, M., Laskin, S., Cristofano, E., Nelson, N. Experimental carcinoma of the lung. Proc Third Nat Cancer Conf Detroit, 1956. 

Philadelphia, Lippincott, 1957. p. 485-95. 

198. Kuschner, M., Laskin, S., Nelson, N., Altschuler, B. Radiation induced bronchogenic carcinoma in rats. Amer J Path 34: 554, 1958. 

199. Lancaster, H. 0. Cancer statistics in Australia: Part II. Respiratory 

system. Med J Aust 1: 1006-11, 1962. 

200. Landy, J. J., White, H. J. B uccogingival carcinoma of snuff dippers. 

Arch Surg 27: 442-7,196l. 

201. Larson, P. S., Haag, H. B., Silvette, H. Tobacco. Experimental and 

Clinical Studies. Williams and Wilkins, Baltimore, 1961. Leukoplakia, p. 629-32. 

202. Ledermann, S. Cancers, Tabac, Vin, et Alcool. Contours Med 77: 

1107,1109-11,1113-q 1955. 

203. Leitch, A. Paraffin cancer and its experimental production. Brit Med 

J 2: 11046,1922. 

204. Leitch, A. Notes on chimney-sweeps’ cancer. Brit Med J 2: 9434, 

1924. 

205. Leuchtenberger, C., Leuchtenberger, R., Doolin, P. F. A correlated histological, cytological, and cytochemical study 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 

tracheobronchial tree and lungs of mice exposed to cigarette smoke. 

II. Varying responses of major bronchi to cigarette smoke. Absence of bronchogenic carcinoma after prolonged exposure. and 

disappearance of bronchial lesions after cessation of exposure. 

Cancer 13: 721-32, l%O. 

206. Leuchtenberger, R., Leuchtenberger, C., Zebrun, W., Shaffer, P. A 

correlated histological, cytological and cytochemical study of the 

tracheobronchial tree and lungs of mice exposed to cigarette smoke. 

III. Unaltered incidence of grossly visible adenomatous lung tumors 

in female CF mice after prolonged exposure to cigarette smoke. 

Cancer 13: 956-8,1960. 

207. Levin. M. L., Goldstein, H., Gerhardt, 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. II. Cancer incidence in urban and rural 

areas of New York State. J Nat Cancer Inst 24: 124357,196O. 

209. Levy, B. M. Experimental oral carcinogenesis. J Dent Res Suppl to 

No. 1 42: 321-7,1963. 

210. Lewis, E. B. Leukemia and ionizing radiation. Science 125: 965-72. 

1957. 

211. Lickint. F. Atiologie und Prophylaxe des Lungenkrebses. 2. Statistische Voraussetzungen zur KlErung der Tabakrauchgtiologie de: 

Lungenkrebses. Dresden and Leipzig, Theodor Steinkopff, 1953. 

76-102. 
212. Lickint, F. Tabak und Tabakrauch als EtioIopische Faktor des Carcinoms. Zeit f Krebsforschung 30: 349-65, 1929. 

213. Liebe, G. B. Originalabhandlungen und Uebersichten. XII. Ueber 

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, CT. 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 Helsingfors 9: l-400, 1935. [cited by Niskanen (6)] 

217. Lisco, H., Finkel. M. 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-Misleading Advertising (filter-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 l-62, 1957. 

220. Lockwood, K. On the etiology of bladder tumors in CopenhagenFrederiksberg. An inquiry of 369 patients and 369 controls. Acta 

Path Microbial Stand 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: 48-7, 1928. 

222. Lombard, H. L., Snegireff, L. S. An epidemiological study of lung 

cancer. Cancer 12: 40613,1959. 

223. Lorenz, E., Stewart, H. L. Squamous cell carcinima and other lesions 

of the forestomach in mice, following oral administration of ZOmethylcholanthrene and 1:2,5,6-d i b enzanthracene (preliminary report). 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 stain -4 mice. Cancer Res 3: 123-4 

1943. 

225. Lynch, C. J. Influence of heredity and environment upon number of 

tumor nodules occurring in lungs’ of mice. Proc Sot Exper Biol Med 

43: 186-9,194O. 

226. Lynch, C. J. Studies on the relations between tumor susceptibility and 

heredity. VI. Inheritance of susceptibilitv to tar-induced tumors in 

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 Industr Health 15: 207-14, 

1957. 

228. RIacDonald. I. G. Chinks in the statistical armor. CA 8: 70, 1958. 

229. ZIacDonald. I. G. Statement of Ian G. MacDonald, University of 

Southern California. In: U.S. Congress 85th House. Committee 

on Government Operations Legal 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 biased selection in forwardgoing surveys w-ith non-professional interviewers. J Chron Dis 4: 

2U, 1956. 

231. Manouvriez. A. Maladies et Hygiene des Ouvriers Travaillant a la 

Fabrication des AgglomCris de Houille et de Brai. Ann Hyg Pub1 

Med ep ser. 2, 45: 459-81, 1876. 

232. Mantel: N., Heston, W. E.. Gurion, J. M. Thresholds in linear doseresponse models for carcinogenesis. J Nat Cancer Inst 27: 203-15, 

l%l. 

233. Marsden, A. T. H. Betel cancer in Malaya. The Med J Malaya 14: 

162-5, 1960. 

234. Maxwell, J. L. Betel-chewing and cancer. Brit Med J 1: 729, 1924. 

235. McArthur, C., Waldron, E.. Dickinson, J. The psychology of smoking. 

J Abnorm Sot Psycho1 56: 267-75, 1958. 

236. McConnell. R. B., Gordon, K. C. T., Jones, T. Occupational and personal factors in the etiology of carcinoma of the lung. Lance& London, 2: 651-6. 1952. 

237. hlills. C. A., Porter, M. M. Tobacco smoking habits and cancer of 

the mouth and respiratory 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: 981-90,1957. 

239. I\Iilmore. B. K., Conover, A. G. Tobacco consumption in the I’nited 

States, 1880-1955. Public Health Mongr No. 45: l-111, 1956. 

210. YIodp. J. K., Ranadive, K. J. Biological study of tobacco in relation to 

oral cancer. Indian J Med Sci 13: 1023-37, 1959. 

241. hloertel. C. G.. Foss, E. L. Multicentric carcinomas of the oral cavity. 

Surg Gynec Obstet 106: 6324, 1958. 

242. Xlold. J. B., Walker, T. B. Isolation of TDE from cigarette smoke. 

Tobacco Sci 1: 161-3, 1957. 

243. \Ioore. C., Christopherson. W. M. The effect of cigarette-smoke condensate on hamster tissues. Exteriorized oral pouch and skin. 

.4rch Surg 84: 63-9, 1962. 

244. Moore. C.. Illiller, A. J. Effect of cigarette smoke tar on the hamster 

pouch. A?vIA Arch Surg 76: 78693,1958. 

245. Moore, G. E.. Bissinger, L. L., Proehl, E. C. Intraoral cancer and the 

use of chewing tobacco. J Amer Geriat Sot 1: 497-506, 1953. 

246. Moore, G. E., Bock, F. G. A summary of research techniques for investigating 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. Inquiry 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. 

Nederl T. Geneesk. 99: 22768, 1955. 

249. Mulay, A. S., Firminger, H. I. Precancerous and cancerous lesions of 

the forestomach and dermal-subcutaneous tumors in rats fed p-dimethylaminobenzene-1-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 Statistics, I1.S. Public Health Service. Special report to the Surgeon 

General’s Advisory Committee on Smoking and Health. 

253. Nelson, A., Fitzhuph. 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. B ronchial carcinoma-A pandemic. 

II. Incidence and tobacco consumption in various countries. Danish 

Med BuIl 1: 194-9, 1955. 

256. Niskanen, K. 0. Observations on metaplasia of the bronchial epithelium and its relation to carcinoma of the lung. Acta Path Microbial 

Stand Suppl80: 1949. 80 p. 

257. Nothdurft, H. Uber die Sarkomausliisung durch FremdkGrperimplantationen bei Ratten in Abhangigkeit von der Form der Implantate. 

Naturwissenschaften 42 : 106, 1955. 

258. Ochsner, M., DeBakey, M. Symposium on Cancer. Primary pulmonary malignancy. Treatment by total pneumonectomy; analyses 

of 79 collected cases and presentation of 7 personal cases. Surg 

Gynec Obstet 68: 435-51: 1939. 

259. O’Donovan, W. J. Carcinoma cutitis in an anthracene factory. Brit 

J Derm 33: 291-7, 1921. 

260. O’NeaI, R. M., Lee: K. T., Edwards. D. Bronchogenic carcinoma. An 

evaluation from autopsy data, with special reference to incidence, 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 induced in rodents by imbedding various plastic films. Proc Sot 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 Emp Cancer Campaign .4nn Rep 33: 

238-9, 1955. 

263. Orris, L., Van Duuren. B. L., Kosak. ,4. 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 chimnev sweeper. Lancet 2: 265, 

1850. 

265. Papanicolaou. G. N.. Koprowska, I. Carcinoma-in-situ of the right 

lower bronchus. Cancer 4: 141-6,195l. 

266. Pasaey. R. D. Experimental 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.. 

Bopland. E.. Pratt. B. M. G.. Sims, P., Hieger, I. Cigarette smoking 

and cancer of the lung. Brit Emp Cancer Campaign Ann Rep 33: 

59-61, 238-9, 1955. 

268. Passey, R. D., Roe. E. M. F., Middleton, F. C., Bergel, F., Everett, J. L., 

Lewis. G. E.: &lartin, J. B.. Boyland, E., Sims, P. Cigarette smoking 

and cancer. Brit Emp Cancer Campaign 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. Production of cancers in mice and rats by chromium 

compounds. AMA Arch Industr Health 21: 530-5,196O. 

271. Peacock, E. E. Jr., Brawley, B. W. An evaluation of snuff and tobacco 

in the production of 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 experimental and epidemiological study. Ann Surg 151: 542-50, 1960. 

273. Peacock, P. R. Cigarette smoking by laboratory animals. Seventh 

International Cancer Congress. London, 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.. Kirby. .A. H. M. Attempts to induce stomach tumors: 

II. The action of carcinogenic hydrocarbons on stock mice. Cancer Res 3: S8-93. 1944. 

277. Pernu. J. An epidemiological study on cancer of the digestive organs 

and respiratorv svstem. A studv based on 7,078 cases. Ann Med 

Intern Fenn 49. (SuppI. 33) : 1-l l?, 1960. 

278. Peel. W. E. Skin as a test site for the bioassav of carcinogens and 

carcinogen precursors. Nat C ancer Inst Monogr No. 10: 611-31, 

1963. 

279. Pott. P. Chirurgical observations. London, 1775. Cancer Scroti. 

p. 63-8. 

280. Potter. E. A.. Tully, M. R. The statistical approach to the cancer problem in Massachusetts. Amer J Pub Health 35: 485-90, 1945. 

281. Raaschou-Nielsen, E. Smoking habits in twins. Danish JIed Bull 7: 

82-8, 1960. 

282. Rabson. A. S., Branigan. W. J.: LeGallais, F. Y. Lung tumors produced by intratracheal inoculation of polyoma virus in Syrian 

hamsters. J Nat Cancer Inst 25: 937-65, 1960. 

2.50 
282a. Radford, Edward P., Jr., Hunt, Vilma R. Personal Communication 

to the Surgeon General’s Advisory Committee on Smoking and 

Health. 

283. Randig, K. Untersuchungen zur Xtiologie des Bronchialkarzinoms. 

6& 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 carcinoma: 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. Rigdon, 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 Advertising (filter-tip cigarettes) July 18-26, 1957. Govt Print Off 1957. 

p. lid-31. 

289. Rockey, E. E., Sp eer, F. D., Thompson, A., Ahn, K. J., Hirose, T. Experimental study on effect of cigarette smoke condensate on bronchial 

mucosa. JAMA 182: 1094-8, 1%2. 

290. Roe, F. J. C. The action of cigarette tar on mouse skin. Brit Emp 

Cancer Campaign Ann Rep 36: 160,1958. 

291. Roe, F. J. C., Glendenning, 0. M. The carcinogenicity of /3-propiolactones for mouse skin. Brit J Cancer 19: 357-62, 1956. 

292. Roe, F. J. C., Salaman, M. H. Further studies on incomplete carcinogenesis : Triethylene melamine (T.E.M.) , I-2-benzanathracene and 

/3-propiolactone, as initiators of skin tumor formation in mouth. 

Brit J Cancer 9: 177, 203, 1955. 

293. Roe, F. J. C., Salaman, M. H., Cohen, J. Incomplete carcinogens in 

cigarette smoke condensate. Tumor-promotion by a phenolic fraction. Brit J Cancer 3: 623-33, 1959. 

294. Roffo, A. H. Cancerizacion gastrica por ingestion de alquitran tabiquico. Bol Inst Med Exp Estud Cancer Buenos Aires 18: 3948, 

1941. 

295. Roffb, A. H. El tabaco en el c&cer de vejiga. Bol Inst Med EXP 

Estud Cancer Buenos Aires 7: 13(X4,1930. 

296. Roffo, A. H. Leucoplasie, exp&imentale produite par le tabac. Rev 

Sud-Amer Med Chir 1: 321-30, 1930. 

297. Roffo, A. H. Leucoplasia tabiquica experimental. Bol Inst Med Exp 

Estud Cancer Buenos Aires 7: 13w4,1930. 

298. Rosenblatt, M. B. Correspondence to Dr. Burney. Surgeon General 

Public Health Service from Dr. Milton B. Rosenblatt. In: United 

States Congress 85th House Committee on Government Operations 

251 
Legal and Monetarv Affairs Subcommittee: Hearings on False and 

Wsleading Advertising I filter-tip cigarettes) July 18-26, 1957. 

Govt Print Off 1957. 753-J p. 

299. Rosenblatt. M. B.. Lisa, J. R. Cancer of the lung; pathology. diagnosis, 

and treatment. Sew I’ork, Oxford I-niv Press 1956. 343 p. 

:iOO. Ross. I’. Occupational skin lesions due to pitch and tar. Brit Med J 2: 

369-7s. 194s. 

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 statistical association between smoking and carcinoma of the lung. J Nat Cancer 

Inst 13: 1237-58, 1953. 

302. Salliotti. U., Cefis, F.. Kolb, L. H., Grote, M. I. Intratracheal injection 

of particulate carcinogens into hamster lungs [Abstract] Proc Amer 

&\ss 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, occupation and residence. Acta Path Microbial Stand 43 : 4761,1958. 

305. Sanderud. K. Squamous metaplasia of the respiratory tract epithelium. 

An autopsy study of 214 cases. 3. Relation to disease. Acta Path 

Microbial Stand 44: 21.-32, 1958. 

306. Sanghvi: 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 J 1: 1111-4,1955. 

307. Sawicki. E. Symposium analysis of carcinogenic air pollutants. Nat 

Cancer Inst Monogr No. 9: 201-20, 1962. 

308. Saxen. E.. Ekwall, P.. Set&, K. Squamous cell carcinoma of the 

forestomach in mice, following oral administration icannula feeding) of 9.10-dimethyl-1. 2-benzanthracene solubilized in an aqueous 

solution of an associated colloid. Acta Path Microbial Stand 

27: 27&5. 1950. 

,309. Schairer. E.. Schoeniger. E. Lungenkrebs und Tabakverbrauch. Z. 

Krebsforsch 54: 261-9. 1943. 

310. Schamberg. J. F. Cancer in tar workers. J Cutan Dis 28: 644-62, 

1910. 

311. 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. O., Winterstein. .4. E xperimentelle LTntersuchungen zur 

Frage Tabak und Krebs. Z Krebsforsch 42: 7692, 1935. 

313. Schwartz. D., Denoix. P. F. L’enquete francaise sur l’etioloaie du 

cancer broncho-pulmoniire. Role du tabac. Sem Hop Paris 33: 

363&U, 1957. 

314. Schwartz, D., Denoix. P. F., Anguera, G. Recherche de localisations 

du cancer associees aux facteurs tabac et alcool chez l’homme. Bull 

Ass Franc Cancer 44: 33661, 1957. 

252 
315. Schwartz, D., Flamant. R., Lellouch, J., Denoix, P. F. Results of a 

French survey on the role of tobacco. particularly inhalation, in 

different cancer sites. J Nat Cancer Inst 26: 1085-1108, 1961. 

316. Sepi. M., Fukushima, I., Fujisaku, S., Kurihara. M.. Saito. S., Asano. 

K., Kamoi, M. An epidemiological study on cancer in Japan. 

Gann 48: (Supplement) l-63, 1957. 

317. Segi, M.. Kurihara, M. Cancer mortality for selected sites in 24 

countries. No. 2 11958-1959 1. Dept. of Public Health, Sendai, 

Tohoku I’niversity School of \ledicine. Japan 1962. 127 p. 

318. Seltser. R. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

319. Shanta. V.. Krishnamurthi. S: A study of aetiological factors in oral 

squamous cell carcinoma. Brit J Cancer 13: 381-8. 1959. 

320. Shimkin, M. B. I n d uce d pu 1 monary- tumors in mice. I. Susceptibility 

of seven strains of mice to the action of intraveneouslp injected 

methylcholanthrene. Arch Path 29: 229-38. 1940. 

321. Shubik. P., Saffiotti. I-.. Lijinskv. ‘X.. Pietra. G., Rappaport. H.. Toth. 

B., Raha, C. R., Tomatis, L., Feldman. R.. Ramahi, H. R. Studies on 

the toxicity of petroleum waxes. Toxic App Pharmacol 4: l-62, 

1962. 

322. Soemmerring, S. Th. De Morbis Vasorum Abeorbentium Corporis 

Humani. Varrentrappii Wenneri, Traiectic ad Moenum, Pub1 1795. 

109 p. 

323. Spain, D. M. Recent changes in relative frequency of various histologic 

types of bronchogenic carcinoma. J Nat Cancer Inst 23: 427-38, 

1959. 

324. Stanton, M. F., Blackwell, R. Induction 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: 37W7,1%1. 

325. Staszewski, D. J. Smoking and its relation to carcinoma of the upper 

digestive tract (esophagus and stomach) and to peptic ulcer. Pol 

Tyg Lek 16: 287-92, l%O. 

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. tonsils 

and larynx. Nowotwory 10: 121-32. 1960. 

328. Steiner, P. E. Symposium on endemiology of cancer of the lung: 

etiological implications of the geographical distribution of lung cancer. Acta Un Tnt Caner 9: 450-75, 1953. 

329. Steiner, P. E. The etiology and histogenesis of carcinoma of the 

esophagus. Cancer 9: 43tXi2, 1956. 

330. Stewart, H. L. Pulmonary tumors in mice. In: Homburger, F. ed. 

The Physiopathology of Cancer. Sew 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 Institute 39: Rept No 135, 1962. 
332. Stewart: H. L., Lorenz, E. Ad enocarcinoma of the pyloric stomach 

and other gastric neoplasms in mice induced with carcinogenic hydra. 

carbons. J Nat Cancer Tnst 3: 175-89, 1942. 

333. Stewart, H. L.. Lorenz, E. Induction 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 and histo. 

pathogenesis of forestomach carcinoma in mice fed carcinogenic 

hydrocarbons in oil emulsions. J Nat Cancer Inst 10: 14766,1949. 

335. Stocks, P. Cancer, incidence in North Wales and Liverpool region 

in relation to habits and environment. IX. Smoke and smoking. 

Brit Emp Cancer Campaign 35th Ann Rep Suppl to Part 2, 66-95: 

1957. 

336. Stocks, P. Statistical investigations concerning the causation of various forms of human cancer. In: Raven, R. W., ed., Cancer. 

337. Stocks. P., Campbell, J. M. Lung cancer death rates among nonsmokers and pipe and cigarette smokers: An evaluation in relation 

to air pollution by benzpyrene and other substances. Brit Med J 

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 lesions 

in the rat. Cancer Res 2: 770-5, 1942. 

340. Summary of meeting on pathogenesis of lung cancer (Toronto). 

Special communication to the Surgeon General’s Advisory Committee 

on Smoking and Health. 

341. Sunderman, F. W.) Kincaid, J. F., Donnelly. A. J., West. B. Nickel 

poisoning. IV. Chronic exposure of rats to nickel carbonyl. A 

report after one year of observation. AMA Arch Industr Health 

16: 480-5, 1957. 

342. Sunderman, F. W., Sunderman, F. W. Jr. Nickel poisoning. XI. 

Implication of nickel as a pulmonary carcinogen in tobacco smoke. 

Amer J Clin Path 35: 203-9, 1961. 

342a. Suntzeffi V.. Croninger, A. B., Wynder, 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: 25&254, 1957. 

343. Tabah, E. J.. Gorecki. Z.. Ritchie, A. C., Skoryna, S. C. Effects of 

saturated solutions of tobacco tars and of 9, lo-dimethyl-1, 2- 

benzanthracene on the h,amster’s cheek pouch. [Abstract] Proc 

Amer Ass Cancer Res 2: 254, 1957. 

35%. 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-l1, 1962. 

346. Truhaut, R., DeClercq, M. Premiers resultats de l’etude chimique et 

biologique des produits obtenus dans la pyrolyse de la nicotine. Bull 

Ass Franc Cancer 44: 426-39, 1957. 

254 
347. Turner, F. C. Sarcomas at sites of subcutaneously implanted bakelite 

discs in rats. J Nat Cancer Inst 2: 81-3, 1941. 

347a. Turner, R. C., Radley, M. M. Naturally occurring alpha activity of 

cigarette tobaccos [Letter to the Editor]. Lancet 1: 1197-8, 1960. 

348. Twort, C. C., Twort, J. M. Th e carcinogenic potency of mineral oils. 

J Industr Hyg 13: 204-26, 1931. 

349. Umiker, W., Storey, C. Bronchogenic carcinoma-in-situ. Report of 

a case with positive biopsy. cytological examination, and lobectomy. 

Cancer 5: 369-74, 1952. 

350. University of Minnesota Hospital, Minneapolis. Personal communication 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: l-60, 1960. 

352. Valentine, E. H. Squamous metaplasia of the bronchus. A study of 

metaplastic changes 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 Otolaryng 1: 102-5, 1952. 

354. Van Duuren, Nelson N.. Orris, L., Palmes, E. C., Schmitt, F. L. Carcinogenicity of epoxides, lactones and peroxy compounds. J Nat 

Cancer Inst 31: 41-55, 1963. 

355. Vogler, W. R., Lloyd, J. W.: M’l I more, 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 Sot B 128: 62-81,1939. 

357. Vorwald, A. J. Ad Hoc, Conference on Lung Carcinogenesis, Toronto, 

April, 1963. Sponsored by the Surgeon General’s Advisory Committee on Smoking and Health. 

358. Vorwald, A. J., Durkan, T. M., Prat, P. C. Experimental studies of 

asbestosis. Arch Industr Hyg Occup Med 3: l-43, 1951. 

359. Wagner, J. C. Asbestosis in experimental animals. Brit J Industr Med 

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 underground metal 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 Pharmaco1 9: 3&23, 1954. 

363. Wassink, W. F. Ontstaansvoorwaarden voor longkanker. Nederl T 

Geneesk 4: 373247, 1948. 

364. Waterman, N. Experimental production of carcinoma in the stomach 

of mice. Acta Cancrol 2: 375-88, 1936. 

714-422 064-18 255 
365. Watson, W. L., Conte, A. J. Smoking and lung cancer. Cancer 7: 

245-9, 1954. 

366. Weller, R. W. Metaplasia of bronchial epithelium. il postmortem 

study. Amer J Clin Path 23: 768-74, 1953. 

367. Wells: C. R. Betel nut chewing and its effects. U.S. Nav Med Bull 22: 

437-9,1925. 

368. White, J.. Stewart, H. L. Intestinal adenocarcinoma and intraabdominal hemangio-endothelioma in mice ingesting methylcholanthrene. J Nat Cancer Inst 3: 33147, 1942. 

369. Wilkins, S. A., Vogler: W. R. Cancer of the gingiva. Surg Gynec 

Obstet 105: 145-52, 195’7. 

370. Williams, >I. 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. Laboratory contributions to the tobacco-cancer problem. Acta Med Stand Suppl 369: 63-101, 1961. 

373 Wynder, E. L. ed. The biologic effects of tobacco. Boston, Little, 

Brown, 1955. 215 p. 

374. Wynder. E. L.: Bross. I. J. A study of etiological factors in cancer of 

the esophagus. Cancer 14: 389-413, 1961. 

375. Wynder, E. L.. Rross, I. J., Cornfield, J.: O’Donnell, W. E. Lung cancer in women. A study of environmental factors. New Eng J Med 

255: 1111-21, 1956. 

376. Wynder, E. L., Brass: I. 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. Epidemiological approach to the 

etiology of cancer of the larynx. JAMA 160: 1384-91,1956. 

378. Wynder, E. L., Brass, I. J., Feldman, R. M. A study of the etiological 

factors in cancer of the mouth. Cancer 10: 1300-23: 1957. 

379. Wynder, E. L.. Cornfield, J. Cancer of the lung in physicians. NewEng J Med 248: 444? 1953. 

380. Wynder, E. L.. Fritz, I,., Furth, N. Effect on concentration of benzopyrene in skin carcinogenesis. J Nat Cancer Inst 19: 361-70, 1957. 

381. Wynder, E. L., Graham, E. A. T o b acco smoking as a possible etiologic 

factor in bronchiogenic carcinoma. ,4 study of six hundred and 

eighty-four proved cases. J.4bIA 143: 329-36, 1950. 

382. Wynder, E. L.. Graham. E. .4., Croninger. A. B. Experimental production of carcinoma w-ith cigarette tar. Cancer Res 13: 855-65. 195:3. 

383. Wynder, E. L.. Graham, E. .4.. Croninger. A. B. Experimental production of carcinoma with cigarette tar. II. Tests with different mouse 

strains. Cancer Res 15: 445-8. 1955. 

384. Wy-nder, E. L.. Hoffman. 1). A study of tobacco carcinogens. No. 8. 

Role of acidic fractions as promoters. Cancer 14: 130615,196l. 

385. Wynder, E. I,.. Hultberg: S.. Jacobsson, F.. Brass: I. J. Environmental 

factors in cancer of the upper alimentary tract. A Swedish study with 

special reference to Plummer-Vinson (Patterson-Kelly) Svndrome. 

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 incidence between 

Seventh-Day Adventists, and others. Calif Med 89: 267-72, 1958. 

387. Wynder, E. L., Lemon, F. R., Brass, I. J. Cancer and coronary artery 

disease among Seventh-Day Adventists. Cancer 12: 1016-28, 1959. 

388. Wynder, E. L., Navarrette, A., Arostegui, G. E., Llambes, J. L. Study 

of environmental factors in cancer of the respiratory tract in Cuba. 

J Nat Cancer Inst 20 : 665573,1958. 

389. Wynder, E., Onderdonk, J., Mantel, Iv. An epidemiologic investigation of cancer of the bladder. Cancer 16: 13881407,1963. 

390. Wynder, E. L., Wright, G. A study- of tobacco carcinogenesis. I. 

The primary fractions. Cancer 10: 255-71,1957. 

391. Wynder, E. L., Wright, G. Studies on the identification of carcinogens in-cigarette tar. [Abstract] Proc Amer Ass Cancer Res 2: 

159, 1956. 

392. Wynder, E. L., Wright, G., Lam, J. A study of tobacco carcinogenesis. 

V. The role of pyrolysis Cancer 11: 1140-8, 1958. 

257 
Chapter 10 

Non-Neoplastic Respiratory Diseases, 

Particularly Chronic Bronchitis 

and Pulmonary Emphysema 
Contents 

Page 

ALTERATIONS IN THE RESPIRATORY TRACT AND IN 

PULMONARY PARENCHYMA INDUCED BY TOBACCO 

SMOKE ........................ 

Characteristics of the Exposure ............. 

Composition of Tobacco Smoke ............ 

Regional Deposition or Retention of Tobacco Smoke ... 

Mouth Retention of Tobacco Smoke ......... 

Retention of Particles by the Trachea, Bronchi, and 

Pulmonary Tissue ................ 

Retention of Gases by the Trachea, Bronchi, and Pulmonary Parenchyma ............... 

Metabolism and Toxicity of Specific Components in 

Tobacco Smoke .................. 

Clearance of Smoke Deposits ............. 

Effects of Tobacco Smoke on Defense Mechanisms of the 

Respiratory System ................. 

Pulmonary Hygiene and Ciliary Activity ....... 

Mucus Secretion. ................. 

Alveolar Lining .................. 

Phagocytosis ................... 

Other Mechanisms. ................ 

Histopathologic Alterations ............... 

RELATION OF SMOKING TO DISEASES OF THE RESPIRATORY 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 EmPh Y sema .................... 

260 

263 

263 

263 

263 

264 

264 

265 

265 

267 

267 

267 

268 

269 

269 

270 

270 

275 

275 

275 

276 

277 

278 

278 

278 

279 
RELATION OF SMOKING TO DISEASES OF TllE Rl*:SPIRATORY SYSTEM-Continued 

Chronic Bronchopulmonary Diseases-Continued 

Evidence Relating Smoking to Chronic Bronchitis and 

Emphysema. ................... 

Epidemiological Evidence ............. 

Prevalence Studies ............... 

(1.) Smoking and Respirator!- Sjmptomd .... 

(a.) Chronic Cough ........... 

(I).) Sputum .............. 

(c.) Cough and .Sputum ......... 

(cl.) Breathlessness. ........... 

(e.) Smoking and Chest lllnehs ...... 

(f.) Combinations of S?.mptoms. ..... 

(g.) Relationship Betw-een Svmptornh or 

Signs and Amount SmokEtl ..... 

(h.) Relationship Between 5) mptoms and 

Signs and _\lethod of Smoking. ... 

(i.) Ventilatory Function. ........ 

Prospective Studies .............. 

Clinical Evidence ................ 

Relationship of Smoking, Environmental Factors. and 

Chronic Respiratory Disease ............ 

Atmospheric Pollution .............. 

Basis for Interrelationship and Relative Magnitude 

of Exposure. ................ 

(1.) Experimental Evidence. ........ 

(2.) Relative Magnitude of the Exposure ... 

Epidemiological Evidence ............ 

Occupational Factors. .............. 

SUMMARY ....................... 

CONCLUSIONS ..................... 

REFERENCES. ..................... 

Figure 

FIGURE l.-Black pigment and emphysema in lungs of 83 

patients . . . . . . . . . . . . . . . . . . . 

List of Tables 

TABLE l.-Summary of reports on the prevalence of cough in 

relation to smoking . . . . . . . . . . . . . . 

TABLE 2.-Summary of reports on the prevalence of sputum in 

relation to smoking . . . . . . . . . . . . . . 

QBLE 3.--Summary of reports on the prevalence of cough and 

sputum in relation to smoking . . . . . . . . . 

TABLE J.--Summary of reports on the prevalence of breathlessness in relation to smoking . . . . . . . . . . 

TABLE S.-Summary of reports on history of chest illness in the 

past three years in relation to smoking . . . . . 

TABLE 6.--Summarv of reports on the prevalence of combinations 

of certain symptoms in relation to smoking . . . . 

281 

283 

284 

285 

287 

288 

Pa@! 

280 

280 

280 

280 

280 

283 

283 

286 

287 

388 

289 

289 

289 

293 

294 

295 

295 

295 

295 

296 

297 

298 

300 

302 

302 

273 
Chapter 10 

This chapter presents the evidence on smoking in relation to the development and progression of the non-neoplastic respiratory diseases. The c hf onic 

bronchopulmonary diseases pose a health problem of substantial and steadily 

growing importance. Bronchitis and emphysema, in particular, severely 

disable large numbers of men of workin g age, and have a considerable effect 

upon mortality as a direct or contributory cause of death. Because of the 

importance of these diseases to public health, they receive the most attention 

in this chapter, in accord with the fundamental purpose of the Committee’s 

Report. 

The design of this chapter is to consider first the experimental and pathological data, then the clinical and epidemiological data. 

ALTERATIONS IN THE RESPIRATORY TRACT AND IN 

PULMONARY PARENCHYMA INDUCED BY TOBACCO 

SMOKE 

CHARACTERISTICS OF THE EXPOSURE 

Composition of Tobacco Smoke 

Although the material under this subtitle is dealt with in greater detail 

in Chapter 6, Chemical and Physical Characteristics of Tobacco and Tobacco Smoke, it is considered here because particle size and other properties 

of tobacco smoke constituents are of prime importance in the relation between smoking and respiratory diseases. 

Tobacco smoke is a heterogeneous mixture of a large number of compounds with gaseous and particulate phases. As it enters the mouth, cigarette smoke is an extremely concentrated aerosol with several hundred million 

to several hundred billion liquid particles in each cubic centimeter (lO’i, 

116, 122). Measurements of the median particle size range from about 

0.5 to 1.5 microns; the majority of the measurements have a median closer 

to 0.5 microns (2). Some of the major classes of compounds which constitute the particulate phase of cigarette smoke and notation of their toxic 

action on the lung (2) are presented in Table 1 of Chapter 6. 

Nine of the gases present in cigarette smoke are considered irritant to 

the lung (2) ; Table 2 in Chapter 6 lists some of the known constituents 

of the gas phase. 

Regional Deposition or Retention of Tobacco Smoke 

Little is known about the exact composition of cigarette smoke in the 

respiratory tract after it leaves the mouth. Inhalation of cigarette smoke 

undoubtedly exposes the airways and pulmonary parenchyma to smoke with 

263 
substantially different characteristics from the smoke that first enters the 

mouth. Insufficient direct evidence is available to characterize this exposure, 

and existing information is deriv,ed largely from s&stances with analogous 

physical and chemical features. 

The retention or deposition of smoke constituents in the several regions of 

the respiratory system varies because many factors alter the characteristics 

of the smoke and probably result in losses as the constituents are drawn 

deeper into the respiratory system. Included among such factors are the 

amount and composition of the constituents immediately after burning the 

tobacco, the method of smoking, the depth of inhalation. and the temperature 

and humidity of inhaled smoke. The physical laws which govern deposition 

of particles and absorption of gases and the anatomic structure ultimately 

determine the pattern of regional retention (2). 

When cigarette smoke is inhaled, total retention of particles in the mouth, 

respiratory tract, and pulmonary parenchvma is about 80-90 percent, even 

when the smoke is held in the lung for a relatively short period, two-to-five 

seconds. When deliberately held for periods as long as 30 seconds, retention 

of particles is almost complete (135). 

MOUTH RETENTION OF TOBACCO SMOKE 

Removai of tobacco smoke constituents while in the mouth has been studied 

incompletely. When cigarette smoke is drawn into the mouth and promptly 

expelled without inhalation, the analyzed weight or fluorescence of the retained tars ranges from 33 percent to 66 percent (18, 71,135). Experiments 

utilizing a model of the mouth and airways, but without the deeper portions 

of the lung, have demonstrated differential regional deposition of certain tar 

distillation fractions. A cigarette tar fraction distilling at less than 120” C. 

was deposited in concentrations three times greater in the simulated bronchi 

than in the mouth; a high-boiling fraction, however, was deposited equally 

in the mouth and bronchi (57). 

The available information suggests that removal of smoke constituents in 

the mouth may be an important defense mechanism that prevents delivery 

of certain noxious agents to the tracheobronchial tree and lung parenchyma, 

hut such information is not sufficient to determine which substance may be 

removed while tobacco smoke components are in the mouth. 

RETENTION OF PARTICLES BY THE TRACHEA, BRONCHI, AND 

PULMONARY TISSUE 

Most information pertaining to retention of smoke constituents by the 

tracheobronchial tree and pulmonary tissue is based on knowledge of physical 

factors M hirh determine retention of inhaled aerosol particles and on analogies drawn from physiologic studies of aerosol retention in man. In general: the particles of greater size and density are less able to traverse the 

twisting course of the airways and tend to be removed high in the tracheobronchial tree. Smaller particles penetrate more deeply into the lung and 

are deposited through gravitational settling or inertial impingement. except 

for verv fine particles which diffuse onto the surface. 

The size of virtually all the individual particles in inhaled smoke is 

probably less than two microns. Data from a number of laboratories indi- 
cate that particles smaller than two microns are deposited in the lower 

respiratory tract during normal breathing under rest conditions. Deep 

breathing shifts deposition of larger particles into the lower respiratory 

tract also (2, 83). The lowest proportion of deposition occurs for particles 

between 0.25-0.50 microns. D’I ff usion increases for particles below 0.25 

microns, and extremely fine particles, approaching molecular size, diffuse 

so rapidly that many probably remain on the upper bronchial tree. The 

importance of such minute particles in tobacco smoke. even if present 

initially, probably is not great since they act as nuclei for vapor condensation and would be expected to grow rapidly (2, 3). Data on sites of intrapulmonary deposition derived from phy-siological studies indicate that even 

for particles smaller than two microns, only about five percent are deposited 

along the bronchial tree. 

Radioactive tracers in smoke have been used to stud\- site deposition in 

animals, Deposition in a diffuse llattern was obtained in dogs inhaling 

smoke from cigarettes impregnated with K 42. Na 23. and As 76 I 192). 

A similar experiment using I 131 as the tracer demonstrated substantial 

bronchial deposition but the physical state of the tracer. whether vapor or 

particulate, remains uncertain (191 I. In rabbits. cigarettes impregnated 

with As 76 produced deposition on the lark-nx, carina. and major bronchi 

but this deposition contributed only a small fraction of the total activity 

retained by the smaller bronchi, bronchioles, and pulmonary tissue ( 100). 

From indirect data, therefore, it is most probable that the vast majority 

of cigarette smoke particles penetrate deeply into the respiratory tract and 

are deposited on the surface of the terminal bronchioles, respiratory 

bronchioles, and pulmonary parenchyma. 

RETENTION OF GASES BY THE TRACHEA. BRONCHI, .4ND PULMONARY PARENCHYMA 

Insufficient data are available on the intrapulmonary fate of gases of 

cigarette smoke to warrant detailed consideration at present. Thorough review of the available information and the known physical characteristics of 

gas absorption suggest that the speed and depth of inhalation may affect 

both the amount and site of gas retention; moreover, while the distribution 

pattern may be diffuse, it seems possible, although not yet demonstrated, 

that a substantial portion of inhaled tobacco gas and vapor will deposit 

along the upper bronchial tree (2). In view of the ability of certain of 

these gases to interfere with normal function of the cleansing mechanisms 

of the respiratory system (e.g.: ciliary motility ) : such deposition could be of 

significance in production or augmentation of diseases of the bronchi. 

Jfetabolism and Toxicity of Specific Components in Tobacco Smoke 

Little is known about the metabolism of most compounds in tobacco 

smoke. The fragmentary data have been thoroughly reviewed ( 2 i . 

Hydrogen cyanide is present in cigarette smoke in concentrations that 

would be fatal for man were it not for a number of factors which accrue to 

Prevent such a lethal consequence of smoking (2, 60 ) . Among these factors 

are dilution of the small smoke volume, discontinuous exposure, rapid de265 
toxification, and absence of cumulative effect. The cyanide ion is capable 

of stopping cellular respiration abruptly through inactivation of cytochrome 

oxidase. In sublethal exposures, the cyanide ion is gradually released from 

its combination with the ferric ion of cytochrome oxidase, converted to 

thiocyanate ion (SCN) , and excreted in the urine. Thiocyanate blood levels 

in smokers are three times higher than in non-smokers and differences in 

relative urinary excretion are even more pronounced (46: 127). It seems 

quite likely, therefore, that cyanide derived from cigarette smoke is metabolized rapidly in the body, and harmful effects have not been detected. 

The principal oxides of nitrogen, nitric oxide and nitrogen dioxide, are 

present in cigarette smoke in total concentrations varying from 145 to 665 

ppm (23). Oxides of nitrogen are partially absorbed in the mouth; absorption after inhalation, however: is almost complete i 23, 81) . ?Gtric oxide. 

one principal oxide of nitrogen in cigarette smoke, is mainly an asphyxiant 

and is only about one-fifth as toxic as nitrogen dioxide. There is no documented instance of human poisoning due to nitric oxide. 

Nitrogen dioxide, however, is a primary lung irritant, presumably as a 

result of its hydration into nitrous and nitric acids which are subsequently 

converted to nitrites. Exposure to relatively high concentrations of nitrogen dioxide produces injury sufficient in the human lung to result in pulmonary edema (187). Obliterating fibrosis of the bronchioles has also 

been observed in man follow-ing moderately high exposures (126). In 

physiologic studies, changes which resemble those of pulmonary obstructive 

disease have been observed in men who are occupationally exposed to high 

concentrations of nitrogen oxides (19). 

Experimental studies indicate that nitrogen dioxide is capable also of. 

producing pulmonary damage (24, 74, 76). A severe, but reversible, 

inflammatory reaction in the respiratory bronchioles of rats, rabbits and 

guinea pigs occurs after a single two-hour exposure to 8&100 ppm. of 

nitrogen dioxide. Five daily exposures at 15-25 ppm. for two-hour periods 

produce similar but less severe results (109). 

It seems clear from environmental exposures of man to nitrogen dioxide 

that definite pulmonary damage may result from such exposures. Whether 

nitrogen dioxide alone, in inhaled cigarette smoke, is capable of producing 

such damage in man is less certain. Equal amounts of nitric oxide and 

nitrogen dioxide in cigarette smoke have been reported (81)) but rebent work 

indicates that the proportion of nitrogen dioxide is much lower (108‘1. 

These divergent results and the uncertainty as to the level of nitrogen dioxide 

exposure necessary to produce pulmonary damage make it very difficult to 

assess the role of nitrogen dioxide in cigarette smoke. 

Formaldehyde gas is present in cigarette smoke in concentrations of 30 

ppm. Chronic exposure to 50 ppm. of formaldehyde gas produces an irritant 

cellular response in mice similar to that produced by tobacco smoke. These 

changes are found mostly in the trachea; higher levels of exposure are associated with more severe reactions and extension of the involvement to the 

major but not the smaller bronchi (102). 

E xposure of guinea pigs to low concentrations of acrolein, which is also 

present in cigarette smoke, caused an increase in total respiratory llow resistance accompanied by decreased respiratory rates and increased tidal 

266 
volumes ( 143) . It has been found also that acrolein is a potent ciliary 

depressant (80). 

Inhaled vapors of phenol are readily absorbed into the pulmonary circulation 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 properties of other constituents of tobacco, such as the polycyclic hydrocarbons, do 

not suggest that they have a significant role in the development of nonneoplastic respiratory disease in man. 

Clearance of Smoke Deposits 

Little direct evidence pertaining to clearance mechanisms for smoke deposits is available. There is little reason to believe, however, that smoke 

deposits are cleared through routes different from the normal self-cleansing 

mechanism of the lung described in the section on “Pulmonary Hygiene and 

Ciliary Activity” of this chapter. 

EFFECTS OF TOBACCO SMOKE ON DEFENSE MEcHtZNIshls OF THE 

RESPIRATORY SYSTEM 

Pulmonary Hygiene and Ciliary Activity 

The cleansing mechanism of the mammalian respiratory system is dependent upon the efficient, integrated functioning of a complex system. From the 

nose to the terminal bronchioles, a mucous layer in which impacted particles 

and dissolved materials reside is propelled over the surface and removed 

from the respiratory tract by the rapid, rhythmic, and purposeful beat of 

cilia. The mucus is supplied by deep glands in the walls of the airways 

and by goblet cells. Clearance distal to the terminal bronchioles has become more clearly understood in recent years. Fine particles and gases deposited in the lining of the acinus are removed by several mechanisms. 

Even relatively insoluble particles dissolve in the lung because of the large 

surface area-mass ratio of small particles and the high reactivity of body 

fluids (2). After solution, absorption into the blood stream or lymphatics 

may result in removal. Remaining particles may undergo phagocytosis or 

remain free. Some phagocytes enter the alveolar lumen, become laden with 

foreign material, and are transported to the ciliated air passages to be expelled intact. Some disintegrate along the w-ay and deposit their products 

on the surface lining. Still other phagocytes may enter interstitial tissues 

and become sequestrated or be removed to regional lymph nodes. Foreign 

material which remains free in the fluid lining of the alveolus is transported 

onto ciliated mucosa by a relatively slow process. The transport results from 

effects in the fluid lining produced by the mechanics of respiration and replenishment of the alveolar fluid lining. 

Inhibition of ciliary motility following exposure to tobacco tars. cigarette 

smoke, or its constituents has been demonstrated frequently with experimental use of respiratory epithelium from a wide variety of animal species 

(17, 22, 39, 59, 79, 80, 96, 97, 98, 111, 112, 131, 147, 157, 158, 167, 178). 

267 
Similar results have been obtained with ciliated human respiratory epi. 

tbelium i 17, 22 I. Although all investigations have bpen conducted in vitro, 

the uniformity of the inhibitor)- effects in a number of different experimental 

models is impressive. 

Positive ions are present in cigarette smoke. Each cigarette >ields about 

10’” positive ions: negatively charged rjarticles are also present ( 1211. 

These thermally produced gaseous ions have considerable energ>- and may 

produce effects in cells ( 190). In air free of cigarette smoke, positive ions 

decrease or abolish ciliary activitv. The reduction in ciliary motility which 

occurs after exposure to cigareite smoke is augmented and sustained by 

additional exposureto positive ions ( 112). 

Sicotine in high concentrations inhibits ciliary motility although concentrations of nicotine similar to those in tobacco smoke do not affect rahbit. 

chicken, or human ciliary function (22, 121 i. In addition, tobacco smoke 

from low-nicotine cigarettes produced no significant difference in ciliarv 

response from that obtained with cigarettes whose nicotine content had not 

been altered (121). Hydrogen cyanide, ammonia. acrolein. formaldehy-de. 

nitrogen dioxide, all components of cigarette smoke, possess potent inhibitory activity (48 t . 

There seems to be little doubt that cigarette smoke is capable of producing 

significant functional alterations of ciliary activity in vitro. Such alterations 

could interfere markedly with the self-cleansing mechanism of the respiratory tract. These in vitro results cannot be fully extrapolated to the effects 

of cigarette smoke on ciliated respiratory tissue of man because of the many 

variables present in the c.omplex experimental methods, including dosage of 

the I’articular agent. Ciliarv depressant activity in the environment of man 

is not limited to the components of tobacco smoke; agents such as ozone and 

sulfur dioxide. which are important air pollutants but are not found in significant amounts in tobacco smoke. are also potent ciliary depressants. 

Morphologic alteration of cilia of smokers has been described (31. 32, 

104). The length of cilia in the trachea and bronchial epithelium was measured at autops! and found to be shorter than in non-smokers. In addition 

the percentage of cells remainin, u ciliated is loser in smokers than in nonsmokers (9. 10. 1041. 

Mucus Sfw-etion 

Definitive studies on the effrct of cigarette smoking upon the quantit! 

and qualitv of human respiratory tract mucus have not been performed. 

Alteration .in the appearance of mucus after exposure to cigarette smoke 

has been noted several times. Following exposure to sulfur dioxide. a gas 

not present in cigarette smoke. c-hanges in the physical properties of mucu> 

have been observed t-%01. Whether such changes result after exposure to 

Fases present in cigarette smoke has not been estahlished. Morphological 

changes observed in the goblet cells and mucous glands at post-mortem 

examination. however. support the possibility that mucus produrtion ma!- 

have been altered during life. 

In essence. little has been contributed in this regard since the observation 

ahout 100 years ago that a marked increase in mucous secretions in the 

trachea and larger bronchi of the cat occurred after large doses of nicotine. 

268 
Atropinization blocked this effect, indicatin, m that this action of nicotine was 

mediated by stimulation of the mucous glands since goblet cells are not 

under nervous control (185 I_ An increase in mucus-secreting cells after 

exposure of rats to cigarette smoke has also been observed recently i 130). 

Alveolar Lining 

The alveolar surface is covered by a secretion which stabilizes the alveoli 

and is produced by the alveolar epithelium I T9, 151). Little is known of 

the influence of cigarette smoke on this alveolar lining. The application of 

cigarette smoke to rat lung extracts. considered to represent the alveolar 

lining, caused a decrease in surface tension and an increase in surface compressibility. Lung extracts prepared from rats exposed to cigarette smoke 

during life also showed lower surface tension and increase in surface compressibility. These findings differ markedly from results in non-exposed 

animals. Such changes during life would be expected to result in a decrease in the efficacy of surface forces stabilizing the alveoli ( 131). Further interpretation of the results of this single study does not appear warranted; however, because of the great potential significance of the alteration 

described, further studies should be encouraged. 

Phngocytosis 

The importance of phagocytosis as a mechanism for clearance of deposits 

in the acinus has become more clearly established in recent years. The 

uptake of tobacco tars by phagocytes is well documented in experimental 

studies. On the basis of solubility, fluorescence, and pigment characteristics of the phagocytized material, and its resemblance to the fluorescence of 

tobacco smoke condensate: this phagocytized material would appear to contain polycyclic hydrocarbons. The accumulation of exogenous pigmented 

material in mice has been shown to be directly proportional to both the level 

and duration of cigarette smoke exposure (119, 121 j. Similar fluorescent 

material was observed in rats exposed to cigarette smoke (130) and in the 

respiratory lining of the white Pekin duck after application of tobacco 

smoke condensate (166). 

Impairment of the efficiency of the phagocytic clearance mechanism after 

long-term exposure to cigarette smoke apparently occurs in mice 1121). 

Early in the exposure period, the clearance mechanism of the lungs is adequate to the task of aggregating and removing pigmented material and 

pigment-laden phagocptes; in the final stages of the 2-year experiment, 

especially at the high dose levels, the phagocytic mechanism appears to be 

overwhelmed since large areas of parenchyma are flooded with pigment in 

the absence of phagocytes. A similar suppression of the effectiveness of 

the phagocytic clearance mechanism for the human lung has been described 

in pneumoconiosis (41) . 

Fluorescent histiocvtes have been found in the sputum of cigarette smokers 

but were not detected in the induced sputum of non-smokers ( 1%). The 

intensitv of fluorescence and the number of histiocvtes were in dirrct proportion to ;he number of cigarettes smoked. These fluorescent histiur! tes pre269 
sumably represent the phagocytic cells of the acinus which are delivered 

intact to the sputum. 

Phagocytosis appears to serve an important function as a concentrating, 

localizing, and transport mechanism for redistribution of injurious constituents of cigarette smoke. The full significance of phagocytosis of cigarette 

smoke constituents in the pathogenesis of disease has not been clarified. 

Impairment of this function, however, cannot be dismissed since it might be 

expected to result in lung injury. 

Other Mech.anisms 

Little is known about the role of lymphatics in the removal of tobacco 

smoke deposits. The evaluation of the effects of smoking on pulmonary 

function tests will be considered in this Chapter in the section on “Chronic 

Bronchopulmonary Diseases.” 

Because the several defense mechanisms of the respiratory system are affected in various ways by tobacco smoke, it may be useful to recapitulate the 

evidence presented in this section. Substantial experimental evidence indicates that tobacco smoke and certain of its components, like many other 

substances, can reduce or abolish ciliary motility, at least temporarily, and 

can slow mucus flow. Impairment of this mechanism in man has not been 

demonstrated under conditions of cigarette smoking, although it seems logical to assume that alterations would occur. If the removal of noxious agents 

were slowed, the protracted contact might be expected to result in respiratory tract damage. 

Decrease in the number of ciliated cells and shortening of remaining cilia 

have been described in post-mortem examinations of bronchi from smokers, 

with implied functional impairment. Alterations in bronchial mucus have 

been suggested by changes in goblet cells and mucous glands after cigarettesmoke exposure. Increased amount of secretions in the tracheobronchial 

tree is a frequent observation after exposure to cigarette smoke. 

Alteration of the fluid lining of the alveoli in rats as a consequence of cigarette smoke exposure has been reported in the only study of this aspect. The 

decrease in surface tension and the increase in surface compressibility observed in this study could have great potential significance in terms of human 

respiratory disease. 

That tobacco products are ingested by alveolar phagocytes of the experimental animal and of man seems fairly well documented. Experimental data 

from animals indicate that the phagocytic mechanism fails under stress of 

protracted high-level exposure. The potential implications of these observations again appear to loom large for respiratory disease in man but further 

definition of these effects and quantitation will be necessary before their full 

significance can be understood. 

HISTOPAUIOLOGIC ALTFXATIONS Imucm IN TEIE RESPIRATORY 

TR-ICT CD IN PULMOSARY PARENCIIYBI.~ BY TOBACCO SM’OKE 

A variet!- of histopathologic studies from diverse points of Gew indirate 

clearIT that Fmoking is associated with abnormal changes in the structure of 

270 
both the surface epithelium and wall of the airways, including the mouth. 

Many of the studies are open to criticism because of inadequate numbers, 

lack of proper controls, and defects of experimental design. but specific 

criticisms are different for each study, and the sum of the evidence points 

unmistakably to the reality of deleterious consequences upon the respiratory 

tract from tobacco smoke. 

Several reports implicate smoking, in particular pipe smoking. as an important etiolopic agent in the development of a condition of the hard palate, 

and less often the soft palate, known as stomatitis nicotina (34. 70, 172, 181). 

This condition is associated with excessive proliferation of the surface epithelium and overproduction of keratin : the hyperplasia frequently involves 

the stomas of the salivary gland s, leading to blockage and subsequent dilatation 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 lawnIthat correlates closelv with the cigarette smoking history (45. 170). Epithelial hyperplasia with hyperkeratosis and variable degrees of chronic inflammation and squamous metaplasia are present in the true vocal cords, 

false cords, and the subglottic area. 

The trachea and bronchi show many morphological changes in the cigarette 

smoker as compared to the non-smoker (9. 10, 11, 31,33. 35,38, 171 I. Various degrees of hyperplasia, with and without overt atypical change. and 

metaplasia of the surface epithelium have been described. Deviations from 

the normal have also been found in the goblet cells, cilia, and mucous glands 

of smokers. Significant increases in the number of goblet cells and in the 

degree of mucous distension of the goblet cells were present in whole mounts 

of bronchial epithelium of smokers (31). Hyperplasia and hvpertrophy of 

mucous glands and a higher proportion of cells with shorter cilia also were 

observed more frequently in smokers (33, 1711. The hypertrophy and 

hyperplasia of mucous glands from miners correlated much better with the 

degree of smoking than with exposure to silica (35). Even though the number of non-smokers among the miners was small, the relationship between 

smoking and mucous gland alteration was very striking. 

The studies on goblet cells and mucous glands in smokers and non-smokers 

are especially important when considered in the light of current concepts 

vf the pathology of chronic bronchitis. It is now apparent that one of the 

commonest morphologic alterations in the bronchi in chronic bronchitis is 

an increase in goblet cells, and hypertrophy and hyperplasia of the mucous 

glands (69, 163, 164). Similar findings have been noted in examination 

of patients with chronic bronchitis in the U.S.A. (182, 183: 1831. Although 

many cases of chronic bronchitis show other morphologic signs of acute and 

chronic inflammation, these are not as constant as are the glandular changes. 

Provided further investigation of the pathologic anatomv of chronic 

bronchitis in other countries indicates that the disease is essentiallk identical 

pathologically, the few British studies on goblet cells and mucous glands in 

smokers offer the first anatomic support for the relationship between smoking 

and chronic bronchitis suggested by seTera epidemiologic reports. conceivably, one or more components of cigarette tobacco smoke have the prop714-422 o-64- 19 271 
erty of stimulating mucous cell hypertrophy and hyperplasia in a manner 

similar to that of other unknown factors which appear to be important in 

the pathopenesis of chronic bronchitis I cf. 64). This mucous cell activity, 

accompanied by excessive mucus production, may increase the susceptibility 

of the tracheobronchial tree to secondary infection with various microorganisms which in turn may lead to acute and chronic inflammation and 

their consequences. .!lthough this hypothesis (64) has many attractive 

features, especially in reconcilin g the epidemiologic and anatomic findings 

in regard to smoking and chronic bronchitis, it must be emphasized that the 

anatomic data relating to smoking are still essentially preliminary in nature 

and require confirmation by more extensive and thorough studies. 

Experimental studies on chronic cigarette smoke exposure in animals, although 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 bronchiolitis severe enough in some instances to cause massive atelectasis, bronrhiectasis 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 mentioned, scattered areas of purulent bronchiolitis, small abscess cavities, 

bronchiolar dilatations and alveolar changes also have been observed. The 

studies in animals therefore support a conclusion that cigarette smoke is 

irritating to the tracheobronchial tree and is capable of inducing severe 

acute and chronic bronchitis. 

It must be emphasized that the tracheobronchial tree makes only a limited number of histopathologic responses to a large number of different types 

of injuries. This restriction, perhaps a reflection in part of our methodologic limitations, makes it difficult to identify with any certainty the basic 

nature of the etiologic agent in any given disease process. It is therefore 

important to be aware of this element of uncertainty when attempting to 

compare histopathologic findings in the respiratory system under different 

environmental conditions and in different species of animals. 

Recent studies indicate that changes in the pulmonary parenchyma are 

associated with cigarette smoking (12, 136). Formalin fume-fixed lungs 

from 83 patients over 40 years of age, from which coal miners were excluded, 

were examined in a preliminary analysis of a continuing study of the relationship of smoking, parenchymal pigment, and emphysema (136). The 

causes of death included “cliff use obstructive bronchopulmonary disease.” 

The quantity of “departitioning” ( i.e., emphysema) and the amount of black 

pigment were graded from zero to three. The pigment was not analyzed 

but was considered to be enthracotic. A close correlation was observed 

between the quantity of smocking, the quantity of pigment deposited, and 

the amount of departitioning. At this early phase of the study, the potential 

etiologic relationships, if any. between the anatomic changes and smoking 

have not been defined I Fi‘guurc 1) . 

Histologic examination of peripheral lung sections has revealed changes 

in pulmonary parenchyma, the severity of which was proportional to the 

272 
+ 

BLACK 

I I 

I I 

PIGMENT 

I I E 

I I E 

BLACK PIGMENT AND EMPHYSEMA IN LUNGS OF 83 PATIENTS 

DEPARTITIONING 

0 

AAAQ 

AAA 

AAA 0 

AA 

:: 

A0 

0= 

NON-SMOKERS <I5 CIGARETTES PER DAY >I5 CIGARETTES PER DAY 

A= 

+ 

I 1 

I I 

A0 

A 

l ee 

. ..a 

l 

moo 

A0 

l .e 

l eee 

l oae 

0 

l o 

0 

l .e 

0.0 

l ee 

l oe 

l ee 

FIGURE 1. Source: Mitchell, R. S. (136) 
intensity of cigarette smoking as well as to its duration (12). One section 

from each of four major lobes of the lung was obtained at autopsy from 

1,340 patients for whom a careful smoking history was available. Nonsmokers were matched with various categories of smokers by age, race, 

and occupation and then placed in random order for microscopic examination. The pulmonary ahnormalities, measured by arbitrary gradations, 

included the following: (a) fibrosis or thickening of alveolar septa, (b) 

rupture of alveolar septa, (c I thickening of the walls of small arteries and 

of arterioles, and (d) pad-like attachments to alveolar septa. 

The association of increased pulmonary fibrosis and cigarette smoking 

was apparent in all age groups (less than 45, 4549, 60-64, 65-69, 70-74, 

75 + ) , even in those who smoked less than one pack per day. The increase 

in fibrosis was most marked in heavy smokers. Whereas the degree of 

fibrosis rose slightly with advancing age (60+ ) in the non-smokers, the 

rise was far more dramatic in smokers. The findings were similarly dramatic for the degree of rupturing of alveolar septa, the most severe changes 

being detected in smokers in the older age groups. The same association was 

found for the degree of thickening of walls of arterioles and small arteries. 

Findings in matched pairs of subjects, who differed in respect to one factor but who were alike in respect to another factor, were compared. The 

degree of pathological change was significantly greater in three categories 

(pulmonary fibrosis, rupture of alveolar septa, thickening of the walls of small 

arteries and arterioles) for the following groups: 

(1) The older cigarette smoker greater than the younger cigarette 

smoker ; 

(2) The one-two pack cigarette smoker greater than “never smoked”; 

(3) The one-half pack a day cigarette smoker greater than “never 

smoked” ; 

(4) The one-two pack smoker greater than one-half to one pack cigarette 

smoker ; 

(5) The current cigarette smoker greater than ex-cigarette smoker who 

had stopped 20 years. 

In addition, the degree of fibrosis (but not the other three indices) was 

significantly greater: 

(1) In one-half to one pack a day cigarette smokers than in less than 

one-half per day cigarette smokers; 

(2) In two pack per day cigarette smokers than one-two pack a da! 

cigarette smokers; 

I .3) In current cigarette smokers than in ex-cigarette smokers stopped 

3-4 years. 

Degree of fibrosis, rupturing of alveolar septa, and thickening of walls of 

the small arteries (but not arterioles) was significantly greater in current 

cigarette smokers than in ex-cigarette smokers who had stopped 5-19 years. 

,A11 the changes above were statistically significant at the five percent level. 

The degree of fibrosis among men over 60 years of age was studied further 

by relation to smoking habits in an “age standardized” percentage distribution. Increased fibrosis over that found in non-smokers was striking for 

current cigarette smokers but some trends in this direction were also noted for 

current smokers of cigars: of pipes. and of cigars and pipes. 

274 
After review of the design of the study with the investigators and the microscopic sections on which judgments were made, some concern remains about 

two of the four pulmonary abnormalities. Increased thickness of the walls 

of arteries or arterioles is difficult to interpret on microscopic section, as 

contraction with decrease in lumen size may simulate an increase in wall 

thickness. The pad-like attachments are puzzling and the possibility of artifact has been discussed repeatedly. The conclusions drawn from this stud!- 

are based in large part upon the findings pertaining to fibrosis or thickening 

of alveolar septa and rupture of alveolar septa. 

In summary, histopathologic alterations in the mouth, larynx, tracheobronchial tree and pulmonary parenchyma, associated with smoking, have 

been documented in man. The alterations in the bronchi support the 

hypothesis that cigarette smoking is a cause of human chroni,c bronchitis. 

Whereas definite pathologic changes in the lung parenrhvma of man also are 

clearly associated with cigarette smoking, the abnormalities observed in the 

lung parenchyma cannot be related with certainty to recognized disease 

entities at the present time. 

RELATION OF SMOKING TO DISEASES OF THE 

RESPIRATORY SYSTEM 

EFFECTS OF SMOKIKG ON THE NOSE, MOUTH, AND THROAT 

Edema, vascular engorgement, dryness, excess mucus production and 

epithelial changes have been attributed to cigarette smoking on the basis of 

clinical observation. Rhinitis, angina, and laryngitis, also observed frequently in cigarette smokers, are reversible on cessation of smoking. 

-4ggravation and prolongation of sinusitis are also attributed to smoking. 

These observations have become clinical tradition, yet surprisingly little 

documentation of predictable changes in these tissues as a consequence of 

smoking is available (129). 

Changes in the palatal mucosa (“stomatitis nicotina”) and in the laryngeal 

epithelium (45’1 closely associated with tobacco smoking have been considered in the earlier discussion of histopathological alterations. 

Thus, evidence of progressive non-neoplastic disease in the upper respiratory tract, induced by smoking, is lacking. Only in studies of “stomatitis 

nicotina” and of epithelial changes in the larynx has there been adequate 

pathological substantiation of the clinical opinion that alterations are induced 

by smoking. 

SIWOKING AND ASTHIVIMA 

The definition of asthma of the American Thoracic Society will be used 

for the purposes of this report (4j : 

“Asthma is a disease characterized by an increased responsiveness of 

the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy. 
“The term asthma is not appropriate for the bronchial narrowing 

which results solely from widespread bronchial infection, e.g., acute or 

chronic bronchitis; from destructive diseases of the lung, e.g., pulmonary 

emphysema; or from cardiovascular disorders. Asthma, as here defined 

may occur in vascular diseases, but in these instances the airway obstruc. 

tion is not causally related to these diseases.” 

In rare instances, allergy to tobacco products has been ascribed a causative 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 predominantly ( 155 J . The absence of smoking data on unaffected members of the 

same population leaves the question of an additive effect of cigarette smoking 

unanswered. One study suggests that non-smokers may have a slightly 

greater prevalence of asthma than smokers; the possibility of bias due to 

self-selection of the base population could not, however, be excluded in this 

study (84). 

Apart from the exceptions noted above, it is clear that cigarette smoking 

is of no importance as a cause of asthma. A hypothetical contraindication 

to cigarette smoking can be postulated for asthmatics on the basis of the 

physiologic alterations induced in the tracheobronchial tree by tobacco 

smoke. Nonetheless, substantiation of worsening from cigarette smoking 

in asthmatics has not been reported frequently. A cause-and-effect relationship between cigarette smoking and asthma, as defined above, is not 

supported by evidence available. 

RELATION OF SMOKING AND INFECTIOUS DISEASES 

The category, influenza and pneumonia (ISC 480-493)) contributed to the 

excess mortality of smokers observed in six of seven prospective studies 

( Chapter 8, Tables 19 and 26). Details sufficient to warrant conclusions 

about the nature of this association are not presented in these studies, nor 

has the apparent association been evaluated further by careful epidemiolopical research. 

Studies adequate for examination of this association are available for only 

two categories of infectious diseases, upper respiratory viral illness ,and 

tuberculosis I 30 I . Experiments on transmission of common colds failed 

to demonstrate increased susceptibility in volunteers with a history of cigarette smoking (50 J . Jloreover, common colds were detected among 5,500 

employees over a P-year period with approximately the same frequency in 

smokers and non-smokers (110). In a study of illness in a group of families 

under close observation for several years, the frequency and severity of 

common respiratory diseases, such as the common cold, rhinitis, laryngitis, 

acute bronchitis, and nonbacterial pharyngitis, were the same in cigarette 

smokers and non-smokers (21). Similar results were obtained by questionnaires in an analysis of the frequency of common colds in a group (Jf 

college graduates followed over a 20-year period (85). 

276 
A number of studies have suggested a substantial relationship between 

smoking and pulmonary tuberculosis (55, 125, 133, 175). The possibility 

that the relationship is not a direct one needs further careful examination. 

Certain social factors, important to epidemiological assessment in tuberculosis, have not been considered in detail in these studies. Of particular 

interest in this regard is a study (29) in which both cigarette and alcohol 

consumption were found to be in excess in tuberculosis patients as compared 

to the matched controls. The number of cigarettes consumed in the two 

groups was the same, however, at each level of alcohol intake. Matching by 

cigarette consumption failed to weaken the association between alcohol consumption and tuberculosis (29). Thus, the relationship between tuberculosis and smoking in this study was only an indirect one: the association 

was found to occur between smoking and alcohol consumption and between 

alcohol consumption and tuberculosis, rather than between smoking and 

tuberculosis. 

Thus the association between smoking and the infectious diseases is confined at present to a single cause-of-death category : Influenza and pneumonia 

contribute to the excess deaths in cigarette smokers, but the data are insufficient to evaluate this observation. In the limited number of studies available, cigarette smoking has not been shown to contribute to the incidence or 

severity of either naturally acquired or experimentally induced upper respiratory viral infections. 

CHRONIC BRONCHOPULMONARY DISEASES 

Mortality for certain respiratory diseases (bronchitis, bronchiectasis: 

chronic pulmonary fibrosis, chronic interstitial pneumonia, and emphysema) 

increased in the decade 1949-1959 (48) and continues to show an upward 

trend (132, 141) . In 1955, cancer of the lung was certified as the underlying cause of death in 27,133 persons and chronic bronchopulmonary diseases in 11,480 persons. A tabulation of all diagnoses, both contributing 

as well as underlying causes of death, however, showed that cancer of the 

lung was entered upon a total of 28,123 death certificates, whereas the chronic 

bronchopulmonary diseases were certified as contributing to 32,051 deaths 

(47). The possibility that mortality data, as presently recorded, may underestimate the role of chronic bronchopulmonary diseases through incorrect 

listing by the physician as contributory rather than the principal cause has 

also been suggested (115). 

Social security records in 1960 show that chronic bronchopulmonary diseases, particularly emphysema, ranked high among the conditions for which 

disability benefits were allowed to male workers 50 years of age or older 

in the United States (186). 

Chronic bronchitis and emphysema are the chronic bronchopulmonary 

diseases of greatest public health importance in the United States. They 

contribute to the excess mortality of cigarette smokers. but there is little 

information about the effects of smoking on the other chronic bronchoPulmonary diseases. The scope of the subsequent remarks is limited therefore to the possible relationship of smoking to chronic bronchitis and 

27; 
emphysema. Since dexriptions of both were published long before ciga. 

rette smoking became commonplace (13, 14, II4), it seems reasonable to 

suggest at the outset that cigarette smoking alone 1s not the only cause oI 

chronic bronchitis and emphysema. 

Chronic Bronchitis and Emphysema 

DEFINITIONS 

Many definitions of chronic bronchitis and emphysema have been sue. 

gested. For the purposes of this report the definitions proposed by the 

American Thoracic Society (4) will be used: 

“Chronic bronchitis is a clinical disorder characterized by excessive 

mucous secretion in the bronchial tree. It is manifested by chronic 

or recurrent productive cough. Arbitrarily, these manifestations should 

be present on most days for a minimum of three months in the year and 

for not less than two successive years. Many diseases of the lung, e.g., 

tuberculosis, abscess, and of the bronchial tree, e.g., tumors, bronchiec. 

tasis, as well as certain cardiac diseases, may cause identical symptoms: 

furthermore, patients with chronic bronchitis may have other pulmonary 

or cardiac diseases as well. Th us, the diagnosis of chronic bronchitis 

can be made only by excluding these other bronchopulmonary or 

cardiac disorders as the sole cause for the symptoms.” 

Tb is . . definltlon and classification of chronic bronchitis later considers 

complications. listing three: infection, airway obstruction, and pulmonary 

emphysema : 

“Emphysema is an anatomic alteration of the lung characterized by 

an abnormal enlargement of the air space distal to the terminal, nonrespiratory bronchiole, accompanied by destructive changes of the 

alveolar walls.” 

DIAGNOSIS 

The diagnosis of chronic bronchitis is based essentially on descriptions 

of clinical manifestations and is achieved by exclusion. Recollection and 

interpretation on the part of the subject are necessary. There is, no simple 

sensitive pulmonarv function test that will indicate which person has chronic 

bronchitis. 

A clinical diagnosis of emphysema, based on the clinical syndrome and 

certain changes in pulmonary function, is even less exact. The clinical 

features usually encountered in emphysema tend to be very similar to those 

found in chronic bronchitis. Most of the symptoms and signs and many 

of the physiological changes usually thought to indicate the presence of 

emphysema may result from airway obstruction due to bronchitis (66, 180). 

There is no completely satisfactory method of detecting emphysema by 

pulmonaq function testin, - and no pulmonary function test is specific for 

the detection of pathologic lesions of emphysema (521. The clinical detec. 

tion of emphysema is therefore not a simple matter, especially in the presence 

of chronic bronchitis. 

27% 
The following, adapted from the American Thoracic Society-‘s statement 

(4), epitomizes the situation for emphysema: 

Clinicopathologic correlations have demonstrated that certain persons who have this morphologic alteration at autopsy have symptoms of 

pulmonary insufficiency during life and die of this disease. Others showing qualitatively similar pathologic findings had no respiratory symptoms during life and died of unrelated causes. In some persons, emphysema may be strongly suggested by the patient’s symptoms and its 

existence predicted on clinical grounds with considerable accuracy. 

On the other hand, clinical manifestations identical with those of patients 

with emphysema may occur in persons who are not found to have this 

disease at autopsy but who have some other lung disease. Emphysema 

may exist without any clinical manifestations, and its clinical and functional 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 c 1nucal ’ ’ continuum appears to extend from 

bronchitis at one end, through a mixture of the two conditions in the majority of cases, to emphysema at the other end (123). 

An alternative method of assessing the relationship is by study of pathological change. A c 1 ose relationship is found between chronic bronchitis 

and emphysema on purely morphologic grounds. Although emphysema 

occurred more frequently in patients with chronic bronchitis than could be 

accounted for by chance, the two conditions also occurred independently 

of one another (183). 

Three of the possible reasons why chronic bronchitis and emphysema are 

found in association more often than would be expected by chance are the 

presence of a common cause and causation each by the other. The protective 

mechanisms for the upper respiratory tract are cilia and a mucous sheath, 

and the lower respiratory tract mechanisms involve macrophages, the 

lymphatic system, and possibly the fluid lining of the alveoli. Although not 

yet proved, failure of the protective mechanisms of the upper respiratory 

tract might be expected to lead to chronic bronchitis and failure of the protective mechanisms for the lower respiratory tract to emphysema, On this 

hypothetical basis, a common cause would not seem unlikely; noxious environmental agents in gaseous or aerosol form would be likely to affect upper 

and lower respiratorv tracts simultaneously, perhaps with potentiation of 

the injury in the lower tract by particles. Several ways in which chronic 

bronchitis might cause or aggravate emphysema have been suggested: such 

as through trauma resulting from pressure changes induced in the thorax by 

cough (138) and by airway obstruction (114). Clinical evidence of bronchitis preceded clinical evidence of emphysema in over 50 percent of cases in 

one continuing study (137). 

of chronic bron,chitis 153 I. 

Others suggest that emphysema may be a cause 

It seems likely that a common cause. causation 

of emphysema by chronic bronchitis, and causation of chronic bronchitis 

hy emphysema are all operatin g mechanisms, with varying importance in 

different populations and different individuals (123). 

270 
Evidence Relating Smoking to Chronic Bronchitis and Emphysema 

Experimental and pathological evidence bearing on the possible rela. 

tionship of smokin g to chronic bronchitis and emphysema has been presented in an earlier section of this chapter. Epidemiological and clinical 

evidence relating smoking to these diseases will be considered here. 

EPIDEMIOLOGICAL EVIDENCE 

Chronic bronchitis and emphysema probably represent disorders of multiple causality. Such problems are particularly suited for analysis by the 

epidemiological method, especially with regard to the identification of causes 

and the disentanglement of their relations (140). Two types of studies, 

prevalence studies and prospective studies, will be considered. 

PREVALENCE STUDIES.-The most important epidemiological evidence 

available relating smoking to non-neoplastic respiratory diseases is found in 

the prevalence studies which concern the number of cases in a population at 

one point in time. The definitions and criteria for diagnosis of chronic bronchitis and emphysema are not ideal for the purposes of these epidemiological 

surveys. The absence of standardized diagnostic methods in chronic bronchitis and the non-specificity of clinical diagnostic criteria for emphysema 

have resulted in the use of prevalence of symptoms and signs of the respiratory diseases under study as a basis for the surveys. 

Studies of the prevalence of chronic bronchitis and emphysema in the 

United Kingdom and in the United States over the last decade have developed 

highly reliable epidemiological methods. Because of the nature of the diseases 

in question, these surveys present results by the prevalence of specific symptoms and signs, or combinations, rather than diagnostic labels of disease entities. Various levels or grades of severity of the symptoms or signs are 

defined and the data are obtained and handled in a standardized manner, 

permitting comparisons between different populations and communities; 

thus it becomes feasible to evaluate whether smoking is associated with certain signs or symptoms to a greater extent than with other findings. 

( 1. I Smoking and Respiratory Symptoms-( a.) Chronic Cough-The 

common phrase “smoker’s cough” suggests that this symptom is popularly believed to be associated with smoking. Several workers have investigated the 

relationship between smoking and cough; Table 1 lists surveys that tabulate 

the frequency of cough in smokers as compared with non-smokers. Several 

different types of populations have been surveyed; the purpose of presenting 

the findings together is to demonstrate the variation found among the different populations. 

The 1,456 mill workers studied by Balchum et al. ( 16) constituted the random sample of those who volunteered for chest X-rays and pulmonary function tests. Of 1.198 smokers, 23.3 percent reported cough; of the 253 nonsmokers, 10.2 percent reported cough. When the percentage of smokers reporting cough is considered in each of several categories described by packyears of smoking experience, a gradient was found for those reporting cough, 

ranging from 11 percent of those who smoked less than one pack-year of 

cigarettes up to 50 percent of the subjects with 60 or more pack-years of 

smoking experience. 

280 
TABLE I.-Summary of reports cm the predence of cough in relation to 

smoking 

Author I Year 

Numhrr of subjects 

Hrfrr- __- 

ence 

Smokers Non- 

; smokers 

23. R In. 2 

31. 5 13. n 

n.6 4. 1 

21. 2 78 

20.6 1% 7 z 

54. R qu 

12 1 0 

IR. 9 R. 3 

64 IA 

60 I 0 

Boucot and others (251 considered the relationship in older men of smoking and chronic cough in a self-selected population 45 vears of age and older. 

Chronic cough was defined as cough existing for months or rears. Again. a 

considerably higher percentage of the smokers reported cough. and a clearcut 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 conditions. Eighteen percent of 95 men and 17 percent of 77 women admitted 

to cough “more or less every day.” Of the smokers, 27.6 percent admitted 

to daily cough (12 of 42 men, 9 of 34 women), whereas 4.1 percent of nonsmokers 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 percent of 514 non-smokers. 

Fletcher and Tinker (67) studied male workers aged 30 to 59 in the 

British General Post Office and in the London Transport Executive. In the 

G.P.O., 18.7 percent of 166 smokers reported cough during the whole of the 

day in the winter, compared with none of 10 non-smokers. Among smokers 

of the L.T.E., 20.6 percent of 272 admitted to a comparable cough pattern 

whereas none of 30 non-smokers described such a cough pattern. 

Flick and Paton (68) in a study of patients excluding those with cardiac 

and respiratory disorders, found 55 percent of 157 smokers admitted to 

habitual cough compared with 10 percent of 51 non-smokers. After the 

first hundred patients, the admission to the study was weighted in the older 

age groups. The questioning was not as standardized as in some of the more 

recent surveys. 

Olsen and Gilson (148) ~ in their study comparing findings in population 

samples in Britain with those in Denmark, found cough in 32.1 percent of 

162 British smokers and in 18.9 percent of 132 Danish smokers: the corresponding 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 medical-care center, mostly in the age group 45 to 74. The results for cough 

!“constantly present for two years or more”) are presented in terms of 

281 
years of smoking. although the original figures were not published and 

are not included in Table 1. By recalculation, it appears that of those who 

smoked more than 10 years, 43.9 percent of 2,153 subjects had cough 

whereas 18.0 percent of 718 u-ho had smoked less than 10 years had cough. 

In the population samples quoted thus far. the percentage of smokers 

admitting to cough ranged from 17.3 percent to 55 percent, whereas the 

range for non-smokers was 0 percent to 13.0 percent. 

Two other studies show a considerably lower prevalence of cough both 

among smokers and non-smokers in two unusual types of population. Short 

and others I 176) reported the frequency with which unselected policyholders 

admitted to cough on periodic health examination, a time when they would 

be expected to minimize their symptoms. Of 1,292 smokers, 6.4 percent 

admitted to cough whereas 1.6 percent of non-smokers admitted to cough. 

In a study of a parachute brigade, Liebeschuetz (120) found 6.0 percent 

of 83 smokers and none of 52 non-smokers admitted to cough. The study 

of members of this unit with particularly high fitness standards was conducted at the time of discharge. 

Hammond ( 82) has presented the frequency of cough in smokers and has 

compared this with the frequency of cough among non-smokers. The 

subjects were asked to state whether they had a cough at the time of the 

questionnaire. They were also asked the question: “Have you had a cough 

over a period of many years?” They also were asked to estimate its severity 

as slight. moderate, or severe. The analysis of complaints has been reported 

so far for 43,068 questionnaires, 18,697 for men and 24,371 for women. 

For each age group and for both sexes, cough was significantly more common 

among those who smoked cigarettes. The percentage with cough (and the 

percentage with more than a slight cough ) increased rapidly with the numher of cigarettes per day in both sexes and in all four age groups. Except 

for ex-smokers. the relationship between “chronic cough” and smoking habit 

was very much the same as the relationship between “present cough” and 

smoking habits. The proportion of male smokers with the complaint of 

cough \vas almost three times as ,areat as might have been expected on the 

basis of cough prevalence among non-smokers. For women: the ratio of 

observed-to-exl:ected smokers w-ith the complaint of cough was 2.5 to 1. 

The ratio of ohserved-to-expected numbers complaining of cough “more 

severe than slight” \\as 4.09 for males and 2.74 for females. The difference 

in frequent!- of the comf)laint of cough or of cough “more severe than slight” 

bet\\een smokers and non-smokers is statistically significant at the 0.001 

level. The study sample was not a random sample of the population, but it 

pro\-idrs information about the relationship between smoking and various 

complaints for larger numbers of subjects than does any other study. The 

results again make it clear that a larger proportion of cigarette smokers are 

aware of couph than are non-smokers. 

In earh of the surve\s. smoking \cas found to be associated with the 

e\mptom of rough defined in a variety of ways. The studied populations 

varied considerably-from hospital patients. workers in dusty trades and 

clean offices. urban and rural population samples to members of a parachute 

brigade. Despite the diversity of these groups. it is surprising to note the 

consistency of the difference between smokers and non-smokers in regard 

282 
to cough. In each of the surveys, a larger proportion of the subjects admitting 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 production has been tabulated separately for smokers and non-smokers in prevalence surveys. Most of the studies were considered in the section on cough 

and in Table 1. It is interesting that in most of these studies non-smokers 

report sputum production more frequently than cough. 

TABLE 2.--Summary of reports on the prevalence of sputum in relation to 

smoking 

London Transport .._._.........._.._. ~... ._ 1961 

Post Offic% . . . . . .._......_.... -.~ _... ~.._ 1961 

Flick..... .__..._._. ..__...._........_...... _ 1959 

Olsen: 

( Numhw of suhjrctn 

United Kingdom . . . . . . . . . . .._. . . .._..... ~- 

Denmark.-.........--.....~.-..-...-.--...- 

1 Percentages standardized for age. 

T’wcfnt with sputum 

30.4 

34. 2 

21.9 

11.1 

204 

13 R 

1 4”. 3 

’ lY.8 

1 13. R 

19.4 

16. 9 7 0 

1% i 10 II 

64. 7 24. 5 

27. 7 

11.4 

- 

0 

R. :3 

Ferris and Anderson (61) studied a sample of the population of a town; 

their results are presented as percentages: standardized for age. The sample 

sizes were 542 males and 695 females. Among males 40.3 percent of smokers 

and 13.8 percent of non-smokers admitted to sputum production with the 

corresponding figures for females being 19.8 percent for smokers and 9.4 

percent for non-smokers. 

Thus, sputum production in each of the diverse populations was found 

associated with smoking and a consistent difference between smokers and 

non-smokers was present in regard to sputum production. 

(c.1 Cough and Sputum.-The closely associated symptoms of cough and 

sputum have been combined in the results of a number of epidemiologic surveys. Table 3 shows the prevalence of cough and sputum in smokers and 

in non-smokers among samples studied. 

Of particular interest is the series of comparisons made by Higgins and 

his colleagues (88, 90, 92. 93, 95)) on samples drawn from contrasting populations, selected for their different backgrounds. Lapse rates were low, 

and a high degree of uniformity was achieved in the collection of information. In the disparate groups studied-including male and female subjects, 

older and younger, and varyin g in degree of dust exposure and exposure to 

rural or urban environment-the consistent direction and extent of the difference between prevalence rates in smokers and non-smokers demonstrates 

a strong relationship hetween smokin g and productive cough in a variety 

of different situations. and the predominance of smoking as a determinant 

of these symptoms. 

281 
TABLE 3.-Summary of reports on the prevalence of cough and sputum i,, 

rehion to smoking 

Author i year 

(153) 1.400 

(l.3) 

(156) .iz 

WC 91 

;:3 

43 

I 83 

--I---- 

Non- 1 Smokers / x,,,, 

smokws 1 i SInok;.,, 

-__- __ --. 

1: 

flf 

33 

ifi 

364 

1,468 

451 

46 

81 

52 

- 

23. 9 17.2 : I 

4 !, 

24.0 

30.0 

(, 

:i , 

29.8 Ii 1 

29.1 44.7 L. ',4 

:i , 

11.0 

6. 0 1 .* 

I (8 

51.0 2.11 

23.1 4. i 

1% 6 4 !4 

7. 2 u 

The percentages of symptoms noted by Oswald and Medvei (1501 are 

unusually high because occasional cough or sputum is included, in addition to more frequent or persistent symptoms. The results are not shown 

in Table 3, which considers only smoking and cough with sputum; among 

males, 63.7 percent of 2,617 smokers and 47.7 percent of 985 non-smokers 

in Oswald and Medvei’s study had cough or sputum. Among females, 63.2 

percent of 970 smokers and 47.7 percent of 1.272 non-smokers admitted to 

either or both of these symptoms. 

Payne and Kjelsberg (153) presented data on respiratory symptoms, 

lung function, and smoking habits in the adult population of Tecumseh, 

Michigan, where a comprehensive epidemiological study is being made of 

the entire community. Cough and sputum were graded in severity as Grade 

I or Grade II, the latter being defined 3s both cough and phlegm, of which 

at least one was present throughout the day for three months in the year 

or longer. The prevalence of Grade II sy-mptoms is noted in Table 3. During an interview period continued for 18 months, authors were able to 

show that the prevalence of symptoms did not vary significantly with the 

season of the year. Cough and sputum at the Grade II level were admitted 

to by 11 percent of 1.400 cigarette-smokin, m males, and 2 percent of 364 nonsmoking males. The corresponding figures for females were 6 percent of 

888 smokers and 2 percent of 1,X% non-smokers. These Grade II symptoms 

increased in prevalence with advancing age in men, and in women up to 49 

j ears. It is interesting to note that lesser degrees of cough and sputum, 

classed 3s Grade I symptoms. showed little change in frequency after 19 

years of age in either sex. In both sexes, Grade I symptoms of cough and 

sputum uere considerably more prevalent among smokers than among nonsmokers-45 percent of 1,400 smokers and 19 percent of 364 non-smokers 

among the males, and 29 perucnt of 888 smokers and 17 percent of 1,468 nonsmokers among the females. 
Phillips and his associates (156) studied two groups: one of male employees in a steel-making plant, examined as part of an industrial hygiene 

program, and containing sub-groups with different types of industrial exposure, and a second group consisting of 300 patients in a Veterans Administration 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 environmental factors-geographic area, air pollution, specific work environment. 

and smoking-were considered. Fifty-one percent of 823 cigarette smokers 

were recorded as having cough, and 2 percent of 451 non-smokers. In a 

tabulation of chronic cough by age in decades, for cigarette smokers and 

non-smokers, it was shown that the increasing prevalence of chronic cough 

with age was much greater in the cigarette-smoking group. 

Read and Selby (159) in a mixed group of 302 subjects, some of them 

clinic patients, some patients’ friends, and some hospital staff, found that 

male smokers admitted to cough or sputum ten times as often as did male 

non-smokers, and to cough and sputum five times as often. In their female 

subjects the ratios for these categories were eight to one and four to one. 

Liebeschuetz (120) in his study of parachute brigade members found. 

as might be expected, a much lower proportion of subjects with cough and 

sputum; these do not include subjects previously noted in Table 1 as having 

cough alone. 

Considering these surveys as a group, it appears that the presence of 

cough, sputum, or the two symptoms combined, is consistently more frequent 

among smokers than non-smokers, in a variety of samples drawn from 

populations differing so widely in other respects that this association ma) 

be taken to be a general one. 

TABLE 4.-Summary of reports on the prevalence of breathlessness in relation 

to smoking 

ReferNumber of 

subjects 

Smokers 

1.19R 

2. 530 

272 

166 

222 

93 

is 

20 

315 

z 

1.400 

Rx4 

1. 292 

Nonjmokers 

14. 5 

25.3 

R. 5 

9. 0 

19. R 

9. 7 

9% 

42 i 

285 
Some of these surveys are limited in one respect. and some in another. 

The degree to which bias has been avoided varies; several of the survevs 

quoted are open to criticism in this regard. but in others considerable pains 

have been taken to avoid any possihility of suggesting a relationship which 

mav not trulv exist. It would be Mrong to extrapolate from. say. a hospital 

population to the general public. but the groups surveyed vary enough that 

the evidence demonstrates clearly that cigarette smokers more often report 

symptoms of cough. sputum. or both. than do non-smokers. 

t d. I Breathlessness.-Table 4 summarizes the prevalence of breathlessn?ss 

as reported in surveys of various populations. 

Balchum and others (16) in their survey of mill workers. reported a 

greater prevalence of breathlessness among the smokers in their sample, 

Tabulation of the frequency of this complaint by pack-years of smoking 

experience showed a less smooth gradient than for prevalence of cough and 

sputum. 

Densen and others 144), who studied respiratory symptoms in transit 

workers and postmen in New York City. found that 25.3 percent of 2,530 

smokers and 16.9 percent of 514 non-smokers admitted to breathlessness of 

Grade II or worse iindicated by positive answers to specific questions on the 

questionnaire). 

Fletcher and Tinker (67)) in a study of Transport Executive employees 

and Post Office employees, had only one non-smoker out of 40 complain of 

breathlessness. and 38 smokers out of 438. These figures are for workers 

complaining of dyspnea (a positive answer to the question, “DO you have 

to walk slower than most people on the level?” or “Do you have to stop 

after a mile or so on the level at your own pace?“). 

In the four studies by Higgins listed in the table. the difference in 

prevalence of breathlessness between smokers and non-smokers is more 

variable. In his study 188) in the agricultural district of the Vale of 

Glamorgan, the author bresents prevalence figures for the various symptoms 

among females in two age groups. those under age 45, and those over age 

45. His reason for doing so is the considerable difference in frequency of 

the smoking habit between women in these two age-groups. In both the 

age groups of females, the prevalence of breathlessness is greater among the 

non-smokers. but the difference is not statistically significant. Female 

smokers in the over 45 age groups have rather more cough and sputum and 

wheeze than the non-smokers. but apparently have less breathlessness. In 

his study in Annandale (93 1 the prevalence of breathlessness among all men 

and all women studied MBS greater in the non-smokers than in the smokers. 

although the numbers of non-smoking men and of smoking women were 

small. When males aged 55 to 64 are considered. from the three surveys 

1901, breathlessness is more prevalent among the smokers. and the same 

thing applies to the t\\ o different age groups of males studied in Staveley (92 I. 

Payne and Kjelsberg i 153 I : in their survey of a total community, ha\-e 

stated that among the men, cigarette smokers were affected more often with 

breathlessness at all ages. Among the women, cigarette-smokers had a higher 

prevalence of breathlessness than non-smokers below the age of 40, and above 

this age the non-smokers had a higher prevalence. Considering all ages 

together. twice the proportion of male smokers admitted shortness of breath 

286 
compared to non-smoking males; the prevalence of shortness of breath among 

females was the same for smokers and non-smokers. 

Short et al. (176)) in a study of answers to a questionnaire on routine medical examination for insurance purposes, obtained a larger percentage of complaints of breathlessness amon g smokers than among non-smokers. 

Hammond 182) also presents figures for the frequency with which breathlessness was noted in answer to a questionnaire by 18.697 men and 24.371 

women. The relationship between breathlessness and smoking is less clear 

than the relationship between cough and smoking. A significantly greater 

proportion of complaints of breathlessness was encountered among male 

and female cigarette smokers, both for total complaint of breathlessness and 

complaint of breathlessness “more severe than slight.” The ratio of observed-to-expected complaints of breathlessness among male smokers was 

1.97 for the total number with this complaint, and 2.62 for those complaining of breathlessness more severe than slight. The ratios for females were 

1.36 and 1.49. A consideration of the frequency of complaints of shortness 

of breath in smokers and in non-smokers, by age group and by sex, shows 

that the excess of breathlessness among cigarette smokers is greater and more 

consistent for men than for women. The older age groups of women show 

only a slight excess. 

Thus, the relationship between smoking and the symptom of breathlessrrcss 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 populations. For males the association is clear: male cigarette smokers complain of breathlessness more often than do non-smokers, particularly in the 

older age groups. Females present a less uniform pattern. In several surveys, females show a higher prevalence of breathlessness in non-smokers 

than in smokers, particularly in the older age-groups. The reasons for this 

sex difference have not been explained. 

(e.) Smoking and Chest Illness.-The percentage of smokers and nonsmokers who reported chest illness in the three vears prior to the interview 

TABLE 5.-Summary of reports on history of chest illness in the past 3 years 

in relation to smoking 

I 

.-__ _-- .~~ 

114-422 o-64-20 
date is presented in Table 5. For men, the prevalence was consistently higher 

among smokers, and in one study (93), the association of smoking and chest 

illness was apparent for the younger (25-34) as well as the older males (5% 

6.11. For female smokers and non-smokers, the prevalence of chest illness 

was about the same. 

cf.) Combinations of Symptoms.-A number of prevalence studies (7,54, 

61, 62. 77, 150 ) hav-e reported results, either totally or in part, under diag 

nostic headings which cannot be translated into single symptoms. The 

symptom combinations and the names applied to them varied; some of the 

studies gave the percentages of smokers and non-smokers with “any” signs 

or symptoms rather than specified combinations. The results are presented 

in Table 6. 

TABLE 6.-Su.mmary of reports on the prevalence of combinations of certain 

symptoms in relation to smoking 

Smokers 

.___~ 

(7) 3.214 

(54) 779 

I::{ 

340 

209 

NOD Smokers NOW 

smokers smokws 

-- 

677 

524 

21.7 10.3 

29.4 19. 5 

’ 24.9 ’ 7.3 

’ 17.5 ’ 9.4 

42. 6 15. 0 

20.0 10.0 

43.0 31. 4 

Per@ant with 

symptoms 

16. 1 9. 7 

15.4 9.1 

Ashford and his colleagues I 71 found twice the proportion of “respiratory symptoms” among Scottish coal mine workers who smoked than among 

those who did not smoke. “Respiratory symptoms” were regarded as present in those who have caugh or sputum all day for more than three months per 

year and walk slower than others on the level, or wheeze, or if the weather 

affects their chest. or if they have had a chest illness in the last three years. 

Those who had wheeze and who claimed the weather affected their chest 

were also classed under “respiratory symptoms.” 

Edwards and others (541 I-resented the percentage of smokers and nonsmokers with bronchitis. according to clinical assessment by one of 11 

general practitioners coooerating in the survey. No attempt to standardize 

the diagnosis was reported. Of ii!, smokers. 29. I percent had “bronchitis” 

compared with 19.5 percent of 524 non-smokers. 

Ferris and Anderson (61: presented the prevalence of “irreversible obstructive lung disease.” which was defined as the report that wheezing or 

whistling in the chest occurred most days and nights, that the subject had 

to stop for breath when walking at his own pace on the level, or had a forced 

expiratory volume in the first second of expiration ( F.E.V. 1.0) of less than 

00 percent of the total forced expiratory volume. According to this definition. 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 percent. These percentages were age-standardized. 

ln a study conducted in a flax mill, Ferris, et al (621 presented the prevalence of “chronic respiratory disease,” defined as productive couEh on 

four days of the week, for three months of the year: for three successive 

years; or wheezing in the chest most days and nights; or breathlessness. of 

Grade III or more, in the winter; or asthma diagnosed by the physician at 

the time of the survey; or F.E.V. 1.0 less than 60 percent of forced vital 

capacity. rnder this definition, 42.6 percent of 54 male smokers and 15.0 

percent of 20 male non-smokers had “chronic respiratorv disease.” For 

females. the figures were 10.0 percent of 10 smokers and lo.0 percent of 60 

non-smokers. 

Goldsmith and others c 77’). in their study of longshoremen. classified the 

subject as having a “respiratory condition” if he had ever had asthma or 

bronchitis, or currently was “troubled by constant coughing.” With this 

definition, 43.0 percent of 1:238 moderate or heavy smokers had a respiratory condition, compared with 31.4 percent of 744 non-smokers. 

Oswald and Medvei (1501, defining “bronchitis” as disability from acute 

exacerbations of chest symptoms, or breathlessness, or both, found a prel-- 

alence of 16.1 percent among 2,617 male smokers. and of 9.7 percent among 

985 non-smokers. In their female subjects, 15.4 percent of 970 smokers 

compared with 9.1 percent of 1,272 non-smokers had “bronchitis.” 

Although these various combinations of symptoms are not comparable. 

the consistency and extent of the differences between prevalence of symptom combinations in smokers and non-smokers are striking. 

(g.j Relationship between Symptoms or Signs and Amount Smoked.-In 

several surveys, smoking categories were based on the daily consumption or 

total lifetime consumption (16, 61, 67, 82. 90, 153, _ In the majority. the 

Prevalence of cough and sputum increased with amount smoked. A recent 

study (82) showed that those who smoked cigarettes of low nicotine content 

tended to cough less than those who smoked cigarettes of high nicotine content. Other symptoms and measurements of pulmonary function show a less 

clear relationship between prevalence and amount smoked. 

fh.) Rebztionship bettceen Symptoms and Signs and Method of Smokinp.- 

The numbers of pipe and cigar smokers in many prevalen,ce studies are so 

small that conclusions about the effects of these methods of smoking are not 

reliable, but they all tend to show that pipe and cigar smokers are likely to be 

intermediate between non-smokers and cigarette smokers in prevalence of 

Symptoms and signs. 

(i.) Vent&tory Function-Pulmonary tests and the method of presenting 

results, though varyin g widely, are important features of the prevalence 

surveys. 

ln the study by Ashford and others 171 of 4,014 coal miners, the forced 

exPiratory volume in the first second of expiration (F.E.V. 1.0’1 of nonsmokers was slightly higher than that of the smokers. and a small but statistically siunilicant difference was found even after correction for differences attributable to physique. No consistent relationship was reported 

between the amount smoked and the average F.E.V. 1.0. 

289 
Balchum and others (16) reported that 19.3 percent of 1,194 srnoken 

and 7.8 percent of 243 non-smokers had an “abnormal” test, an F.E.Vr. l.O 

of less than 70 percent. When the “abnormal” test was compared \,ith 

the number of pack-years of cigarettes smoked, a steady increase in tl,,. 

proportion of men with decreased F.E.V. 1.0 was found with inereasirlz 

pack-years. 

Ferris and Anderson (61) showed a progressive decrease in the ,,,,,a,1 

F.E.V. 1.0 in successive age groups for male smokers, male non-smoker, 

and female non-smokers. In males. there was also a regular decrease i,, 

F.E.V. 1.0 within each age group with increase in the number of cigarrtt,., 

currently smoked. In females, there was little difference in the F.E.V. l.(, 

between smokers and non-smokers except in one age group. The peak 

expiratory flow rate showed a decrease with age and a decrease within th, 

age groups w.ith cigarette smoking. 

Chivers (36) showed that smoking. age. and height were correlated “ia. 

nificantly with the expiratory flow rate. The older and shorter men ha,1 

greater impairment associated with smoking. 

Flick and Paton (68) demonstrated a distinct decline, beginning at about 

40 years of age. in expiratory flow rate among smokers, but no appare,,t 

change among non-smokers until 70 years of age. 

Fletcher and Tinker (67), measuring expiratory flow rates by the Peak 

Flow Meter, found one group of smokers, but not another, had lower value. 

than the non-smokers. In a later paper (58). Fairbairn, Fletcher and Tinker 

reported that the Peak Flow Meter appeared to be a less satisfactory screen. 

ing test than the forced expiratory volume. 

Franklin and Lowell (73), in a study of 1,000 apparently healthy factor, 

workers, found the mean expiratory flow rate during the third quarter 01 

maximal forced expiration to be approximately 20 percent less in “heal\ 

smokers” than in “light smokers.” “Heavy smokers” were defined as thos, 

who had smoked 30 pack-years or more, and “light smokers” less than 111 

pack-years. 

Higgins (88) showed a decrease in F.E.V. 0.75 among smokers of 15 

grams or more of tobacco per day. compared with non-smokers and with 

those who smoked less than 15 grams a day. For this test, there was ncl 

significant difference between non-smokers and the lighter smoking group. 

Peak how measurements indicated a difference between heavy and light 

smokers. and also between nonsmokers and light smokers. In each lo-year 

age group over 45, the peak flow was lower in smokers than in non-smokers. 

but the numbers were small. Th ese differences are not explained by differ. 

ences in age, social class, or occupation. The difference between smoker5 

and non-smokers in peak flow measurement was not seen in tests of women. 

Higgins ( 90) summarized the difference in F.E.V. 0.75 in a variety of 

different samples of the population. Tabulations for 16 different groups 

included miners and ex-miners in varying pneumoconiosis categories and 

non-miners in the same district, and agricultural workers in two different 

areas in Britain. In the 13 group.. s in which comparisons were feasible. 

non-smokers recorded a higher F.E.V. 0.75 than the smokers. The small 

over-all difference in means was recorded (as indirect Maximum Breathing 

Capacity) as 50 liters per minute, which was significant at the one percent 
level. By pooling subjects with different occupations in the older age 

groups, differences between light and heavy smokers were apparent, though 

not statistically significant. Higgins commented on a strong trend in the 

prevalence of persistent cough and sputum, with amount of tobacco smoked. 

without a significant trend in ventilatory capacity. His possible explanation 

of the difference is that smokers are more likely to give up smoking or reduce the amount smoked, once their lung efficiency becomes impaired. than 

they are when their only symptoms are cough and sputum. 

In their study of miners and foundry workers in Staveley I 92 j. Higgins 

and his colleagues showed a decrease in the F.E.V. 0.75 in smokers. Nonsmokers, light smokers. and heavy smokers ( 15 grams per da!- and over I 

ranked in that order for decreasing F.E.V. 0.75, both in men aged 25 to 3-l 

and in those aged 55 to 61. The d i ff erence between the non-smokers and 

the light smokers was smaller than the difference between the light and the 

heavy smokers in the younger age group; in the older age group the difference was larger between non-smokers and light smokers. 

Olsen and Gilson ( 148) measured the F.E.V. 0.75 in a sample of a population in Denmark for comparison with British population samples. Cigarette smokers had a lower mean F.E.V. 0.75 than cigar smokers or pipe 

smokers who in turn had a higher mean than non-smokers. but these differences were not statistically significant. If non-smokers. cigar smokers, and 

pipe smokers are grouped-together, non-cigarette smokers had a significantly 

higher mean F.E.V. 0.75 than the cigarette smokers. 

Payne and Kjelsberg (153)) who presented mean values of F.E.V. 1.0 for 

men and women by age group and by smoking category, found a lower mean 

value for cigarette smokers than for non-smokers in each age group of men 

Over 19. In the 16-to-19 ape group. cigarette smokers had a slightly higher 

mean value than non-smokers. A comparison of the mean values by age group 

for non-smokers and for cigarette smokers shows a decline with advancing 

Years in both, but more rapid in the cigarette smokers. Women also show a 

decline of F.E.V. 1.0 with advancing vears. but this is no more marked and no 

more rapid in the cigarette smokers than in the non-smokers. The reduction 

in F.E.V. 1.0 in cigarette smokers amounted to 7 percent and :< percent of 

the mean values in non-smoking men and women respectively when values 

adjusted to the over-all mean age of 40 years were compared. 

Read and Selby (159) measured peak flow rates in smokers with cough. 

and in smokers with cough and sputum. To a statistically significant extent. 

male smokers without cough or sputum showed a more rapid fall in peak ilow 

rate with age than expected. Male smokers with cough showed a still more 

rapid fall with age. and those with cough and sputum. the most rapid fall. 

Amount smoked had no obvious effect. Results were similar for women. 

Revotskie and his colleagues i 165), who grouped smokers in Framingham 

as never smoked, light smoker, medium smoker, and heavy smoker. found 

that the F.E.V. 1.0 measurements show a gradient from never smoked to 

heavy smoker in the “normal” subjects, both for males and females: in the 

other groups this gradient is not clear. The “Puffmeter” ratios tended in 

the same direction. but in less clear-cut fashion than the F.E.V. 1.0 

measurements. 

20 I 
Goldsmith and others (77) showed that smokers, regardless of amount 

smoked. have a slight diminution in the pulmonary function test results, Eden 

in the absence of respiratory symptoms. The total vital capacity was murh 

less sensitive in this regard than the F.E.V. 1.0 or the “Puffmeter” 

Longshoremen with “respiratory conditions,” and particularly th 

reading, 

0%~ with 

shortness of breath, had a more marked decrease in pulmonary function 

Cough was associated with the greatest diminution of pulmonary function 

measurement. 

The relationship between cigarette smoking and abnormal results of pul. 

monary function tests is more difficult to evaluate from the published SUf,.p,., 

than is the relationship between symptoms and cigarette smoking. pL,I. 

monary function test results are influenced by several factors, among which 

are age, physique: and perhaps occupation. When allowance is made for 

these factors. there appears to be a clear difference in the ventilatory funr. 

tion between smokers and non-smokers. 

In the majority of prevalence surveys, the subjects were not forbidden to smoke pcor 

to pulmonary function testing. Since acute alterations due to smoking might be mix. 

interpreted as due to a permanent abnormality, it is important to examine the magnitude 

and significance of the acute effects of smoking on pulmonary function. 

Rickerman and Raracb (2Oj found no consistent alterations in vital capacity or in 

maximum breathing capacity before and after their patients and normal subjects smoked 

three cigarettes. Simonsson (177) found a small decrease in the F.E.V. 1.0 in 13 ,,f 

16 young subjects after smoking, and the difference for the group was statistically sic. 

nificant. No significant change was found in the total capacity. 

Several authors have studied more sensitive tests of airway resistance and lung co,,,. 

pliance. Eich. Gilbert and .4uchincloss (56) made compliance and airway resistaac? 

measurements, using an esophageal balloon technique, on a group of nine healthy ad& 

five of whom had respiratory symptoms. No difference was detected after one cigarette. 

In a group of emphysematous patients, a statistically significant increase in airflow rp. 

sistance was found, but without significant change in compliance. 

Attinger and others (8) reported no statistically significant difference in expiratop 

airflow resistance or compliance, but in a later study of subjects with pulmonary diseasr. 

significant physiological changes-increased mechanical resistance and increased work of 

breathing--were noted after smoking one or two cigarettes. 

Motley and Kuzman (142) studied the lung volumes, spirometry, blood gas exchaner. 

and pulmonary compliance in 141 subjects, before and after smoking two cigarettes. Not 

all of these measurements were made on all subjects. There was no significant change in 

the mean values of vital capacity performed after smoking, some subjects showing a 

d errease, and others an increase. Six of the normal subjects showed a decreased compliance after smoking. In 33 subjects with cardiac or respiratory disease, 17 had a sip. 

nificant decrease in romplianrr after smoking. The authors felt that a decrease in pul. 

monary romplianre was the only notable abnormality which followed smoking acut+ 

Forced rxpiratory volume and airflow rcsiktance studies were not included. 

Miller i ]34a), who constructed pressure-volume work loops, demonstrated increased 

airflow rP<ibtancr and unexrn \rntilation, resulting in increased work of breathing. 

This author ~~oncluti~~d that inhalation of ciparrttv make gives rise to a significant 

degree of unevrn \enfi]atinn. which is responsible for the observd decrease in dynamic 

compliance and incrraqcd elastic work of hrrathinp. 

Nadel and Comroe I 146) showed a mran decrease of 31 percent in the ratio of airwa! 

conductance to thoraric gal; volume after inhalation of cigarette smoke, the changes being 

highly slpnificant Ftatisticatly, and similar for smokers and non-smokers. Repeated testing after smoking showed the responv 10 last for from 10 to 80 minutes. Without inhalation. no significant change in the conductance to thoracic gas volume ratio occurred. 

Inhalation of Isuprol aerosol before smoking prevented the increase in airway resistance. 

and when piben after cigarette smokin, v it counteracted the increase. 

292 
Zamel, Youssef, and Prime (194) found that the smoking of one cigarette increased 

airway resistance in smokers and non-smokers, and that the inhalation of Isuprel reduced 

airway resistance in both groups. The authors comment that the difference in airway 

&stance between non-smokers and cigarette smokers is apparent only when the actual 

P<timates of airway resistance are compared with predicted values based on lung volume, 

hecause 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 

romparable unless allowance is made for the volume of the lungs in each. 

To sum up this point, the acute effects of cigarette smoking upon pulmonary function 

are t-xpressed 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 

4xiently sensitive to detect the acute effects. The differences in results of pulmonary 

function tests between smokers and non-smokers, therefore, are greater than can be 

arcounted for by acute effects from a recently smoked cigarette. 

PROSPECTIVE STUDIES.-In six of seven prospective studies. chronic hronrhitis and emphysema contribute markedly to the excess mortality among 

rigarette smokers; in the remaining study the mortality ratio was increased 

hut to a lesser extent. In all these studies, mortalitv 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 obsdrred 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 

5.6. For emphysema, the observed number of deaths among smokers was 

115, whereas the expected number was 8.8, or a mortality ratio of 13.1. 

In a recent study (82)) information is available on the first 22 months of 

follow-up of 447,831 men between the ages of 35 and 89, of whom 11.612 have 

died. The observed number of deaths attributed to emphysema in cigarette 

smokers was 115 whereas the expected number was 15.4; the mortality ratio 

was 7.47. For other pulmonary diseases the mortality ratio was 1.65, with 

185 observed deaths in smokers as compared with 112.7 expected deaths. The 

duration of follow-up is not yet sufficiently long to allow one to expect deaths 

from chronic bronchopulmonary disease in persons who w-ere not afflicted at 

entry. 

The paucity of published morbidity studies is striking. Very little is 

known of the progression in population samples of symptoms or signs related 

10 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 

%ptoms and signs in the different categories of subjects constituting popu- 

(ation samples. This is unfortunate. as prospective studies of morbidity irr 

Population samples can best measure the possible health hazard of smoking. 

Several studies are under way, but some of the important information will 

Qcern changes occurring 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-vear follow-up study on ventilator); 

QPacity in a population sample in a mining district in Wales. In nonminers this measurement fell more over the five years in smokers than in 

“Oa*smokers and within the smoking group there was an increasing fall 

with amount’of smoking. When the miners and ex-miners were ronsidered. 

293 
the pattern was less clear. In three of the four groups, the F.E.V. 0.73 o, 

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.ul, 

was intended, and that the sample was not very suitable for this purpose. 

Thus, morbidity data are insufficient at present to be of value irr tllr 

estimation of the possible health hazard of smoking. Prospective studies i,, 

populations followed over long periods offer the best opportunity for fillille 

the major gaps in knowledge about the relationships of smoking and chror,i, 

bronchopulmonary diseases. 

CLINICAL EVIDENCE 

Several studies concerned with individual patients rather than define~l 

populations form the basis for the clinical evidence. 

A current and continuing study of an “emphysema registry” with ,=iltr, 

based on clinical and physiological evidence, has been reported ( 138). of 

131 patients with diffuse pulmonary emphysema, 20 had findings at necrops! 

of widespread alveolar destruction. Clinical differentiation was made int,, 

three groups: a “bronchitic” group in whom a history of cough was prer;e,,t 

years before onset of dyspnea on exertion, a “dyspneic” group in whoa, 

cough and dyspnea occurred at about the same time or in whom dyspnea 

occurred first, and an “asthmatic” group who gave a history of episodi,. 

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 baaed on smoking habit< 

of Americans. In a later report (137), the number of patients had in. 

creased to 150; 99 percent of the “bronchitic” group, 98 percent of thr 

“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 (1, 125) have also noted the fre. 

quent association of cigarette smoking with emphysema. A number of 

clinical studies indicate the frequent association of cigarette smoking in 

chronic bronchitis I 106. 117, 139). 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 controls (75) ; no difference in smoking habits was found in 

the men, and 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 all of the studies have 

. . 

shown smoking to be a more common habit among the bronchrtrs or 

emphysema patients than among the control 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 
Relationship of Smoking, Environmental Factors, and Chronic 

Respiratory Disease 

ATMOSPHERIC POLLUTION 

BASIS FOR INTERRELATIONSHIP AND RELATIVE MGNITUDE OF EXPOSURE- 

(1.) Experimental Evidence.-The threshold level below which chroni,c exposure to a toxic agent fails to produce damage to the respiratory system has 

not been established even for many of the known components of tobacco 

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. chemiral. and biologic interaction may result from 

multiple, simultaneous exposure to a wide variety of the components. Potentiation of the irritative action of certain gases when inhaled together it ith an 

aerosol of small particles has been demonstrated (5, 113, 152). A possible 

example of potentiation may be found by- contrast of two natural atmospheric 

pollution disasters; the 1962 London smog episode had lower 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. .\t present. information concerning the effects on the respiratory 

system is available for relatively few of these components. In an earlier 

chapter of this report (Chapter 6)) the toxic actions of the particulate phase 

and major gas constituents of cigarette 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 widely. largely 

because of differences in source, meteorologic variables, and photochemical 

interactions. The effects of some of the major gas constituents in air pollution upon the respiratory system are known and will be presented briefly. 

Sulfur dioxide is rapidly absorbed into the lung but removed slowly, persisting for one week after a single exposure (15). Interference with the 

clearance mechanism is produced through effects upon the mucus. rather 

than by inhibition of ciliary motility as seen with cigarette smoke. 

Sulphur dioxide usually exerts its effects upon the upper bronchial tree but 

intensive, protracted exposure may result in damage to the more distal airways. In animals, short-term: high-level exposures result in increased airflow 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 low-level sulfur dioxide exposures have produced fibrotic bronchitis (86). Experimental human exposures confirm the 

increased airflow resistance which may occur without symptoms; augmentation of the effects of sulfur dioxide in the presence of particulates also has 

heen observed 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 irh-alation of 1 ppm. produces chronic 

bronchitis and bronchiolitis in rodents, especially rats. but no detectable ef295 
fects are produced in dogs (179). ITnder conditions of acute exposure, 

somewhat more than 1 ppm. of ozone produced increased airway resistance 

and decreased diffusing capacity in man (76). It is not known whether 

chronic low-level 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, 14). No data 

are available on the long-term inhalation qf low concentrations of irradiated 

exhaust gases or photochemical smoc g 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 msg. 

nitude of exposure to constituents common to both cigarette smoke and 

atmospheric pollution are made diffcult by the complex nature of the char. 

acteristics of the exposure, such as the relationship between concentration 

and duration, and by the paucity of studies specifically designed to evaluate 

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 variation in concentration and composition, particularly in the United States. 

The relative magnitude of each type of exposure cannot be accurately 

calculated at present. h+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 aimospheric pollution. The 

smoking of 30 cigarettes per day is estimated to provide a 20- to 25.fold greater 

exposure to carbon monoxide than would be experienced in the ambient air 

of Pasadena by non-smokers (76). The effect of smoking on carboxyhemo. 

globin levels in man has been determined in studies utilizing carbon monoxide in air expired by cigarette smokers and non-smokers with similar high 

level community atmospheric pollution exposure. The effect of cigarette 

smoking on carboxyhemoplobin levels in man was more than five times 

greater than the effect of atmospheric pollution, even when the studies were 

performed in a relatively heavily polluted area (76). 

The relative magnitude of exposure to the oxides of nitrogen may also 

he estimated for cigarette smokin F 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 

in cigarette smoke vary from l-C5 to 665 ppm.: moreover. virtually complete 

absorption occurs after inhalation (23 ) . During periods of cigarette smoking, therefore: a suhstantiallp greater exposure to nitrogen oxides would br 

expected C 76 I . 

Since cigarette smoking is likely to occur on every day of the year and 

periodically throughout the day and evening, and community air pollution 

is likely to be relatively less common or persistent. the relative magnitude of 

the effect of cigarette smoking for the bulk of the United States population 

is certain to he greater than indicated above. The exact magnitude is per296 
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 greater exposure results from cigarette smoking than 

from atmospheric pollution, even when studies are conducted in a highly 

polluted atmosphere in the United States. Whereas 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 evidence 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 atmospheric pollution. A detailed consideration of the epidemiological data is available (76) ; only selected studies 

will be considered here. 

The prevalence of cough and sputum in the United States appears to be 

determined much more bv the amount and duration of cigarette smoking 

than by atmospheric pollution. In comparable samples of cigarette smokers 

in New York, Baltimore, Los Angeles, and San Francisco no major differences 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 prevalence of chronic nonspecific respiratory disease was present, however, in 

cigarette smokers than in non-smokers of similar age and sex (6, 61). In 

veterans paired by age and smokin p 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). In 

studies in areas with varying severity of atmospheric pollution, the effects 

of cigarette smoking have been observed (16, 77, 165). Pulmonary emphysema is relatively rare in a population of non-smokers who live mostly 

in the areas of California with greatest atmospheric pollution (51). 

In the United 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 

Txcess mortality remains even after removal of possible differences in clasjification and misinterpreted diagnosis (63) _ Moreover, differences in toiacco consumption do not appear to be sufficiently large to account for the 

fxcess mortality due to bronchitis in the United Kingdom. 

In producing simple, uncomplicated bronchitis, cigarette smoking appears 

o have the same result in the two countries (63). Although recurrent chest 

llness and evidence of airway obstruction are more frequent in cigarette 

mokers, the frequency of more advanced forms of chronic bronchitis does 

29i 
not increase ivith increasingly heavy smoking (65). Atmospheric l~ellu~ 

tion in the United Kingdom exerts its effects primarily among chronic bra,. 

chitics (117) almost all of whom are cigarette smokers (64) ; it also is a 

major factor in the urban-rural differences in prevalence and mortalit, 

(37, 65. 154, 160). When those findings are considered together with ether 

evidence documenting the role of atmospheric pollution in chronic bronchi,;, 

(28, 76, 161), it seems probable that atmospheric pollution and cigarr,tt,, 

smoking in the United Kingdom are at least additive and possibly synerpi,. 

tic in their deleterious effect on the respiratory tract. 

Thus the epidemiological evidence on the relationship of cigarette sm,,k. 

ing, atmospheric pollution, and chronic respiratory disease clearly indiecltr\ 

that the dominant association in the United States is between cigaren,. 

smoking and chronic respiratory disease. In the United Kingdom, disalllir,,, 

. . respiratory condrtrons and death are more likely to occur among pers,,r,, 

who smoke cigarettes and are exposed frequently to atmospheric pollutal,~. 

than in those exposed to either alone. 

OCCUPATIONAL FACTORS 

Occupational exposures provide other possible etiologic factors in tl,(. 

production of chronic bronchitis and emphysema. There is little convinc+ 

evidence on specific relationships. Nevertheless, epidemiological studit., 

(reviewed in 123, 128) provide information on the relative importance (,f 

cigarette smoking and occupational exposures in selected groups. 

In a study of 4,014 Scottish coal miners (7)) the prevalence of respirator, 

symptoms among non-smokers was appreciably lower than among smoker> 

of the same age, and the ventilatory function of non-smokers in all agr 

groups was significantly higher than that of the smokers. Among smokcn 

of 50 years of age and above, the prevalence of pneumoconiosis tended to bP 

lowest among the men who smoked the most and highest among men whr, 

smoked the least. However, the prevalence of pneumoconiosis was higher 

in ex-smokers than among smokers and non-smokers, except in the oldest 

age group, suggesting that men with pneumoconiosis tend to reduce their 

tobacco consumption. The possibility that factors of selection eliminatp 

some persons with symptomatic pneumoconiosis from study groups should 

also be considered in the evaluation of these studies. 

In a sample of 11317 men aged 40 to 65 who worked in a variety of non. 

dusty and dusty environments, a greater prevalence of bronchitis (dail! 

cough for at least the preceding six months, productive of one teaspoon of 

sputum per day) was found in moderate and heavy smokers 127). Betweerl 

the non-smokers and the heavy smokers, a significant difference was found 

at all age levels, and also between non-smokers and moderate smokers except 

in the oldest age group. Although effects from dust exposures could be 

noted. it appeared that cigarette smokin, 01 was the dominant etiologic factor 

in “chronic bronchitis” in this selected group. 

Among alkaline dust workers it was found that the dusts in the working 

environment did cause some increase in respiratory illness but the sig. 

nificance of the dusts in the production of respiratory disability, either 

functional or pathological, was not as important as the number of cigarettes 

smoked daily (36). 

298 
In a study of 1.274 steel workers. non-smokers had a comparatively low 

incidence of chronic cough, regardless of their job classification or conditions of work or residence. Th ere was a direct relationship between chronic 

cough and the number of cigarettes smoked daily in each occupational 

category (156) . Cigarette smoking was of greater importance in determining the prevalence of chronic cough than was the occupational exposure. 

In a study of New England flax mill workers, 161 subjects were subjected 

to a questionnaire and measurements of pulmonary function to determine 

the presence of “chronic non-specific respiratory disease.” The prevalence 

of such a syndrome. based on a certain combination of symptoms or signs. 

was related to age. sex. smoking habits. years of exposure to dust. and 

estimated inhaled quantity of dust. The effect of smoking “far out-shadows 

any effect due to age or occupational exposure to dust” (62). 

The studies by Higgins and his colleagues (87. 88. 89. 91. 92 I show that 

smoking and occupational exposure are both related to the prevalence of 

chronic respiratory disease but do not allow quantitative assessment of their 

relative importance in the populations defined. As this series of studies was 

undertaken to demonstrate any effect from industrial exposure. and the populations surveyed were such that exposure to occupational dusts was more 

varied than in the general population. the importance of the effect of smoking 

in this group of studies on the production of respiratorv symptoms is rather 

convincing (1231. The authors comment in one of the papers in this series: 

“So important is the influence of tobacco smoking that it is essential to allow 

for differences in smoking in comparable groups before drawing ‘conclusions 

about the importance of other factors.” 

In a recent study of bituminous coal miners (103,) ex-smokers had pulmonary function results and prevalence of respiratory symptoms comparable 

to those of non-smokers; no impairment was attributed to pure pipe or cigar 

smoking. Cigarette smokers had the most symptoms of respiratory disease 

and. except for vital capacity, they had the lowest pulmonary function. The 

authors comment: “. . . although smoking definitely impairs pulmonary 

function, the impairment of pulmonary function by years worked underground is clear and separate from the effect of smoking.” 

In a study of 7,404 metal mine workers, aged 35 years and older. a comparison was made of the effects of 20 years’ aging and smoking on pulmonaryventilation, as measured by the F.E.V. 1.0 in individuals without X-ray evidence of silicosis. A decrease of 23 percent occurred with the process of 

aging 20 years. For heavy smokers (those who smoked for 25 years or more 

and now smoke more than 20 cigarettes a day 1, there was an additional decline of 10 percent over that of aging alone. “The decline in pulmonary 

function associated with heavy smoking was equivalent to the decline that 

comes about by the process of aging 10 years. For the entire group of 

metal mine workers, the reduction in pulmonary function assmiated with 

smoking was equivalent to half the effect of heavy smoking, or about five 

years of aging” (128). 

The population at risk from occupational exposure is relatively small compared to the population of cigarette smokers. Among occupational groups, 

cigarette smoking is an important variable that must be considered in all 

299 
studies of rhronic hronchopulmonary disease. 

the relative importance of cigarette smokin, 

In most studies, but not all, 

u is greater than occupational ex. 

posures in the production of symptoms and signs of chronic bronchitis ur 

emphysema. 

SUMMARY 

Tobacco smoke is a heterogenous mixture of a vast number of compounds. 

several of which have the ability to produce damage to the tracheobronchial 

tissues and lung parenchyma. Retention of inhaled cigarette smoke particles 

in the respiratory system of man is about 80-90 percent complete with breatl, 

holding of two-to-five seconds. Particles penetrate deeply into the respira. 

tory tract and are deposited on the surface of the terminal bronchi&. 

respiratory bronchioles, and pulmonary parenchyma. Little information j, 

available concerning the specific toxic properties of the particulate phaW 

components. Gas phase components probably have a diffuse though not 

uniform pattern of distribution. It seems likely on the basis of the physical 

characteristics of gas absorption and distribution, that a substantial portioa 

is retained along the upper bronchial tract. Certain of the gases known to 

be present in cigarette smoke are capable of producing pulmonary damaPe 

in experimental animals and man. 

Cigarette smoke produces significant functional alterations in the upper 

airways. Like several other agents, cigarette smoke can reduce or abolish 

ciliaty motility in experimental animals. Post-mortem examination of 

bronchi from smokers s.hows a decrease in the number of ciliated cells, 

shortening of the remaining cilia, and changes in goblet cells and mucouY 

glands. The implication of these morphological observations is that func. 

tional impairment would result. 

Cigarette smoke is also capable of interference with functions in the lower 

airways. In animal experiments, cigarette smoke appears to affect the phy. 

sical characteristics of the lung lining layer and to impair alveolar stability. 

Alveolar phagocytes ingest tobacco smoke components and assist in their removal from the lung. This phagocytic clearance mechanism decompensates 

under the stress of protracted high-level exposure to cigarette smoke and tnbacco smoke components accumulate in the pulmonary parenchyma of 

experimental animals. 

The acute effects of cigarette smoking result in an increase in airway rr. 

sistance but clinical expression of this change in pulmonary function is ncft 

common. The chronic effects of cigarette smoking upon pulmonary function are manifested mainly by a reduction in ventilatory function as measurer! 

by the forced expiratory volume. 

Histopathological alterations occur as a result of tobacco smoke exposure 

in the tracheohronchial tree and in the lung parenchyma of man. Changes 

regularly found in chronic bronchitis-increase in the number of goblet 

cells. and hypertrophy and hyperplasia of bronchial mucous glands-are more 

often present in the bronchi of smokers than non-smokers. In experimental 

animals, cigarette smoke consistently produces significant functional altera. 

300 
tions in the upper and lower airways. Such alterations could be expected to 

interfere with the cleansing mechanisms of the lung. 

Pathological changes in pulmonary parenchyma, such as rupture of alveolar septa and fibrosis, have a remarkably close association with past history of cigarette smoking. Th ese I changes cannot be related with rertaint? 

IO emphysema or other recognized diseases at the present time. 

Chronic bronchitis and pulmonarv emphysema are the chronic hronrhoIbulmonary disease* of greatest health significance. Epidamiologiral evidence 

provides the most important information relating cigarette Pmokinc to 

chronic bronchitis and emphysema. All seven of the major prospective 

qtudies show a higher mortality rate for chronic bronchitis and emphysema 

among cigarette smokers than among non-smokers. In the few studier; that 

have examined mortalitv rates separatelv for the tjro conditions. chronic 

bronchitis or emphysema, both rates ar, higher among cigarette smokers 

than among non-smokers. In one of the studies. the risk of mortalit!- from 

rhronic bronchitis was four times greater among cigarette smokers than 

among non-smokers. Emphysema was listed as a cause of death 13 times 

more frequentlv among smokers in one studv. and 71& times more frequpntlv 

among smokers in another study. 

Extensive prevalence studies. based largely on prevalence of specific 

Fymptoms and signs rather than imprecise diagnostic labels. show a consistently more frequent occurrence of cough, sputum, or the two symptoms 

combined. in cigarette smokers than in non-smokers. These manifestations 

are the clinical expressions found in chronic bronchitis. The results of the 

prevalence surveys. however. offer less direct evidence relating cigarette 

Smoking to pulmonary emphysema. as clinical diagnosis of this disease is less 

exact. Breathlessness, which may result from emphysema or airway obstruction in chronic bronchitis, is associated with cigarette smoking -in males. 

Particularly in the older age groups. but not females. Similarly. a consistent 

association of cigarette smokin, w and chest illness is more evident for males. 

In the prevalence surveys in which various combinations of respiratory 

manifestations have been studied, a greater prevalence of these conditions is 

found consistently among cigarette smokers. 

The majoritv of clinical studies have noted a relationship between cigarette smoking and chronic bronchitis and emphysema. Cigarette smoking is 

a more Scommon habit in the United States among patients with chronic 

bronchitis or emphysema than in the control groups studied. The clinical 

studies also show a decrease in clinical manifestations of chronic bronchoPulmonary disease after cessation of smoking. 

Examination of experimental evidence shows that the lung may be damaged by noxious agents found in either tobacco smoke or atmospheric pollution. In the United States, Ihe noxious agents from cigarette smoking 

are much more important in the causation of chronic broncho[mlmonar~ 

disease than are those present as community air pollutants. In the United 

Kingdom, persons who smoke cigarettes and are exposed frequentl! to atmospheric pollutants are at greater risk of developing disabling respirator! 

di%se and death than those exposed to either alone. 

301 
The relative importance of cigarette smoking also appears to be mu,+, 

greater than occupational exposure as an etiologic factor for the chronic 

bronchopulmonary diseases. 

Cigarette smoking does not appear to cause asthma; in rare instances 

allergy to tobacc,o products has been ascribed a causative role in asthma: 

like syndromes. 

Evidence does not support a direct association between smoking and in. 

fectious diseases of the respiratory system. The category, influenza and 

pneumonia, contributes moderately to the excess mortality of cigarett? 

smokers but other data are r?ot available to extend this observation. Th,. 

sssociation of cigarette smoking and tuberculosis does not appear to be ;, 

direct one, but both are associated with the use of alcohol. 

Only for “stomatitis nicolina” and the epithelial changes in the laryn, 

i? there sufficient documentation to substantiate the clinical opinion that non. 

malignant alterations in the mouth. nose. or throat are induced by smoking. 

The changes in the mouth are more often associated with pipe smoking hut 

disappear after cessation of smoking. 

CONCLUSIONS 

1. Cigarette smoking is the most important of the causes of chronic, 

bronchitis in the [-nited States. and increases the risk of dying from chronic 

bronchitis. 

2. A relationship exists between pulmonary emphysema and cigarettp 

smoking but it has not been established that the relationship is causal. The 

smoking of cigarettes is associated with an increased risk of dying fronl 

pulmonary emphysema. 

3. For the bulk of the population of the United States, the importance oi 

cigarette smoking as a cause of chronic bronchopulmonary disease is much 

greater than that of atmospheric pollution or occupational exposures. 

-L Cough, sputum production. or the two combined are consistently morr 

frequent amon? cigarette smokers than among non-smokers. 

5. Cigarette smoking is associated with a reduction in ventilatory fun,.- 

tion. Among males, cigarette smokers have a greater prevalence of breath 

lessness than non-smokers. 

6. Cigarette smoking does not appear to cause asthma. 

7. Although death certification shoha that cigarette smokers have a motl. 

erately increased risk of death from influenza and pneumonia, an association 

of cigarette smoking and infectious diseases is not otherwise substantiatefl. 

REFERENCJ3 

1. Abbott. C. A.. Hopkins, W. A.. Van Fleit. W. E., Robinson. J. S. :\ 

new approach to pulmonary emph)-sema. Thorax 8: llG-32: l!M. 

2. Albert. R. E., Nelson. N. Special report to the Surgeon General’. 

IZd\ iaory Committee on Smoking and Health. 

302 
3. Altschuler, 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 on 

Inhaled Particles and Vapors. Oxford, England: April 1960. London. Pergamon Press. 1961. p. 281-92. 

6. Anderson, D. O., Ferris, B. G., Jr. Role of tobacco smoking in the 

causation of chronic respiratory disease. New En? 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, ventilatory function, and radiological pneumoconioais, 

amongst coal workers at three Scottish collieries. Brit J Prev Sot 

Med 15: 10617, 1961. 

8. Attinger, E. O., Goldstein, M. M., Segal, M. S. Effects of smoking 

upon the mechanics of breathing: I. In normal subjects. II. In 

patients w-ith cardiopulmonary disease. Amer Rev Tuberc 77: 1-16. 

195s. 

9. Auerbach, 0.: Stout, A. P.: Hammond, E .C., Garfinkel. L. Bronchial 

epithelium in former smokers. N Eng J Med 267: 119-25. 1962. 

10. Auerbach, 0.. Stout. A. P.. Hammond. E. C.. Garfinkel. L. Changes 

in the bronchial epithelium in relation to cigarette smoking and in 

relation to lung cancer. New Eng J Med 265: 253-67, 1961. 

11. Auerbach. O., Stout. &\. 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. 

12. Auerbach, 0.. Stout. A. P., Hammond, E. C.. Garfinkel, L. Smoking 

habits and age in relation to pulmonary changes: rupture of the 

alveolar septums. fibrosis and thickening of walls of small arteries 

and arterioles. New Eng J Med 269: 1045-53. 1963. 

13. Hadham: C. Observations on the inflammatory affections of the mucous 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., Dybicki, J., Meneely, G. R. The dynamics of sulphur 

dioxide inhalation. AMA Arch Industr 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 industrial city. Amer Rev Resp Dis 86: 675-85, 1962. 

17. Ballenger, J. J. Experimental effect of cigarette smoke on human 

respiratory cilia. Yew Eng J Med 263: 832-5, 1960. 

18. Baumberger, J. P. The amount of smoke prodmed from tobacco and 

its absorption in smoking as determined bv electrical precipitation. 

J Pharmacol Exp Ther 21: 47-57, 1927. 

714-422 O-64-21 303 
19, Bwklake. M. R.. Goldman. H. I.; Bosman, A. R., Freed, C. C. Longterm effects of exposure to nitrous fumes. Amer Rev Tuberc and 

Pul Dis 76: 398309: 1957. 

20. Bickerman. H. A.. Barach, A. L. The effect of cigarette smoking on 

ventilator\ function in patients with bronchial asthma and obstructive 

pulmonary emphysema. 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. Borhe. R. D.. Quill&an. J. J. The effects of air pollutants on tissue 

cultures. Fed Proc Bull 18: 559, 1959. 

23. Bokhaven. C., Niessen, H. J. Amounts of oxides of nitrogen acd 

carbon monoxide in cigarette smoke, with and without inhalation. 

Nature tlondon) 192: 458-9, 1961. 

24. Boren, H. Carbon as a carrier mechanism for irritant gases. Presented at California State Department of Public Health Sixth Air 

Pollution Medical Research Conference. San Francisco, 1963. 

25. Boucot. K. R., Cooper, D. A., Weiss, W. Smoking and health of older 

men. 1. Smoking and chronic cough. Arch Environ Health (Chicagoi 4: 59-78, 1962. 

26. Bower. G. Respiratory symptoms and ventilatory function in 172 

adults employed in a bank. Amer Rev Resp Dis 83: 684-9, 1961. 

27. Brinkman. G. L.. Coates, E. 0.. Jr. The prevalence of chronic bronchitis in an industrial population. Amer Rev Resp Dis 86: 47-55, 

1962. 

28. Bronchitis. Report of a Sub-Committee of the Standing Medical Advisory Committee. Scottish Home and Health Department. Edinburgh. H M Stationer). Off: 1963. 59 p. 

29. Brown. K. E.. Campbell. A. H. T o b acco, alcohol, and tuberculosis. 

Brit J Dis Chest 55: 150-8, 1961. 

30. Butler, W. T., Alling. D. W.. Knight, V. Special report to the Surgeon General’s .4dvisory Committee on Smoking and Health. 

31. Chang. S. C. lIicroscopic properties of whole mounts and sections of 

human bronchial epithelium of smokers and non-smokers. Canrer 

10: 121&61. 1957. 

32. Chang. S. C. Studies of bronchial epithelium from smokers and nonsmokers. [Abstract] Proc Amer Ass Cancer Res 2: 99-100, 1956. 

X Chang. C. S. Studies of subepithelial tissue of bronchi from smokers 

and non-smokers;. ( Ab-t c ract] Proc Amer Ass Cancer Res 2: 286-i. 

1058. 

34. Chapman. I.. Rrdish. C. H. T o b acco-induced epithelial proliferation 

in hutllan 5uLjtW. Long-term effects of pipe smoking on epithelium 

of hard palate. .\%IA Arch Path 70: 13310, 1960. 

%5. Chatgidakis. C. 8. A study of bronchial mucous glands in white South 

Afric,an pold miners. A>lA Arch Environ Health 1: 53% 12. 1960. 

XX Chi\tw. C. 1’. Respiratory function and disease among workers in 

alkaline (lust-. Brit J Industr Med 16: 51-60, 1959. 

::;. Colle;t~ of Genrral Practitioners: Chronic bronchitis in Great Britain : 

A national sur\e\. Brit Med J 2: 973-9, 1961. 

304. 
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 Sot 51: 13730, 1961. 

39. Dalhamn, T. The effect of cigarette smoke on ciliary activity in the 

upper respiratory tract. AMA A\rch Otolaryng 70: 166-8, 1959. 

-10. Dalhamn, T., Rhodin, J. M- ucous flow and ciliary activity in the 

trachea of rats exposed to pulmonary irritant gas. Brit J Industr 

Zled 13: 110-3, 1956. 

-El. Davies, C. M. The handling of particles by the human lung. Brit. 

Med Bull 19: 49, 1963. 

$2. 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. 

53. Deirhmann, W. B.. Witherup, S., Dierker. M. Phenol studies 12. J 

Pharmacol Exp Ther 105: 265. 1952. 

-1-1. Densen, P. M., Breuer? J., Bass, H. E., Jones, E. W. New York City 

Health Department Chronic Respiratory Disease Survey. Interim 

Report. May 1963. 

45. Devine, K. D. Pathologic effects of smoking on the larynx and oral 

cavity. Proc Mayo Clin 35: 319-52, 1960. 

46. Djuric, D., Raicevic, P.. Konstantinovic, I. Excretion of thiocyanate 

in the urine of smokers. Arch Environ Health 5: 12-5, 1962. 

47. Dorn, H. F. Personal communication to the Surgeon General’s Advisory Committee on Smoking and Health. 

48. Dorn, H. F. The increasing mortality from chronic respiratory diseases. Amer Stat Ass Proc Sot Stat Set p. 14%53,1961. 

49. Dorn, H. F. The mortality of smokers and non-smokers. Amer Stat 

,%ss Proc Sot Stat Set p. 34-71, 1958. 

50. Dowling, H. F., Jackson, G. G., Inouye, T. Transmission of the experimental common cold in volunteers. 2. The effect of certain host 

factors upon susceptibility. J Lab Clin Med 50: 31625. 1957. 

51. Dysinger, P. W., Lemon, F. R. Pulmonary emphysema in a non-smoking 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. Pathogenesie of pulmonary emphysema. 

Arch Intern Med 111 I 34, 1963. 

54. Edwards, F., M c K eown, T., Whitfield, A. G. W. Association hetweeir 

smoking and disease in men over sixty. Lanret 1: 196. 1959. 

55. Edwards; J. H. Contribution of cigarette smoking to respiratory 

disease. Brit J Prev Sot Med 11: 10-21, 1957. 

56. Eich, R. H., Gilbert, R., Auchincloss. J. H.. Jr. The acute effect of 

smoking on the mechanics of respiration in chronic obstructive 

pulmonary emphysema. i\mer Rev Tuberc 76: 22. 1957. 

57. Ermala. P., Holsti, L. R. Distribution and absorption of tobacco tars 

in organs of the respi,-atory tract. Cancer 8: 673. 19.55. 

58. Fairbairn, A. S., Fletcher, C. M.. Tinker, C. M., Wood. C. 11. ,A corn--£ 

parison of spirometric and peak expiratory flow measurements in 

men with and without chronic bronchitis. Thorax 17: 10%71. 1062. 
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 and toxicology; Fassett, D. W. and Irish, D. D. eds. Toxicology. 2 rev ed. New York. Interscience Pub., 1962. Chapter 44, 

p. 1991-2036. 

61. Ferris, B. G., Jr., Anderson, D. 0. The prevalence of chronic respiratory disease in a New Hampshire town. Amer Rev Resp Dis 86: 

165-77, 1962. 

62. Ferris, B. G., Jr., Anderson, D. O., Burgess, W. A. Prevalence of respiratory disease in a flax mill in the IJnited States. Brit J Industr 

Med 19: 18@-5, 1962. 

63. Fletcher, C. M. Chronic bronchitis in Great Britain and America. 

An account of chronic bronchitis in Great Britain with a comparison between British and American experience of the disease. Dis 

Chest 44: l-10, 1963. 

a. Fletcher, C. M. Chronic bronchitis: Its prevalence, nature and pathogenesis. Amer Rev Resp Dis 80: 483-98, 1959. 

65. Fletcher, C. M. Chronic Bronchitis, Smoking and Air Pollution. Tobacco and Health. Charles C. Thomas, Springfield, Illinois, 1962. 

p. 380-401. 

66. Fletcher, C. M., Hugh-Jones, P., McNicol, N. W., Pride, N. B. The 

diagnosis of pulmonary emphysema in the presence of chronic 

bronchitis. Quart J Med 32-51, 1963. 

67. Fletcher, C. M.. Tinker, C. M. Chronic bronchitis; a further study 

of simple diagnostic methods in a working population. Brit Med J 

1: 1491-8. 1961. 

68. Flick, A. L.. Paton. R. R. Obstructive emphysema in cigarette smok. 

ers. AMA Arch Intern Med 104: 51826, 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 t Chicame I 83: 9X-50. 1961. r 

il. Foster. D.. Gassney. H. An investigation of the retention of smoke 

1)articulate matter by inhaling and non-inhaling type of cigarette 

smoker. Presented at the Tobacco Chemists Conference. Hoboken: 

S.J.. Oct. 1958. 

72. Frank. N. R.. .\mdur. 11. 0.. Worcester. J.. Whittenherger. J. L. 

Effects of acute controlled exposure to SO1 on respiratory mechanics 

in healthy adult males. J Appl Phy-siol 17: 232-8. 1962. 

7.3. Franklin. W.. Lowell. F. C. L:nrecognized airway- obstruction assocrated with smoking: A probable forerunner of obstructive pulmonary rtnphy scma. Ann Intern lied 5 1: 379-86. 1961. 

ill. Freeman. G.. Haydon. G. Effects of continuous low-level exposure 

to nitrogen dioxide. Presented at California State Department of 

Public Health Sixth Annual Air Pollution Medical Research Conference. San Francisco. 1963. 

306 
75. Fry, J. Chronic bronchitis in general practice. Brit Med J 1: 190-4, 

1954. 

76. Goldsmith, J. R. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

77. Goldsmith, J. R., Hechter, H. H., Perkins, N. M., Borhani, N. 0. Pulmonary function and respiratory findings among longshoremen. 

Amer Rev Resp Dis 86: 867-X. 1962. 

78. Gray, E. LeB. Oxides of nitrogen: Their occurrence toxicity, hazard. 

AMA .1rch Industr Health (Chicago1 19: 379-86, 1959. 

79. Gross, P., Hatch, T. Pulmonary clearance: Its mechanism and relation to pulmonary disease. J Occup Med 5: 191-4, 196.3. 

80. Guillerm, R., Badre: R., Vignon. B. Inhibitory effects of tobacco 

smoke on the ciliary activity of the respiratory epithelium and nature 

of the responsible constituents. Bull Acad Nat Med (Paris) 145: 

416-23, 1961. 

81. Haagen-Smit, A. J., Brunelle. bl. F.. Hara. J. Nitrogen oxide content 

of smokes from different types of tobacco. AMA Arch Industr 

Health (Chicago) 20: 399-1.00. 1959. 

82. Hammond, E. C. Special report to the Surgeon General’s Advisor? 

Committee on Smoking and Health. 

83. Hatch, T. Respiratory dust retention and elimination. Proc Pneumoconiosis 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. WHO 

Monogr Ser No 46: 159-220, 1961. 

87. Higgins, I. T. T. An approach to the problem of bronchitis in industry : 

Studies 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 ventilator>- 

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. T o b acco smoking, respiratory symptoms, and ventilatory capacity. Studies in random samples of the population. Brit 

Med J 1: 325-9, 1959. 

91. Higgins, I. T. T., Cochrane, A. L. Chronic respiratorv 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. Population studies of chronic respiratory disease: 4 comparison of miners, 

foundry workers and others in Staveley, Derbyshire. Brit J. Industr 

Med 16: 255-68, 1959. 

307 
93. Higgins, I. T. T., Cochran, J. B. Respiratory symptoms, bronchitis and 

disability in a random sample of an agricultural community in Dumfriesshire. Tubercle 39: 296301, 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. Respiratory symptoms and pulmonary disability in an industrial town. Survey 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 bronchial tree and removal by ciliary 

action. New Eng J Med 254: 1154-60, 1956. 

97. Hilding. -1. C. On cigarette smoking, bronchial carcinoma and ciliary 

action. 3. Accumulation of cigarette tar upon artificially produced 

deciliated islands in the respiratory epithelium. Ann Otol 65: 

11630, 1956. 

98. Hill, L. The ciliary movement of the trachea studied in vitro. Lancet 

2: 802-5, 1928. 

99. Hogner, R. Tobacco poisoning without using tobacco. Amer Med 

26: 111-2, 1920. 

100. 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, 1958. 

101. Holland, W. W. A respiratory disease study of industrial groups. 

Arch Environ Health I Chirago) 6: 15-22, 1963. 

102. Horton, A. W.. Tye. R., Stemmer. K. L. Experimental rarcinogenesis 

of the lung. Inhalation of gaseous formaldehyde or an aerosol of 

coal tar by C3H mice. J Nat Cancer Inst 30: 31-43, 1963. 

103. Hyatt, R. E., Kistin. A. D.. Mahaw. T. K. Respiratory disease in 

southern West Virginia coal workers. Amer Rev Resp Dis (In 

Press). 

104. Ide, G., Suntzeff. V., Cowdry. E. V. .\ comparison of the histopathology of the tracheal and bronchial epithelium of smokers and 

non-smokers. Cancer 12: .173&U, 1959. 

105. Jimenez-Diaz. C., Sanchez Cuenca, B. Asthma produced by susceptibility- to unusual allergies. Linseed, insects, tobacco, and chicory. 

J Allerg 6: 39-103. 1935. 

106. Joules. H. A preventive aljproach to common diseases of the lung. Brit 

Med J 2: 125963. 19.5-1. 

107. Keith. C. H., New some. J. R. Quantitative studies on cigarette smoke. 

1. An automatic smoking machine. Tobacco 144: i 13 ) 2632. 

Mar 29. 1957. 

108. Kensler, C. J.. Battista, S. P. Components of cigarette smoke with 

ciliary-depressant activity. Their selective removal by filters containing activated charcoal granules. New Eng J Med 269: 1161-66, 

1963. 

308 
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: 1X-2.1. 1961. 

110. Kler, J. H. An analysis of colds in industry. Tr Amer Acad Opthal 

Otol 49: 201-7. 19.15. 

111. Kordik, P.; Billbring. E.. Burn. J. H. Ciliary movement and acetylcholine. Brit J Pharmarol 7: 67-79. 1952. 

112. Krueger, L1. P.. Smith, R. F. Effects of gaseous ions on tracheal 

ciliary rate. Proc Sot Exp Rio1 Med 98: 112-I. 1958. 

113. LaBelle. C. W., Long. J. E.. Christofano. E. E. Synergistir effects of 

aerosols. Particulates as carriers of toxic vapors. ?rrch Tndustr 

Health (Chicago I 11: 297-304. 1955. 

114. Laennec, R. T. H. A treatise on the disease of the rhest. Translated 

by J. Forbes. Published under the auspices of the Librar! of the 

New York Academy of Medicine by Hafner. NY 81-97. 1962. 

115. Landau, E., Morton, J. .4n epidemiologic view of chronic pulmonarv 

insufficiency in the United States. Amer Rev Resp Dis 83: 1057. 

1961. 

116. Langer, G.: Fisher, M. .4. Concentration and particle size of cigarettesmoke particles. AMA Arch lndustr Health t Chicago I 113: 372-y. 

1956. 

117. Leese, W. L. B. An investigation into bronchitis. Lancet 2: 762-5. 

1956. 

118. Leuchtenberger, C., Leuchtenberger, R.. Doolin, P. F. A correlated histological, cytological and cytochemical study of the tracheobronchial 

tree and lungs of mice exposed to cigarette smoke. Cancer 11: $90- 

506, 1958. 

119. Leuchtenberger, C., Leuchtenberger, R.. Zebrun, WY., Shaffer. P. A 

correlated histological, cytological, and cytochemical study of the 

tracheobronchial tree and lungs of mice exposed to cigarette smoke. 

2. Varying responses of major bronchi. Cancer L<: 721-:<2. 1960. 

120. Liebeschuetz, H. J. Respiratory signs and svmptoms 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 to 

the Surgeon General’s Advisory Committee on Smoking and Health. 

122. Lindsey, A. J. Some observations on the chemistry of tobacco smoke. 

In: James, G., Rosenthal, T.. eds. Tobacco and Health. Springfield. 

Ill., Thomas, 1962. p. 21. 

123. Loudon, R. G. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

124. Lowe, C. R. An association between smoking and respiratory tuherculosis. Brit Med J 2: 1081-6, 1956. 

125. Lowell, F. C., Franklin, W., Michelson, A. I,., Schiller. I. W. Chronic 

obstructive pulmonary emphysema: 4 disease of smokers. .4nn 

Intern Med 45: 268-74, 1956. 

126. Lowry, T., Schuman, L. M. Silo-fill er’s disease- -a syndrome caused bv 

nitrogen dioxide. J.4M.4 162: 153-60, 1956. 
127. Maliszewski. T. F., Bass. D. E. True and apparent thiocyanate in body 

fluids of smokers and nonsmokers. J Appl Physio18: 289-91,195s 

128. Manos, N. E., Cooper, W. C. Special report to the Surgeon 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 cigarette smoke. [Abstract] Proc Amer Ass Cancer Res 2 : 325,195s. 

131. Mendenhall. W. L., Shreeve, K. Effect of tobacco smoke on ciliary 

action. J Pharmacol Exp Ther 69: 295, 1940. The effect of cigarette 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) 

C 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 lung 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 retention in 

the respiratory tract. Amer Rev Resp Dis 85: 526-33, 1962. 

136. Mitchell, R. S. Personal communication to the Surgeon General’s Advisory Committee on Smoking and Health. 

137. AIitchell, R. S., Filley, G. F. P ersonal communication to the Surgeon 

General’s Advisory Committee on Smoking and Health. 

138. Mitchell, R. S.: Toll, G.. Filley, G. The early lesions in pulmonary 

emphysema. Amer J Med Sci 243: 409-18,1962. 

139. Mork, T. A comparative study of respiratory diseases in England and 

Wales and Norway. Yorwegian Universities Press: 1962. Also: 

ACTA Med Stand 172 i Suppl384) : l-100,1962. 

140. Morris, J. Iv. I-ses of epidemiology. Edinburgh, Livingstone. 1957. 

135 p. 

141. IIloriyama. I. M. Ch ronic respiratory disease mortality in the [-nited 

States. Public Health Rep 78: 743-8, 196:3. 

142. Motley. H. L.: Kuzman, W. J. Cigarette smoke. Its effect on pulmonary function measurements. Calif &Led 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 h! 

drugs. J Pharmacol Exp Ther 141: 79-83, 1963. 

144. Murphy-. S. D., Leng, J. K.- Ulrich, C. E., Davis, H. V. Effects on experimental animals on brief exposure to diluted automobile exhaust. 

Presented at Air Pollution Research Conference, December 9, 1961. 

California. 

116. Nadel. J. A., Comroe, J. H. Acute effects of inhalation of cigarette 

smoke on air\\ ay conductance. J Appl Physiol 16: 713-6. 1961. 

310 
147. Nakashima, T. Pharmacological studies on ciliary movement. Nagasaki Igasakkai Zassi 14: 2219-37, 1936. [Abstract in English] 

Jap J Med Sci, Sect pharmacol 11: ,12, 1938. 

148. Olsen, H. C., Gilson. J. C. Respiratory symptoms, bronchitis and 

ventilator): capacity in men. An Anglo-Danish comparison, with 

special reference to differences in smoking habits. Brit Med J 1: 

450-6, 1960. 

149. Oswald, N. C., Harold, J. T.: Martin. W. J. Cliniral pattern of chronic 

bronchitis. Lancet 2: 539-13, 1953. 

150. Oswald, N. C., Medvei, V. C. Chronic bronchitis; the effect of cigarette 

smoking. Lancet 2: 833%&y, 1955. 

152. Pattle, R. E. Properties. function. and origin of the alveolar lining 

layer. Proc Royal Sot Biol 118: 21T--10, 1958. 

152. Pattle, R. E., Burgess, F. Toxic effects of mixtures of sulfur dioxide 

and smoke with air. J Path Bact 73: 411-9,1957. 

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 .imerican Public 

Health Association in Miami Beach, October 17, 1962. 

154. Pemberton, J., Goldberg, C. Air pollution and bronchitis. Brit Med 

J 2: 567-70, 1953. 

155. Phelps, H. W., Koike, S. Tokyo-Yokohama asthma. Amer Rev Resp 

Dis 86: 55-63, 1962. 

156. Phillips, A. M., Philiips, 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. Pro&: A. Some preliminary experiments in the study of cigarette 

smoke and its effect upon the respiratory tract. Ann Otol48: 176 

94, 1939. 

158. Rakieten, N., Rakieten, M. L.: Feldman, D., Boykin. M. J., Jr. Mammalian ciliated respiratory epithelium. Studies with particular reference to the effects of menthol, nicotine, 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. ,1ir pollution and other local factors in respiratory disease. Brit J Prev Sot Med 12: 94-103: 1958. 

161. Reid, D. D. General epidemiology of chronic bronchitis. Proc Roy 

Sot Med 49: 767-71, 1956. 

162. Reid, L. Chronic bronchitis and hypersecretion of mucus. Lect Sci 

Basis Med 8: 235-8, 1958-59. 

163. Reid, L. Measurement of the bronchial mucous gland layer: A diagnostic yardstick in chronic bronchitis. Thorax 15: 132-41, 1960. 

164. Reid, L. M. Pathology of chronic bronchitis. Lancet 1: 275-8. 195-1. 

165. Revotskie, N., Kannell, W., Goldsmith, J. R., Dawber, T. R. I’ulmonary function in a community sample. Amer Rev Resp Dis fi6: 

907-11, 1962. 

311 
166. Rigdon, R. H. Effect of tobacco condensate on the respiratory tract of 

the white Pekin duck. AMA Arch Path (Chicago) 69: 55-63,1960. 

167. Rivera, J. A. Cilia, ciliated epithelium and ciliary activity. Int Ser 

Monogr Pure Appl Biol 15: 1-167, 1962. 

168. Rosen, F. L. Bronchial asthma in the young male adult. Ann Allerg 

4: 247-60, 1946. 

169. Rosen, F. L., Levy, A. Bronchial asthma due to allergy to tobacco 

smoke in an infant. A case report. JAMA 144: 620-1, 1950. 

170. Ryan, R. F., McDonald, J. R., Devine, K. D. The pathologic effects of 

smoking on the larynx. AMA Arch Path (Chicago) 60: 472-80, 

1955. 

171. Sanderud, K. Squamous metaplasia of the respiratory tract epithelium. 

2. Relation to tobacco smoking, occupation and residence. Acta 

Path Microbial Stand 4.3: 47-61, 1958. 

172. Saunders, W. H. Nicotina stomatitis of the palate. Ann Otol 67: 

618-27, 1958. 

173. Schoettlin, C. E. The health effect of air pollution on elderly males. 

Amer Rev Resp Dis 86: 878-97,1962. 

175. Shah, J. R., Warawadekar, M. S., Deshumkh, P. A., Phutane, P. N. Institutional survey of pulmonary tuberculosis with special reference to 

smoking habits. Indian J Riled Sci 13: 381-92, 1959. 

176. Short, J. J., Johnson, H. J., Ley, H. A., Jr. The effects of tobacco smoking on health. A study of 2.031 medical records. J Lab Clin Med 

24: 586-9, 1939. 

177. Simonsson, B. Effect of cigarette smoking on the forced expiratory 

flow rate. Amer Rev Resp Dis 85: 534-9, 1962. 

178. Sollmann, T., Gilbert. A. J. Microscopic observations of bronchiolar 

reactions. J Pharmacol Exp Ther 61: 272-85, 1962. 

179. Stokinger, H. E.. Wagner. W. D., Dobrogorski, 0. J. Ozone toxicity 

studies. 3. Chror?ic injury to lungs of animals following exposure 

at low levels. AMA Arch Industr Health 16: 51L-22, 1957. 

180. Sweet, H. C., Wyatt, J. P., Fritsch, A. J.. Kinsella, P. W. Panlobular 

and centrilobular emphysema: Correlation of clinical findings with 

pathologic patterns. Ann Intern Med 55: 565-81, 1961. 

181. Thoma. K. H. Stomatitis nictrtina and its effects on the palate. Amer 

J Orthodont 27: XLli. 1911. 

182. Thurlbeck. W. RI. 4 cliniro-pathological study of emphysema in an 

.\merican hor;pital. Thorax 18: 59-67, 1963. 

183. Thurlbeck. W. M.. Angus. G. E. The relationship between emphysema 

and chronic bronrhitis as assessed morphologically. Amer Rev Resp 

Dis 87: 815-3, 1965. 

181. Thurlbeck. W. M.. i\ngus, G. E., Pare. J. A. P. Mucous gland hypertrophy in chronic bronchitis, and its occurrence in smokers. Brit 

J Dis Chest 5i: 73-7X. 1963. 

185. Truhart. H. Ein heitra;: zur nicotinwirkung. Dorpat, 1869. Thesis, 

70 p. 

186. U.S. Departnlrnt of Health. Education, and Welfare. Disability applicants under the old-age survivors and disability program. 1960 

selected data. Januar\- 1962. 

312 
187. Von Oettingen, W. F. Toxicity and potential dangers of nitrous 

fumes. Public Health Bull 272: l-34, 1941. 

188. Vassar, P. S., Culling, C., S aunders, A. M. Flourescent histiocytes in 

sputum related to smoking. AMA Arch Path iChicago\ 70: 649-52, 

1960. 

189. Walker, I. C. The treatment of patients with bronchial asthma with 

subcutaneous injections of proteins to which they are sensitive. 

J Med Res 36: 423-80, 1917. 

190. Westermark, T. Gaseous ions and their possible role in the etiology 

of lung cancer and some observations on free charges in cigarette 

smoke. Acta Med Stand 170: tSupp1 369) 119-20, 1961. 

191. Wolff, W. -I., Tuttle. J. G., Godfrey, J. M. Radioautographic method 

for studying deposition of cigarette smoke in the dog lung. Abstract 

Fed Proc 13: 32-4, 1954. 

192. Wolff, W. A.. Purdom. E. G.. Isenhower, J. A. The use of radioisotopes as tracers in cigarette smoke. N Carolina Med J 15: 159- 

63, 1954. 

193. Wright, G. W.. Lloyd. T. Th e pulmonary reaction of normal and 

emphysematous persons to inhalation of SO,, fly ash. and moisture. 

3d Air Pollution Research Seminar. U.S. Public Health Service. 

194. Zamel, N., Youssef, H. H., Prime, F. J. Airway resistance and peak 

expiratorv flow-rate in smokers and non-smokers. 

1960. Lancet 1: 1237-8, 1963. 

New Orleans, 

313 
Chapter 11 

Cardiovascular 

Diseases 
Contents 

INTRODUCTION . . . . . . . . . . . . . . . . . . . . 

PERTINENT PHARMACOLOGY . . . . . . . . . . . . . 

GENERAL OBSERVATIONS ON CORONARY HEART DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . 

SMOKING AND CORONARY HEART DISEASE . . . . . 

SMOKING AND NON-CORONARY CARDIOVASCULAR 

DISEASE . . . . . . . . . . . . . . . . . . . . . . . 

CHARACTERISTICS OF CIGARETTE SMOKERS . . . . 

PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION 

TO CARDIOVASCULAR DISEASE . . . . . . . . . . . 

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . 

CONCLUSION . . . . . . . . . . . . . . . . . . . . . . 

REFERENCES. . . . . . . . . . . . . . . . . . . . . . 

List of Tables 

TABLE 1. Death rates per 100,000 from arteriosclerotic and 

degenerative heart disease by sex and age, United 

States, 1958-60 . . . . . . . . . . . . . . . . 

TABLE 2. Ratios of mortality rates for coronary heart disease, 

male smokers to non-smokers, by age and amount 

smoked, in selected studies . . . . . . . . . . . 

Page 

317 

317 

320 

322 

325 

326 

327 

327 

327 

328 

321 

324 

316 
Chapter 11 

__ .- 

INTRODUCTION 

It has been suggested repeatedly that smoking may ha\-e adverse effects on 

the cardiovascular system. Recently. studies of large groups of people have 

shown that cigarette smokers in particular are more prone to die early of 

certain cardiovascular disorders than non-smokers. Chief among theFe disorders is coronary artery disease. and the present chapter deals mostly with 

this subject. The chapter begins with a summary of information ahout the 

acute effects of smoking on the cardiova.scular system. This is followed b\- a 

brief account of coronary disease, its frequency in different kinds of people. 

and the many factors known or thought to affect the likelihood of its development. The aim here is not to reviebj critically our knowledgr of coronary 

disease hut only to give background for what follows. Next is summarized 

the information currently availahle from study of large population groups 

on the association of cigarette smoking with an increased tendency to hal-e 

coronary disease. There follows a brief discussion of smoking and noncoronary cardiovascular disease. Finally, there is a short review of evidence 

relating to the question of whether cigarette smokers may, as a group, differ 

from non-smokers in ways not caused by smoking itself. Mortality ratios 

showing the association between cigarette smoking and deaths from cardiovascular disease, especially coronary disease, do not indicate the magnitude 

of the burden. This can be better appreciated from consideration of the 

following facts: cardiovascular disease deaths now total more than 700,000 

annually in the United States. Of these more than 660,000 were due to heart 

disease, with more than 500,000 due to arteriosclerotic heart disease including coronary disease. The remaining approximately 40,000 were ascribed 

to disease of other parts of the cardiovascular system. Deaths from lung 

cancer total approximately 39,000. A mortality ratio of 1.7 for coronary 

heart disease among cigarette smokers in the seven prospective studies represents from 32.9 percent to 51.7 percent of all excess deaths: whereas the 

much higher lung cancer mortality ratio of 10.8 from the same studies represents only 13.5 percent to 24.0 percent of total excess deaths (Chapter 8. 

Tables 19, 25). 

PERTINENT PHARMACOLOGY 

The acute cardiovascular effects of smoking in man and experimental animals are like those caused by nicotine alone. A smoker who inhales gets 

usually l-2 mg of nicotine from a cigarette (56,57). 

Low concentrations of nicotine stimulate sympathetic ganglia, and high 

concentrations paralyze them. Parasympathetic ganglia respond in the same 

way but are less sensitive. iY ice t ine 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 addition, nicotine produces effects reflexly by stimulating the chemoreceptors of 

the carotid and aortic bodies. Wh en nicotine is given intravenously in increasing doses to dogs or cats the first effects, at about 1 microgram,/kg body 

weight, are increased breathing and sympathetic stimulation, with predominant vasoconstriction, cardiac acceleration, and rise in blood pressure, resulting from stimulation of the aortic and carotid bodies (17). Doses of 4 

to 8 micrograms/kg can stimulate pulmonary and coronary chemoreflexes 

which produce opposite effects. If all these receptors are inactivated, much 

higher doses are needed to evoke the cardiovascular effects of sympathetic 

stimulation, presumably through action on sympathetic ganglia or chromaffin 

tissue. Intravenous administration of nicotine in the experimental animal 

causes a discharge of epinephrine from the adrenal medulla, and in man 

heavy cigarette smoking prnduces an increased urinary excretion of 

catecholamines (B&99). 

Smoking l-2 cigarettes causes in most persons, both smokers and nonsmokers, an increase in resting heart rate of 1.5-25 beats per minute, a rise 

in blood pressure of 10-20 mmHg systolic and 5-15 mmHg diastolic (76, 78, 

85, 86). and an increase in cardiac output of about 0.5 l/min/sq.m (75). 

There is a decrease in digital blood flow and a consequent drop in finger and 

toe temperature (31, 78,103). Th e d ecrease in peripheral blood flow which 

normally follows smoking does not occur in a sympathectomized limb, indicating that the effect is mediated primarily by the sympathetic nervous 

system rather than through the release of catecholamines from other sites or 

the direct effect of nicotine upon the smooth muscle of the blood vessels 

themselves (103) . Intravenous nicotine, and probably cigarette smoking as 

well, can produce a slight transitory increase in the blood flow to resting calf 

muscle (79). 

In the dog, nicotine and cigarette smoke cause an increase in coronary 

flow as the blood pressure, cardiac output, and heart work increase (30, 53). 

These effects. resemble those of epinephrine. Nicotine has been found to 

cause a transient decrease in cardiac oxygen utilization followed by a slight 

increase ( 53) . Relatively little information is available about the effect 

of smoking on coronary blood flow in man. In normal subjects it is reported that cigarette smoking produces an early increase in coronary flow 

as heart work increases. but there is little change in oxygen utilization by 

the myocardium i2). With continued “steady state” smoking the coronary 

flow and cardiac oxygen utilization are maintained at the resting level in 

both normal subjects and persons with coronary heart disease, despite increased blood pressure, heart rate, and heart work ( 74). A larger experience must be gathered in this field before statements about the acute effects 

of smoking on the human coronary circulation can be made with assurance. 

The atherosclerotic rabbit heart, like the normal rabbit heart: shows an 

initial drop in coronary flow on administration of nicotine, but demonstrates 

less of a subsequent increase above the resting level than does the normal 

heart (97). These effects are said to be equivalent to those produced by 

norepinephrine in doses one-tenth as large as the nicotine dose. 

318 
Little or no change in the electrocardiogram of most normal persons or 

cardiac patients, except for an increase in rate, is produced by smoking or 

by the intravenous injection of an equivalent dose of nicotine (82, 98). In 

some persons there is a slight depression of the S-T segment and a flattening 

of l-2 mm in the T wave of the limb leads. These changes are not like 

those associated with my-ocardial ischemia. Rarely in persons with true 

angina. an attack of pain is precipitated by smoking. An ill-defined syndrome consisting of chest pain. palpitation. and shortness of breath, known 

as “tobacco angina”. has been described as occurring in smokers who do 

not have organic heart disease. but it is rarely diagnosed today (73, 82). 

Extrasvstoles and other cardiac arrhythmias have been reported to be caused 

bv smoking. but such cases appear to be unusual. 

I The b a II’ IS t ocardiogram obtained from a high-frequency table is sometimes changed by smoking a cigarette from a normal pattern to one said to 

be typical of coronary disease (78, 91 I Th is phenomenon is rare in healthy 

persons below 50, becomes increasingly common with advancing years in 

apparently healthy persons. but is particularly prone to occur at any age in 

persons with actual coronary disease. The effect has been used as a “stress 

test” to help uncover coronary disease. but false positive and negative results 

are common. The ballistocardiopaphic changes on smoking have been 

variously interpreted as resulting from impaired myocardial contractility 

I 78‘)) from changes in the peripheral circulation (82), or from uncertain 

causes related to the physical properties of the high-frequency table as well 

as changes in the circulation. 

Cigarette smoking causes an increase in the concentration of serum-free 

fattv acids in man ( 50), apparently mediated by stimulation of the sympathetic nervous system (51). Although continued administration of epinephrine to dogs over many hours can produce substantial increases in serum 

cholesterol, phospholipids, and triglycerides, such an effect has not yet been 

reported from nicotine or tobacco smoke (48, 92). 

The clotting time of the blood can be decreased 50 percent or more in experimental animals by stimulation of the sympathetic nervous system or hy 

administration of epinephrine (12, 13, 14)) but attempts to demonstrate that 

cigarette smoking alters the clotting properties of the blood in man have been 

unsuccessful i5, 68). A decrease in platelet survival in viva has been found 

after smoking (68) . Cigarette smokers have been reported to show substantial decreases in hematocrit, hemoglobin, and platelet counts after abstinence 

of l-2 weeks (25)) but hemoglobin concentrations are alike in smokers and 

non-smokers of the same population group (4). 

Attempts have been made to induce atherosclerosis in rats by the chronic 

administration of nicotine for periods up to a year without sucwss (93). 

Tobacco has antigenic properties (29, 43). Rats can be sensitized to tobacco extracts by intraperitoneal injection. Over a third of smokers demonstrate a positive-“immediate” skin reaction to such extracts while only about 

10yc of non-smokers are said to give positive tests. The presence of serum 

reagins in persons with positive skin tests has been demonstrated by passive 

transfer techniques. Persons with thromboangiitis obliterans and smokers 

with occlusive vascular disease of other types are said to show a much higher 

incidence of positive skin tests than healthy smokers. The cardiovascular 

7 14-422 O-64-22 
diseases which have been related to smoking, however, do not in general 

resemble those usually ascribed to an immune mechanism. 

In man and experimental animals smoking or the injection of nicotine 

causes increased secretion of antidiuretic hormone. The renal effects of 

this are easily demonstrable but the quantity of hormone secreted in response 

to smoking is probably too small to have significant vascular effects (17 ) . 

In summary, the acute cardiovascular effects of smoking and of nicotine 

closely resemble those of sympathetic stimulation. and to a considerable 

extent are mediated by excitation of the sympathetic nervous system. No 

additional or unique cardiovascular effects have been demonstrated which. in 

the light of our present understandin,. 0 seem likely to account for the observed 

association of cigarette smokin, c with an increased incidence of coronar\- 

disease. 

CENERAL OBSERVXTIONS ON CORONARY HEART DISEASE 

Heart disease is the most common cause of death in our population. and 

coronary disease is the commonest variety of fatal heart disease (59’1. Iri 

1961 there were 1:701..522 deaths from all causes in the United States. Heart 

disease deaths numbered 663.391 of which 502.351 were due to arteriosclerotic heart disease. 

The disorder consists of obstruction or narrowing of the coronary arteries. 

reducing the blood supply to the heart muscle. The underlying cause of the 

obstruction is coronary atherosclerosis. but an acute coronarv artery occlusion is often caused by the formation of a blood clot in a d&eased arterv. 

The common manifestations of coronary disease are an$na pectoris. recurrent brief attacks of chest pain caused by inadequate blood supply to the 

heart muscle: myocardial infarction, or necrosis of a portion of the heart 

muscle due to acute loss of blood supply; congestive heart failure, a chronic 

state caused bv inability of the heart to pump enough blood to satisfy the 

demands of thk body; and sudden death resulting from cardiac standstill or 

ventricular fibrillation. 

There are considerable differences in the prevalence of coronary heart 

disease in different countries, and often in different ethnic and socio-economic, 

groups within a particular country (ML 02 1. The reported death rate of 

arteriosclerotic heart disease. which is Ibrimarily coronary disease. is higher 

in the United States than in other countries. it is also quite high in Yew 

Zealand. Australia.‘South Africa, Canada. and Finland. and moderately hi?h 

in Great Britain. The death rate in Norway, Sweden, and Denmark is roughI> 

half that in the high death rate countries I 1.5 I. The death rate in Japan 

appears to be about one-sixth that in the United States, although persons of 

Japanese origin living in the United States are said to have a death rate 

similar to that of the Fenera i)opulation of this country i.52). 

Because of changing diagnostic skills and revisions in nomenclature of 

disease, it is d&cult to be certain of the change in incidence of coronar! 

disease in the United States oter the pas! few decades, but there is a general 

opinion that the incidence is increasin, m in this country and in England. 

320 
particularly in the younger male group (59, 62, 65, 83). In 1955 the 

mortality rate from arteriosclerotic heart disease was reported to be about 240 

per 100,000. Although this is an increase of more than 50% over the rate 

in 1940, it has been estimated that less than 157; of the increase represented 

a real chance in incidence of the disease, the remainder depending upon 

changes in diagnosis, in nomenclature and in the age of the population (59 1. 

Since 1955 the death rate from coronary disease (ISC 420) and from 

arteriosclerotic and degenerative heart disease (I%420 and 422) has con. 

tinued to increase gradually. In 1960 the age-adjusted death rate from 420 

and 422 was 330 per 100,000 for white males and 150 for white females ( 55 ) . 

Although the basic cause or causes of coronary heart disease are obscure, 

certain factors other than smoking are known or thought to predispose to the 

condition or to be associated with an increased incidence. 

The incidence of coronary heart disease in men under 45 is about 5 times 

as great as that in women (Table 1) ( 15, 20,59, 62). In both sexes the incidence increases with advancing years. After the menopause the incidence 

increases rapidly in women, and at age 80 the death rates from coronary 

disease are about the same for the two sexes. Coronary thrombosis plays a 

relatively more important role in precipitating myocardial infarction in young 

men than it does in old men i 105 1. In studies of large population groups 

coronary disease has been associated with elevation of the serum cholesterol, 

hypertension, and marked overweight (19, 20, 24, 36,46, 59,62). 

Some individual characteristics have been said to be associated with coronary disease. There is a significant familial tendency to develop it (36, 69, 

81, 96). Persons with a mesomorphic constitution are said to be more vulnerable than endomorphs and ectomorphs (36, 62, 88). A coronary-prone 

1)ersonality has been described as the aggressive, competitive person who takes 

on too many jobs, fights deadlines, and is obsessed by the lack of adequate 

time for the performance of his work (33,34,35). 

TABLE I.-Death rates per 100,000 f rom arteriosclerotic and degenerative 

heart disease* hy sex and age, United States, 195840 

A c”’ G roll p TMall= Frmah rloth SITCUnder 35------------------------------ 3.3 1.2 2.2 

3544--------------------------------- 90.2 18.3 53.3 

45-54 ------__-_-_____----------------- 353.7 79.3 213.5 

55-64 -------___-----_----------------- 928.5 314.5 610.2 

65-74 _________________________________ 2129.2 1082.0 1569.5 

75orover------------------------------ 4765.1 3738.4 4179.7 

*Includes IX numbers 420 and 422. 

Source: WHO Epidemiological and Vital Statistics Report, Vol. 16, No. 2, 1963. 

Certain occupations have been said particularly to favor the development 

of coronary disease, notably those which feature responsibility and stress 

(34, 81, 87), and which are sedentary in nature (71. Others (58, 72, 901 

have not found that executives are more prone to coronary disease than nonexecutive 1)ersonnel. Ph; ~slcians . have been said to habe 3 or 4 times as much 

coronary disease as farmers or laborers 187): and general prac~titioners to 

321 
have 3 times as much as dermatologists (80). Occupations involving much 

physical activity are said to be protective (66, 67, 77). City life has been 

said to be more closely associated with coronary disease than suburban life, 

and men who drove more than 12,000 miles a year seemed, in one study, more 

1Jrone to the disease than those who drove less (64). 

It has been widely held, and occasionally denied, that a diet high in 

saturated fat predisposes to the development of coronary disease (46, 52, 

69, 81). A correlation between the national incidence of coronary disease 

and the percentage of food calories available as saturated fat has been reported among those countries for which adequate data exist (46). The serum 

cholesterol tends to rise when saturated fat is added to the diet, and it falls 

significantly when unsaturated fat is substituted (46). It has also been suggested that general over-nutrition? rather than excess saturated fat predisposes to coronary disease, on the grounds that the correlation of coronary 

disease with total available calories or sugar consumption per capita is as 

good as that for percentage of calories in fat (106). 

In general, it is apparent that multiple personal and environmental factors 

can markedly affect the incidence of coronary disease. 

SMOKING AND CORONARY HEART DISEASE 

Over the last two decades a considerable number of epidemiologic studies 

on different populations, employing different techniques, have shown with 

remarkable consistency a significant relationship between cigarette smoking 

and an increased death rate from coronary heart disease in males, particularly during middle life. There has been little dissenting evidence. 

The association of coronary disease with the use of tobacco in other forms 

has not been striking. The documentation for these statements is given in 

the following paragraphs. Particularly important is the information in 

Chapter 8, Mortality. 

English et al. 126) found the incidence of coronary disease in male 

patients at the Mayo Clinic about 3 times greater in cigarette smokers than 

in non-smokers in the 40-59 year age range, but found little relation to 

smoking above 60. Russek 181) reported a similar relationship, but less 

striking, in young men with coronary disease. Mills (64) in a study of 

reported mortality in a Cincinnati population found that heavy smokers 

in the 30-59 )-ear age range had twice as high a death rate from coronary 

disease as non-smokers. Male Seventh Day Adventists: who are nonsmokers. were found by Wyrlder and Lemon (104) in a study based on 

hospital admissions to hale significantly less coronary disease and to develop it later in life than the general male hospital population. Haag 

and Hanmer I ST I reported that employees in the tobacco industry. \\ ho 

tend to smoke heavily. had a lower death rate for cardiovascular disease 

than the general population ill their geographic region. but no report was 

made of mortality rates within the tobacco-worker group, divided by smoking habits. The study has been criticized on this and other grounds ( 16 I. 

Large-scale prospective studies of mortality in British phyairians ( Doll 

and Hill, 21 I _ United States males 50-69 recruited by volunteer workers 

322 
( Hammond and Horn, 38, 39.40.42) and \‘.A. Life Insurance policyholders 

i Darn: 22) have confirmed the association of death from coronary disease 

with cigarette smoking. In the British study, a step-wise association was 

found between the amount of tobacco consumed (not entirel! cigarettes) 

and the mortality from coronary disease. The association occurred in the 

X-54 !-ear age range. but not in older men. Hammond and Horn found 

a similar graded relationship between coronary deaths and cigarette smoking. the death rate being more than twice ai great in men who smoked 

over a pack a da\- as in non-smokers. Men who had stopped smoking for 

more than a !ear at thr start of the study had a coronary death rate lower 

than those who continued. 

Studies on special groups of men. such as longshoremen (Buerhley et al. 

:: I membrrs of a fraternal order i Spain and Nathan. 89) and industrial 

employees (Paul et al. 71) which. in the latter two instances. incorporated 

clinical coronary disease. as well as coronary deaths. also have shown a 

relationship bet\\een coronary disease and smoking. The relationship It-as 

closer for men under 51 than for older men, and closer for myocardial 

infarcts and death than for angina pectoris (70,891. 

The long-term prospective studies of cardiovascular disease in Framingham (19, and in Albany 124) which have featured a painstaking sparch at 

regular interrals for clinical manifes;tations of disease. have. on pooling the 

data (Doyle et al. 23) shown a threefold increase in the incidence 

of myocardial infarction and coronary deaths in men who are hea\!- cigarette smokers as compared to non-smokers. pipe and cigar smokers. and 

former cigarette smokers. In the pooled data the incidence of angina pertoris did not shoM a significant association with cigarette smoking. The 

lack of this particular relationship had been suggested on the hasis of 

clinical experience (White and Sharber. 102 I. 

An apparent interplay of fa,ctors relating to smoking and occupation 

turned up in a short-term studv of the development of roronar) heart disease in a general North Dakoia population (Zukel et al., 107). Farmers 

had about half the incidence of myorardial infarction experienced b!- others. 

In farmers. smoking had no appreciable effect on the incidence of infarction. but in others the incidence of infarction was twice as high among 

smokers as among the non-smokers. The farmers who smoked cigarettes 

smoked less heavily than males in other occupational groups. 

In Chapter 8. Mortality, there is summarized the most recent information availahle from 7 large completed or current prospective smoking 

and death rate studies (Doll and Hill; Hammond and Horn ; Darn; Dunn, 

Linden and Breslow; Dunn. Buell and Breslow ; Best, Josie. and Walker; and 

Hammond ). The median mortality ratio for coronary disease of current 

cigarette smokers to non-smokers is 1.7 irange 1.5-2.01. 

Table 2 presents data from some of the large prospective s.tudies on the 

ratio of mortality rates due to coronarv heart disease of male qniokers to 

non-smokers, by age and amount smoked. The ratios tend in ;pnrral to 

increase uith amount smoked and to decrease with adl-anciq a;:r. 

The data from the first 22 months. of Hammond‘s (41 I current study 

help to show the size of the coronary problem. For this purl)ose. actual 

uumbers of deaths ma\ be more informative than mortalit\- ratios. Of nearlv 
10.000 deaths of men aged 45-i’). 40 percent were ascribed to coronaq 

disease. 51.i pervent of the 2.030 “excess deaths” associated with cigarette 

smoking were caused by coronary disease. In approximate terms, nearly 

half of middle-aged and elderly males in the United States die of coronarl 

disease. About half of the+,r males smoke cigarettes. Cigarette smokers 

ha\-e heen found it) several studies to have 1.7 times as high a coronar! death 

rate as non+mokers. If cigarettes actually caused the additional coronar\ 

deaths of smokers. they tvould account for many- deaths of middle-aged and 

elderly males in this countr). Like other studies (19. 21, 22. 23. $2’21 this 

one shows that the ratio of !smokers’ coronary death rates to those of nonsmokers inc,rcuses prog:‘e+i\el, \\ ith tile [tail\ cigarette consumption. In 

addition. at each le\cl of consumption the ratio inrreases with the amount of 

inhalation reported I)\- the smokers. Others (21, 23. 26, 891 have indicated 

324 
that the risk of death from coronary disease in male cigarette smokers relative 

to that in non-smokers is greater in middle age than old age, and Hammond’s 

current study supports this. Th e mortality ratio was 3.09 in the age range 

4S49. and in successive decades t+as 2.20. 1.58. and 1.38. 

Men who stop smoking ha\-e a lower death rate from coronary disease 

than those who continue (23, 42. Si) . In the study of Hammond and Horn 

(42) the decrease in death appeared onI!- after a year. 

Angina pectoris is less closely related to cigarette smoking than myocardial 

infarction and sudden death. In the combined Albany-Framingham experience (23)) angina pectoris showed no o\er-all relationship with smoking, 

and the association has not been strong in other studies (71, 89). 

In summary. a significant association has been established between cigarette 

smoking and the incidence of myocardial infarction and sudden death in 

males, especially in middle life. in population groups whose members appear 

so far to be liniilar except for sniokin,n habits. The question of whether they 

are, in fact, similar except for smoking is. of course, basic to the problem of 

whether cigarette smoking actually promotes the development of coronary 

disease or k-hether it is closeI\- associated with some other factor or factors 

which promote the development of coronary disease. It has been pointed out 

that angina pectoris, which indicates advanced coronary atherosclerosis. is 

less closely associated with cigarette smokin, 11 than is m!-ocardial infarction. 

and that this suggests that any etiologic role of smoking in myocardial infarction should relate more to acute occlusive mechanisms, such as intravascular 

thrombosis or coronary spasm, than to the development of chronic arterial 

disease. 

SMOKING AND NON-CORONARY CARDIOVASCULAR 

DISEASE 

In surveys of large groups cigarette smoking has not been found to be 

associated with an incrra*ed pre\ alence of h\ pertension ( 3, 4. 19, 47, 49 1. 

The study of Hammond and Horn I 4.0, 42 I d;d not sho\v an increased death 

rate from hppertension in smokers. However. Darn 122 1 found that the 

death rate of cigarette smokers from h\ I)crtension with heart disease was 

1.53 times that of non-smokers. and frhm h!-pertension without heart disease. 1.41 time3 that of non-smokers. Hammond’s current stud\ she\+ s 

similar figures I41 1 . Smoking has not been found to be associated with 

an increased mortalit!- rate from chronic rheumatic heart disea>e 122. 41. 

42 1. 

Hammond and Horn ( !2) found a Inoderate increase in the mortalit) 

rate from cerebral vascular disease in cigarette smokers as compared to 

non-smokers I ratio 1.30 I. Darn (22 I reported a ratio of 1.33. and Hamnlolld 141 1 a ratio of 1.43. Although non-HI philitir aortic aneurysm is a 

relatilell infrequent cause of death. the mortalit\ ratio for snlokrr; to nonsmokers in thi:. diagnostic, c,ategor\ is larse in relation to the ratios in other 

cardiol ascular disorder>. In the stud\ of llalmnc~ncl atld Horn (,t2 1 it 

was 2.72. and in Hanl~t~ond’s current .-tudv I I1 I it is 3.10. 
It has been reported (100) that diabetic males who smoke have a 50% 

greater incidence of clinically detectable arteriosclerosis obliterans in the 

legs than those who do not smoke. In general, however, there is little 

information about the relation of smoking to peripheral arteriosclerosis. 

Most experienced clinicians advise patients with obliterative peripheral arterial disease to stop smoking (45). 

Buerger’s disease, or thromhoangiitis obliterans, has been traditionally 

associated with smoking. and the literature contains numerous clinical reports 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 recentlv challenged ( 1011, but well defended (61). 

It -is apparent that much mere work will have to be done to determine 

what relationship may exist bet\\-een non-coronary occlusive vascular disease, aneurysmal disease, and smoking. 

CHARA4CTERISTICS OF CIGARETTE SMOKERS 

If it could be shown that cig;arette smokers and non-smokers had significant constitutional differences apart from any differences that might be caused 

by smoking itself, then a possibility w-ould exist that some predisposition of 

smokers to a particular disease might also be of constitutional origin and not 

caused by smoking. Cigarette smokers have, in fact, been found to differ 

as a group from non-smokers, but the differences, such as serum cholesterol 

concentration and resting heart rate, could have resulted from the smoking 

habit itself, so far as present knowledge indicates. 

The concentration of serum cholesterol has been found to be slightly higher 

in smokers than in non-smokers by a number of investigators (6, 18, 49, 63, 

95)) but others have found no relationship (1, 54). Dawber (19) found 

not only that serum cholesterol was higher in smokers than in non-smokers 

but also that it remained higher in those who stopped smoking. 

Smokers tend to be leaner than non-smokers, but to gain when they stop 

smoking (3, 18,491. 

A few personality differences have been reported between cigarette smokers 

and non-smokers. F rle ’ d man’s type A men i the coronary type) tended to be 

heavy smokers (33 j. Smokers are said to be more easily angered and to eat 

more when under stress (94). They have been reported to marry oftener. 

to change jobs more frequently. to be more often hospitalized, and to participate more actively in sports; than non-smokers (60). 

Thomas I 94. 95 I hai rel)or ted that the parents of medical students \vho 

smoke have a significantl!- higher incidence of arteriosclerotic and hypertensive cardiovascular disease than parents of non-smokers. Clearl!-. this 

finding is open to more than c,ne interpretation. 

Smokers tend to have a higher heart rate than non-smokers (3. 94 1. 

The matter of constitutional predisposition to smoking has been investipated in twins. It has been found I 27. 2X. 32 I that the smoking hahits of 

monozygotic twins are siynifirantly morr alike than those of diz\-gotic tGne. 

even when memhers of a tw-in pair are brought up separately. 

326 
In spite of some bits of suggestive evidence the existence of basic constitutional differences between smokers and non-smokers is not presently 

established. The constitutional hypothesis, which links smoking and predisposition to disease, is discussed in detail in Chapter 9, Cancer. 

PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO 

CARDIOVASCULAR DISEASE 

Even less conclusve information is available on the role of psycho-social 

factors of smoking in relation to cardiovascular disease. Studies which have 

focussed on this are limited in number according to Heinzelmann (44 1. Even 

fewer. he found, are those which have specifically examined the relative 

weight of these variables or their interaction. Reviewing those available, 

he observes that the evidence is highly fragmentary and uncertain. The 

findings suggest that the relationship between smoking behavior and coronary 

heart disease may reflect the influence of stress factors and/or personality 

mechanisms. However, they permit no definitive statements with respect 

to the relative role of pyscho-social factors and smoking in relation to 

etiology of the disease. 

SUMMARY 

Smoking and nicotine administration cause acute cardiovascular effects 

similar to those induced by stimulation of the autonomic nervous system, 

but these effects do not account well for the observed association between 

cigarette smoking and coronary disease. It is established that male cigarette smokers have a higher death rate from coronary disease than nonsmoking males. The association of smoking with other cardiovascular 

disorders is less well established. If cigarette smoking actually caused the 

higher death rate from coronary disease, it would on this account be 

responsible for many deaths of middle-aged and elderly males in the United 

States. Other factors such as high blood pressure, high serum cholesterol, 

and excessive obesity are also known to be associated with an unusually 

high death rate from coronary disease., The causative role of these other 

factors in coronary disease, though not proven, is suspected strongly enough 

to be a major reason for taking countermeasures against them. It is also 

more prudent to assume that the established association between cigarette smoking and coronary disease has causative meaning than to suspend 

judgment until no uncertainty remains. 

CONCLUSION 

Male cigarette smokers have a higher death date from coronary artery 

disease than non-smoking males, but it is not clear that the association 

has causal significance. 

327 
REFERENCES 

1. Acheson, R. M., Jessop, W. J. E. T o b acco smoking and serum lipids 

in old men. Brit Med J 2: 1108-1111, 1961. 

2. Bargeron, L. M.. Jr., Ehmke, D., Gonlubol, F.: Castellanos, A., Siegal, 

A., Bing. R. J. Effect of cigarette smoking on coronary blood flow 

and mpocardial metabo.‘ism. Circulation 15 : 251-257, 1957. 

3. Blackburn, H., Brozek, J., Taylor, H. L. Common circulatory measurements in smokers and nonsmokers. Circulation 22: 1112-1124. 

1960. 

4. Blackburn. H. W., Brozek, J., Taylor, H. L., Keys, A. Cardiovascular 

and related ‘characteristics in habitual smokers and nonsmokers. 

In: James, G., Rosenthal, T. ed. Tobacco and Health. Springfield. 

Thomas. 1962. p. 323-351. 

5. Blackburn, H., Jr., Orma. E., Hartel, G., Punsar, S. Tobacco smoking and blood coagulation: Acute effect on plasma stypven time. 

Am J Med Sci 238: M-451, 1959. 

6. Bronte-Stewart, B. Cigarette smoking and ischaemic heart disease. 

Brit Med J 1: 379-385, l%l. 

7. Brunner, D., Manelis, G. M yocardial infarction among members of 

communal settlements in Israel. Lancet 2: 1049-1050, 1960. 

8. Buechley, R. W., Drake, 1~. M., Breslow, L. Relationship of amount 

of cigarette smoking to coronary heart disease mortality rates in 

men. Circulation 18: 1085-1090: 1958. 

9. Burn, J. H. Action of nil:otine on the heart. Ann N Y Acad Sci 90: 

70-73, l%O. 

10. Burn, J. H.. Leach. E. H., Rand, M. J., Thompson, J. W. Peripheral 

effects of nicotine and acetycholine resembling those of sympathetic 

stimulation. J Physiol 148: 332-352, 1959. 

11. Burn, J. H., Rand. M. J. Action of nicotine on the heart. Brit Med 

J 1: 137-139, 1958. 

12. Cannon, W. B., Gray, H Factors affecting the coagulation time of 

blood. 11. The hastening or retardin g of coagulation by adrenalin 

injections. Am J Physiol 34: 232-242, 1914. 

13. Cannon. W. B.. Mendenhall. W. L. Factors affecting the coagulation 

time of blood. III. The hastenin g of coagulation by stimulating 

the splanchnic nerv-es. Am J Physiol 31: 243-250, 1914. 

14. Cannon. W. B.. Mendenhall, W. L. Factors affecting the coagulation 

time of blood. IV. The hastening of coagulation in pain and rmotional excitement. Am J Physiol 34: 251-261, 1914. 

15. Cardiovascular diseases mortality. 19541956, 1958-1960. WIlO. 

Epidemiological Vital Stat Rep 16: 115-205, 1963. 

16. Case, R. A. AI. Smoking habits and mortality among workers in cigarette factories. Nature (London 1 181 : 84-86, 1958. 

17. Comroe. J. H., Jr. The pharmacological actions of nicotine. Ann 

N Y Acad Sci 90: 48iii, 1960. 

18. Damon, A. Constitution and smoking. Science 134: 339-341, 1961. 

328 
19. Dawber, T. R., Kannel, W. B., Revotskie, N., Stokes, J.. Kagan, A., Gordon, T. Some factors associated with the development of coronary 

heart disease. Six years’ follow-up experience in the Framingham 

study. Amer J Public Health 49: 1349-1356, 1959, 

20. Dawber, T. R., Moore, F. E., Mann, G. V. II. Coronary heart disease in 

the Framingham study. Amer J Public Health 47 (Suppl. I : 4-24. 

April 1957. 

21. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation 

to smoking. A second report on the mortality of British doctors. 

Brit Med J 2: 1071-1081, 1956. 

22. Dorn, H. F. Tobacco consumption and mortality from cancer and 

other diseases. Public Health Rep 74: 581-593, 1959. 

23. Doyle, J. T., Dawher, T. R., Kannel, W. B., Heslin, A. S., Kahn, H. A. 

Cigarette smoking and coronary heart disease. Combined experience 

of the Albany and Framingham studies. New Eng J Med 266: 796 

801, 1%2. 

24. Doyle, J. T., Heslin, A. S., Hilleboe, H. E., Formel, P. F. Early diagnosis of ischemic heart disease. New Eng J Med 261: 10961101, 

1959. 

25. Eisen, M. E., Hammond, E. C. The effect of smoking on packed cell 

volume, red blood cell counts, hemoglobin and platelet counts. Canad 

Med Ass J 75: 520-523, 1956. 

26. English, J. P., Willius, F. A., Berkson, J. Tobacco and coronary 

disease. JAMA 115: 1327-1329, 1940. 

27. Fisher, R. A. Cancer and smoking. Nature (London) 182: 596,1958. 

28. Fisher, R. A. Lung cancer and cigarettes? Nature (Londonj 182: 

108, 1958. 

29. Fontana, V. J. Tobacco hypersensitivity. Ann N Y Acad Sci 90: 

138-141, 1960. 

30. Forte, I. E., Williams, A. J., Potgieter, L., Schmitthenner, J. E., Hafkenschiel, J. H., Riegel, C. Coronary blood flow and cardiac oxygen 

metabolism during nicotine-induced increases in left ventricular 

u-ork. Ann N Y Acad Sci 90: 174-185, 1960. 

31. Freund, J., Ward, C. The acute effect of cigarette smoking on the digital circulation in health and disease. Ann N Y Acad Sci 90: 85-101, 

1960. 

32. Friberg, L., Kaij, L., Dencker, S. J., Jonsson, E. Smoking habits of 

monozygotic and dizygotic twins. Brit Med J 1: 1090-1092: 1959. 

33. Friedmann, M., Rosenman, R. H, Association of specific overt behavior 

pattern with blood and cardiovascular findings. JAMA 169: 1286 

1296, 1959. 

34. Friedman, M.. Rosenman, R. H.? Carroll, V. Changes in the serum 

cholesterol and blood clotting time in men subjected to cyclic variation of occupational stress. Circulation 17: 852-861, 1958. 

3.5. Friedman, M., St. George, S., Byers, S. O., Rosenman, R. H. Excretion 

of catecholamines, li-ketosteroids, 17-hydroxycorticoids and 

5-hydroxyindole in men exhibiting a particular behavior pattern 

(A) associated with high incidence of clinical coronary artery disease. J Clin Invest 39: 758-763, 1960. 

32!2 
36. Gertler, M. M., Woodbury, M. A., Gottsch, L. G., White, P. D., Rusk, 

H. A. The candidate for coronary heart disease. Discriminating 

power of biochemical hereditary and anthropometric measurements. 

JAMA 170: 149-152, 1959. 

37. Haag, H. B., Hanmer, H. R. S mo k’ mg habits and mortality among 

workers in cigarette factories. Industr Med Surg 26: 559-567,1957. 

38. Hammond, E. C. The effects of smoking. Sci Amer 207(l) : 3-15. 

July 1962. 

39. Hammond, E. C. Smoking and death rates-a riddle in cause and 

effect. Amer Sci 46: 331-354, 1958. 

40. Hammond. E. C. S mo k il ; g in relation to heart disease. Amer J Public 

Health 50: 20-26, 1960. 

41. Hammond, E. C. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

42. Hammond, E. C., Horn, D. Smoking and death rates-report on fortyfour months of follow-up of 187,783 men. I. Total mortality; 

II. Death rates by cause. JAMA 166: 1159-1172,1294-1308,1958. 

43. Harkavy, J. Tobacco allergy in vascular diseases. Rev Allerg 11: 

189-212, 1957. 

44. Heinzelmann, F. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

45. Hines, E. A. The effects of tobacco on blood pressure and in peripheral 

vascular diseases. Proc Mayo Clin 35: 337-343, 1960. 

46. Jolliffe, N. Fats, cholesterol, and coronary heart disease. A review 

of recent progress. Circulation 20: 109-127, 1959. 

47. Kannel, W. B. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

48. Kaplan, A., Jacques, S.: Gant, M. Effect of long-lasting epinephrine 

on serum lipid levels. Am J Physiol 191: 8-12, 1957. 

49. Karvonen, M., Keys, A., Orma, E., Fidanza, F., Brozek, J. Cigarette 

smoking, serum-cholesterol, blood-pressure, and body fatness. Observations in Finland. Lancet 1: 492494, 1959. 

50. Kershbaum, A., Bellet, S., Dickstein, E. R., Feinberg, L. J. Effect of 

cigarette smoking and nicotine on serum free fatty acids. Cir Res 9: 

631-638, l%l. 

51. Kershbaum, A.: Khorsandian, R., Caplan, R. F., Bellet, S., Feinberg. 

L. J. The role of catecholamines in the free fatty acid response to 

cigarette smoking. Circulation 28: 52-57, 1963. 

52. Keys, A. Diet and epidemiology of coronary heart disease. JAMA 

164: 1912-1919, 1957. 

53. Kien, G. E., Sherrod. T. R. Action of nicotine and smoking on coronary circulation and myocardial oxygen utilization. Ann N Y Acad 

Sci 90: 161-1’73. 1960. 

54. Konttinen, A. Cigarette, smoking and serum lipids in young men. 

Brit Med J 1: 1115-1117, 1962. 

55. Krueger, D. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

56. Larson. P. S. Absorption of nicotine under various conditions of 

tobacco use. Ann N Y Acad Sci 90: 31-35.1960. 

330 
57. Larson, P. S., Haag, H. B., Silvette, H. Tobacco: Experimental and 

clinical studies. Baltimore. Williams and Wilkins Company, 1961. 

932 p. 

58. Lee, R. E., Schneider, R. F. Hypertension and arteriosclerosis in executive and non-executive personnel. JAMA 167: 1447-1450.195s. 

59. Lew. E. A. Some implications of mortality statistics relating to coronary artery disease. J Ch ronic Dis 6: 192-209, 1957. 

60. Lilienfeld. A. M. Emotional and other selected characteristics of cigarette smokers and non-smokers as related to epidemiological studies 

of lung cancer and other disease. J Nat Cancer Inst 22: 259-282. 

1959. 

61. McKusick. V. A.; Harris. W. S.. Otteson. 0. E., Goodman, R. M.. 

Shelley. W. M.. Bloodwell, R. D. Buerger’s Disease: A distinct 

clinical and pathological entity. JAMA 181: 5-12, 1962. 

62. Miller. D. C.; Stare. F. J., White. P. D., Gordon, J. E. The community 

problem in coronary heart disease: A challenge for epidemiological 

research. Amer J Med Sci 232: 329-359, 1956. 

63. Miller, D. C., Trulson. M. F.: McCann, M. B., White, P. D., Stare, F. J. 

Diet, blood 1IPI ’ ‘d s and health of Italian men in Boston. Ann Intern 

Med 49: 1178-1200. 1958. 

64. Mills. C. A.. Porter, M. M. Tobacco smoking and automobile driving 

stress in relation to deaths from cardiac and vascular causes. Amer 

J Med Sci 234: 35-43, 1957. 

65. Morris, J. N. Recent history of coronary disease. Lancet 1: 1-7, 

1951. 

66. Morris, J. N.. Heady-. J. A., Raffle, P. A. B. Physique of London busmen. Epidemiology of uniforms. Lancet 2: 569-570, 1956. 

67. Morris, J. N., Heady, J. A., Raffle, P. A. B., Roberts, C. G., Park, J. W. 

Coronary heart-disease and physical activity of work. Lancet 2: 

1503-1057, 1111-1120, 1953. 

68. Mustard, J. F., Murphy, E. A. Effect of smoking on blood coagulation 

and platelet survival in man. Brit Med J 1: 846, 1963. 

69. Page, I. H., Stare, F. J., Corcoran, A. C., Pollack, H., Wilkinson, C. F. 

Atherosclerosis and the fat content of the diet. Circulation 16: 163, 

1957. 

70. Paul, 0. Personal communication to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

71. Paul, O.? Lepper, M. H., Phelan, W. H., Dupertius, G. W., MacMillan, 

A., McKean, H., Heebok, P. A longitudinal study of coronary heart 

disease. Circulation 28: 20-31, 1963. 

72. Pell, S., D’Alonzo, C. A. Myocardial infarction in a one-year industrial study. JAMA 166: 332-337, 1958. 

73. Pickering, G. W., Sanderson, P. H. Angina pectoris and tobacco. 

Clin Sci 5: 275-288, 1945. 

74. Regan, T. J., Frank, M. J., McGinty, J. F., Zobl, E., Hellems, H. K., 

Bing, R. J. Myocardial response to cigarette smoking in normal 

subjects and patients with coronary disease. Circulation 23 : 365- 

369, 1961. 

331 
Chapter 12 

Other Conditions 

714-422 O-64-23 
Contents 

RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE . 

Conclusion ...................... 

References ...................... 

TOBACCO AMBLYOPIA ................. 

Conclusion ...................... 

References ...................... 

SMOKIIXG A!XD CIRRHOSIS OF THE LIVER ...... 

Conclusion ...................... 

References ...................... 

MATERXR;AI, SMOKING AND INFAXT BIRTH WEIGHT . 

Conclusions .... ................ 

References ..... ................ 

SMOKING AWD ACCIDEKTS .............. 

Conclusion ..... ................ 

References ..... ................ 

List of Tables 

TABLE 1. Summary of methods used in retrospective and crossbectional studies of peptic ulcer and smoking . . . 

TABLE 2. Summary of results of retrospective and cross-sectional 

studies of peptrc ulcer and smoking . . . . . . . 

TABLE 3. l<uperted and observed deaths and mortality ratios for 

ulcer of stomxh and duodenum among current 

cigarette smokers, from Oeven prospective studies . 

337 

340 

340 

341 

342 

3-E 

342 

342 

343 

343 

343 

344 

344 

345 

345 

338 

330 

330 

336 
Chapter 12 

-- 

RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE 

There are five retrospective studies on the relationship of peptic (gastric 

and duodenal) ulcer to smoking, in which data have been obtained about the 

smoking habits of peptic ulcer patients and various kinds of control groups 

11, 2, 7, 14, 18). Also, in one cross-sectional study. the frequency of peptic 

ulcer has been determined in a population of individuals with varying smoking 

habits (11). 

Tables 1 and 2 summarize the methods used and the results of these studies. 

These studies demonstrate an association betr\een cigarette smoking and 

peptic ulcer which appears to be greater for gastric than for duodenal ulcers. 

The proportion of non-smokers is higher among the controls than among the 

ulcer patients in every one of these studies. 

No differences were noted with respect to the frequency of heaT\- smokers 

in the study of Doll 17) and no consistent relationship with amount smoked 

was .observed by Trowel1 (18). 

In the cross-sectional study of Edwards, et al. I 11 I: a larger proportion of 

peptic ulcer cases was found among the cigarette smokers, and this proportion 

increased with amount of cigarette smoking. The heavy cigarette smokers 

had a frequency of peptic ulcer twice that of those who had never smoked 

(12 percent as compared to 6 percent). 

No association with pipe smoking was noted (1: 11. 14, 18). 

In three prospective studies (Table 3) gastric ulcer has been classified 

separately from duodenal ulcer. The mortality ratios of cigarette smokers 

from gastric ulcer are high in all three studies (46/O, 5.1 and 4.3). For 

duodenal ulcers the mortality ratios are more modest (2.2. 2.3 and 1.11. In 

the remaining four prospective studies only the combined mortality ratios 

for gastric and duodenal ulcers are available: their results being based on 

small numbers of deaths, are erratic but their orer-all average mortality 

ratio is about the same as for the three large studies. ConsequentI\-. it appears likely that the excess mortality of cigarette smokers from pepiic ulcer 

can be attributed primarily to gastric ulcer. A breakdown by amount 

smoked (Chapter 8, Table 23) shows no trend. For cigar and pipe smokers 

the peptic ulcer mortality ratio (total over five studies) is 1.6 hut in view 

of the small number of deaths this elevation is not statistically significant. 

Doll, et al., (7) conducted a clinical trial of thr effect of stopping smoking 

on the healing of gastric ulcers. The results were assessed bv measurin; 

radiologically the reduction in the size of the ulcer niche. Patients advised 

to stop smoking had an average 78~; reduction in the size of the ulcer, compared to 57% for those who continued to smoke. In \ieM- of the probable 

existence of other factors which ma>- have concomitantI>- been introdurrd 

in the approach to the smokers. and the complex nature of the ht>alinp prn(‘- 

ess, it is difficult to interpret this ohservation. 

337 
T\HI.K L.-Summary of methods used in retrospeclive and cross-sectional studies of peptic ulcer and smoking 

Controls 

Collection of data 

No. 

I’ntirnts admitted b~twrn 5(lo 

l!l13 nlrll l!l26. Only casrs 

with complctr smoking history sclrctrd. 

1. Retrospective review of 

rcmrds at Peter Bent 

Brigham Hospital. 

2. Ulcer diagnosis probably 

wll established. 

‘L’ro\$cll, (IX, I!134 .I1 

M 

M&F 

I- 

._ 

.- 

1 

.- 

io 

3” 

.) 

Not stated 400 

275 

1. Interviewed by investigator. 

2. Ulcer diagnosis confirmed 

by X-ray and/or surgery. l- Samplr of population in 

Columbus, Ohio. 

Mills, (14) 18.V) Not stated No details eivrn. 

IAllihonc and Flint, (1) 19.58 l?n~lmd 107 Consecutive admissions to hospital of patients with gastric 

and duodenal hemorrha@z 

or verforation. 

107 Matrhrd hy aw, sex, and 

time of admission from aeute 

general surgical cmcrprncy 

admissions. 

Patients and rontrols intervirwcd hy same observer. 

Patients with non-olwr diswscs. Each case nlatched 

with 2 control patients of 

same sex. 5-yew agr group. 

and same type of place of 

residence. Male patients 

matchrd by social class. 

ists were examined and intrrof all such men on thcsc lists, 

I- -l. 

Doll, Jones, and Pywtt 0, 

It)68 

327 Oastric; 338 

Duodenal. 

Ulcer patients in Doll and 

Hill Lung Cancer Study 

plus ,additional patients in 

Central Middlesex IIosvital. 

, 143 

ners’ 

t 84L 

1. Same interrieners and questionnaire in ewes and 

r011tr0ls. 

2. ~Jlccr diapnosis probably 

well established. 

-. 

1,737 men aglxl rxl and over on 11 General Pratt 

viewed by these practitioners. Hepresents ah 

(Y% non-response due to death and/or untraced 

Edwards, McKcown. and 

Whitfield (ll), 193 

Of 14.1 considered to have a 

peptic ulcer, 53 were conAr~ncd by X-ray. 
TABLE 2.-Summary of results of retrospective and cross-sectional studies of 

peptic ulcer and smoking 

Percent Non-smokers Percent Hcary Smokers or hvcragc 

hmo”nts USEd 

1nrcstigator ________ 

CaSCS Controls 

-__- -___- 

Barnett (21 Total 

Gastric :: 

Duodenal 20 ; 

Trowel1 (18) 

Mills (14) 

Allihone and Flint (I) 

Doll et al. (71 

3R .54 -1 

carrtric Glstric 

F 5::; 66.8 4 7 M F10.6 1. 1 11. 1. 3 1 

Duodenal Duodennl 

M 3. I 5.8 M 10.2 12. 7 

F 53.7. 62.0 1 F 1 9 1. 9 

Edwards ct al. (11) Perrcnt of Peptic Ulcer hy Smokine Catceory 

Never smokcd~......--.......-.-~..~...-....--....~~....~... 6.0 

Formerly smoked. __ .._.. . . . . ..__......._._..-.......-.... ~.. 6.7 

Cigarcttrs: 

Pipc and cigarettes . ..~. ..~ . . . . .._......._..-_..--...- .._._ 6. 5 

TABLE 3.-Expected and observed deaths and mortality ratios for ulcer of 

stomach and duodenum ++ among current cigarette smokers, from seven 

prospective studies 

Investigator Type of Ulrcr 

Hammond and Horn (13)” . .._..._ ~... 

Duodenal . . .._. . . . . . 

Both types ~~..~..-_..~..~ 

Dorn (S)**.............~......-....-..- Gastric ~~._...-......-._.~ 

Duodenal _ ~. ._- _ 

Both types .._ -..~_.. 

Hammond (lZ)~~~.................-...- Gastric 

Both typcs.~ .._........_.. 

Doll and Hill (fi) .._. -_- . . . . . . ..__...... Both types . . .._... . . .~... 

Dunn et al., Occupational (9)....-.-... Roth types 

Dunn et al., Legion (lO).~~...- ._..._. ~. Both t)pcs ~.~...~~_.~...~ 

Best et al. (5) __._._._....._ ..__..__. ~. Iloth types _... ~~._~ _.... 

Yncludcs ISC numbers 5dn, 541. 

**The Hammond and IIorn data arc frcnn their original puhlishcd report; the other rcsult~ lisfcrl include 

more recent data as tahulatrd ior the Conunittcc (SW Ch:qacr 8). 

339 
Numerous investigators have studied the clinical and physiological effects 

of snloking on gastric motility and acid secretion in humans with and without peptic, ulcer. Great vaiiation of gastric motility and secretion was 

observed in response to cigarette smoking. 

Some workers found inhibition of gastric motilit>- (15, 17). Batterman 

(3 1 showed three types of response in normal subjects and ulcer patients 

after smoking one cigarette. In one-third no effect was observed. another 

third complete inhihition of motor activity for a time, and in the rest a 

period of hypermotility \vas followed by normal or subnormal activity. 

Smoking appears to produce y;ariable effects also on gastric secretion. In 

a few studies. gastric secretion increased, while in others no change was 

obserl-ed or there was depression of secretory activity (4, 15, 16, 17). Additional studies of the effect of smoking on gastric secretory activity and 

motility are needed to explain the biological meaning of the statistical association between cigarette smoking and peptic ulcer. 

CONCLUSION 

Epidemiological studies indicate an association between cigarette smoking 

and peptic ulcer which is greater for gastric than for duodenal ulcer. 

REFERENCES 

1. Allibone, A.. Flint. F. J. Bronchitis, aspirin, smoking and other factors 

in the etiology of peptic: ulcer. Lancet 2: 179-82, 1958. 

2. Barnett, C. W. Tobacco smoking as a factor in the production of 

peptic ulcer and gastric neurosis. Boston Med Surg J 197: 457-9. 

1927. 

3. Batterman. R. C. The gestro-intestinal tract. In: Wynder, E. L. ed. 

The Biologic Effects of Tobacco. Boston, 1955. Chapter 5, p. 133-S). 

4. Batterman. R. C.. Ehrenfeld. I. The influence of smoking upon the 

managrmcnt of the peptic ulcer l’atient. Gastroenterology 12: 575-85. 

19 19. 

5. Best. E. W. R.. Josie. G. H.: Walker. C. B. A Canadian study of mortalit! in relation to smoking habits, a preliminary report. Canad J 

I’uh Health 52: Y-106: 1961. 

0. Ihll. 1-L. llill. A. 1~. Lun g cancer and other causes of death in relation 

to ~mc~kin~: A r;rcond report on the mortality of British doctors. 

Rrit \It~l J 2: IOYl-21, 1956. 

7. Doll. R.. Jones. F. A.. P!:;ott, F. Effect of smoking on the production 

and maintenance of gastric, and duodenal ulcers. Lancet 1: 657-62. 

1’XX. 

8. Darn. 14. F. Tobarco consumption and mortality from cancer and other 

disrases. Public Health Rep ‘i-1: 581-93, 1959. 
9. Dunn, J. E., Linden, G., Breslow, L. Lung cancer mortality experience of 

men in certain occupations in California. Amer J Pub Health 50: 

1475-87, 1960. 

10. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department of 

Public Health, Special Report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

11. Edwards, F., McKeown, T., Whitfield, A. G. W. Association between 

smoking and disease in men over sixty. Lancet 1: 196-200, 1959. 

12. Hammond, E. C. Special report to the Surgeon General’s advisory 

Committee on Smoking and Health. 

13. Hammond, E. C., Horn, D. Smoking and death rates-Report on 

forty-four months of follow-up of 187,783 men. II. Death rates by 

cause JAMA 166: 1294-1308, 1958. 

14. Mills, C. A. Tobacco smoking: Some hints of its biologic hazards. 

Ohio Med J 46: 1165-70, 1950. 

15. Packard, R. S. Smoking and the alimentary tract: A review. Gut 1: 

171-4, 1960. 

16. Schnedorf, J. G., Ivy, A. C. The effect of tobacco smoking on the 

alimentary tract. JA1lIA 112: 898-903, 1939. 

IT. Steigmann. F., Dolehide, R. U., Keminski, L. Effects of smoking 

tobacco on gastric acidity and motility of hospital controls and patients with peptic ulcer. Amer J Gastroent 22: 3991109, 1954. 

18. Trowell, 0. A. The relation of tobacco smoking to the incidence of 

chronic duodenal ulcer. Lancet 1: 80%9. 1934. 

TOBACCO AMBLYOPIA 

For more than a century clinicians have attributed certain cases of 

amblyopia-dimness of vision unexplained by an organic lesion-to the use 

of tobacco. 

The distinguishing characteristic of tobacco amblyopia is a specific type 

of centrocecal scotoma. Since this disease was defined as a distinct clinical 

entity for the first time in 1930 (4)) the medical literature prior to this date 

is of relatively little value in the’ critical evaluation of the problem (3 ). No 

epidemiological studies with adequate controls are available to establish for 

this disease a relative risk among smokers and nonsmokers. 

Clinical impressions associate tobacco amblyopia with pil)e and cigar 

smoking and very rarely with cigarette smoking. 

It has been suggested that this disease, which is now rare in the United 

States, occurs mainly in individuals with a nutritional deficiency which 

presumably renders the retina or optic nerve unduly sensitive to tobacco 

(1,5). 

Objective attempts at experimentation have been extremely rare and most 

of the literature is related to uncontrolled clinical impressions ( 2 I. 
CONCLUSION 

Tobacco amblyopia had been related to pipe and cigar smoking by clinical 

impressions. The association has not been substantiated by epidemiological 

or experimental studies. 

REFERENCES 

1. Heaton, J. M.: McCormick. A. J. A., Freeman, A. G. Tobacco Amblyopia: 

A clinical manifestation of vitamin B-12 deficiency. Lancet 2: 286- 

90, 1958. 

2. Potts, A. M. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

3. Schwartz, J. T. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

4. Traquair, H. M. Toxic Amblyopia, including retro-bulbar neuritis. 

Trans Ophthal Sot U K 50: 351-85, 1930. 

5. von Sallmann, L. Special report to the Surgeon General’s Advisory 

Committee on Smoking and Health. 

SMOKING AND CIRRHOSIS OF THE LIVER 

Epidemiological studies have noted an association between cigarette smoking and mortality from cirrhosis of the liver. The mean mortality ratio for 

cirrhosis of the liver calculated from all prospective studies was 2.2 (Table 

19, Chapter 8). The individual ratios in six of these studies ranged from 1.3 

in the Canadian veterans study ( 1) to 4.0 in the California occupational study 

(3). The earliest prospective study, by Doll and Hill (2) reported no 

deaths from cirrhosis of the liker among non-smokers. 

The small amount of information on the biological effects of nicotine and 

tobacco smoke on the liver of experimental animals is contradictory (5). 

In several studies (4, 6, 7) it has been reported that heavy smokers also 

tend to drink alcoholic liquors excessively. It is well established that heav) 

consumption of alcohol and nutritional deficiencies are associated with increased mortality from cirrhosis of the liver. The increased death rate from 

cirrhosis among smokers may reflect the consumption of alcohol and associated nutritional deficiencies rather than the effect of cigarette smoking. 

CONCLUSION 

Increased mortality of smokers from cirrhosis of the liver has been shown 

in the prospective studies. The data are not sufficient to support a direct or 

causal association. 

342 
REFERENCES 

1. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mortality 

in relation to smoking habits. a preliminary report. Canad J Pub 

Health 52: 99-106, 1961. 

2. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation 

to smoking: A second report on the mortality of British doctors. Brit 

Med J 2: 1071-81, 1956. 

3. Dunn, J. E., Linden, G.: Breslow, L. Lung cancer mortality experience 

of men in certain occupations in California. Amer J Pub Health 50: 

1475-87, l%O. 

4. Heath, C. W. Differences between smokers and non-smokers. AMh 

Arch Int Med 101: 377,1958. 

5. Larson, P. S., Haag. H. B.. Silvette, H. Tobacco-experimental and 

clinical studies. A comprehensive account of the \\-orld literature. 

Balliere, Tindall S Cox. London. 1961. p. 319-321. 

6. Matarazzo, J. D.. Saslow, G. Psychological and related charartcristi,cs 

of smokers and non-smokers. Psycho1 Bull 57: 493, 1960. 

7. McArthur, C., Waldron, E., Dickinson, J. The psychology of smoking. 

J Abnorm Sot Psycho1 56: 267-275, 1958. 

MATERNAL SMOKING AND INF:lNT BIRTH WEIGHT 

Five retrospective and two prospective studies have shown an association 

between maternal smoking during pregnant)- and birth I+.eight of the infant 

(2, 4, 5, 6, 8, 9, 10). Women smoking during pregnancy have babies of 

lower birth weight than non-smokers of the same social class. They have 

also a significantly greater number of premature deliveries (defined as 

birth weight of 2,500 grams or less) than the non-smoking controls. 

While several studies reported a slightly c oreater neonatal death rate of 

the children of smokers 12. 5), others did not demonstrate any significant 

difference in the fetal and neonatal death rates of the two groups (6, 7). 

Studies on alterations of placental morphology and function as a response 

to smoking are insufficient for judgment. The difference in infant weight 

may be due to vasoconstriction of the placental blood vessels (1) or to toxic 

substances such as CO in the circulation of the smoker and fetus (3’1. 

It is not known whether the lower hirth weight of the infants of smokers 

has any clinical significance. In one of the groups studied ( 5 I there \+as 

less need for surgical induction of labor among mothers who smoked. 

CONCLUSIONS 

1. Women who smoke cigarettes during pregnancy tend to have babies 

of lower birth weight. 

2. Information is lacking on the mechanism by which this decrease in 

birth weight is produced. 

3. It is not known whether this decrease in birth weight has any influence on the biological fitness of the newborn. 

343 
REFERENCES 

1. Essenherp, J. M., Schwind, J., Patras, A. The effects of nicotine and 

cigarette smoke on pregnant female albino rats and their offsprings. 

J Lab Clin Med 25: 708-17, 1940. 

2. Frazier, T. M., Davis, G. H., Goldstein, H., Goldberg, I. D. Cigarette 

smoking and prematurity: a prospective study. Amer J Obstet Gynec 

81: 98%96, 1961. 

3. Haddon, W. Jr., Nesbitt, R. E. Smoking and pregnancy: carbon monoxide in hlood during gestation and at term. Obstet Gynec 18: 262-7, 

1961. 

4. Herriot, .4., Billewicz, W. F., Hytten, F. E. Cigarette smoking in pregnanq. Lancet I : 771-3, 1962. 

5. Lowe. C. R. Effect of mother’s smoking habits on birth weights of their 

children. Brit Med J 2: 673-6, 1959. 

6. O’Lane, J. M. Some fetal effects of maternal cigarette smoking. Obstet 

Gvnec 22: 181-4, 1963. 

7. Save], L. E., Roth, E. Effects of smoking on fetal growth. Obstet Gynec 

20: 313-6, 1962. 

8. Simpson, W. J. A preliminary report on cigarette smoking and the incidence of prematurity. Amer J. Obstet Gyn’ec 73: 808-15. 1957. 

9. Villumsen. A. L. Cigarette smoking and low birth weights: A preliminary report. Ugeskr Lang 124: 630-1, 1962. 

10. Yerushalmy. J, Statistical considerations and evaluation of epidemiological evidence. In: James. George and Rosenthal. Theodore eds. 

Tobacco and Health. Springfield. Ill. Charles C. Thomas. 1962. 

p. 208-30. 

SMOKIYG AND ACCIDENTS 

Smoking has heen aF.Gociated with a variety of accidents. Among these. 

fires hale the most obvious and important consequences. 

In a special stlld\ of home accident fatalities in 1952 through 1953. the 

Public Health Ser\-ic,e and the Sational Safet! Council reported that 231 

I 18c; ) of 1.21-1. deaths from fires 6f known origin were due to cigarettes. 

cigars or ])ipel; I1 1. 

The Rletropolitan Life Insuranre Compan!- reported that of 352 deaths in 

1956 and 19X anlo p their polir! holder5 from fires and burns with know11 

causes in and about the home. ii7 I lC,(; ) were due to smoking 12 1. 

Of I)h!-sioloFic,al responsr%s rrlated to dri\ inp. snlokin= degrades detectah]!- 

only thr differralltial hrightne~,s threshold and thi, effect increases \\ith 

amount of c,tll,kirlg I 1 I. ThcL el)iclemiologic~al data a\ ailaljle on the effectof srnokillg on traflir ac,r.itlerlts are inconcluiir-e. 

It has been she\\ n that a level of carhos!-hemogltrl,in of .5 percent- -a le\rl 

rvhich is not uncon1mon among heat v cigarette smokers i 3. 6) ~~deprca~es 

visual perception to as great an extent as anosia at KOOO to 10,090 feet 

altitude (4, 5). 

344 
CONCLUSION 

Smoking is associated with accidental deaths from fires in the home. No 

conclusive information is available on the effects of smoking on traffic 

accidents. 

REFERENCES 

1. Home Accident Fatalities: 1952-1953. National Office of Vital Statistics,, 

U.S. Public Health Service, 1956. Mimeographed report. Table 12. 

2. How fatal accidents occur in the home. Metrop Life Insur Statist Bull 4Q: 

6-8, November-December, 1959. 

3. Larson, P. S., Haag, H. B.. Silvette, H. Tobacco: Experimental and 

Clinical studies. Baltimore, Williams and Wilkins. 1961. Carhoxyhemoglobin, p. 107-110. 

4. McFarland, R. A., Moseley, A. L. Carbon monoxide in trucks and buses 

and information from other areas of research on carbon monoxide. 

altitude and cigarette smoking. In : Conference proceedings: Health, 

medical and drug factors in highway safety. National Academy of 

Sciences-National Research Council Publication 328, 1954. Sect. 

4.17-4.33. 

5. McFarland, R. A., Roughton, F. J. W., Halperin, M. H., Niven, J. I. The 

effects of carbon monoxide and altitude on visual thresholds. J Aviat 

Med 15: 6, 381-94, 1944. 

6. Schrenk, H. H. Results of laboratory tests. Determination of concentration of carbon monoxide in blood. Pub Health Hull 278: 36-49, 

1942. 

345 
Chapter 13 

Characterization of the 

Tobacco Habit and 

Beneficial Effects of Tobacco 
Contents 

CHARACTERIZATION OF THE TOBACCO HABIT . . . . 

Nicotine . . . . . . . . . . . . . . . . . . . . . . . 

Distinction Between Drug Addiction and Drug Habituation . 

Tobacco Habit Characterized as Habituation . . . . . . . 

Relationship of Smoking to Use of Addicting Drugs . . . . 

Measures for Cure of Tobacco Habit . . . . . . . . . . . 

Summary. . . . . . . . . . . . . . . . . . . . . . . 

BENEFICIAL EFFECTS 01’ TOBACCO . . . . . . . . . 

Summary. . . . . . . . . . . . . . . . . . . . . . . 

References . . . . . . . . . . . . . . . . . . . . . . 

Page 

349 

349 

350 

351 

352 

354 

354 

355 

356 

356 

348 
Chapter 13 

CHARACTERIZATION OF THE TOBACCO HABIT 

NICOTINE 

Of the known chemical substances present in tobacco and tobacco smoke. 

only nicotine has been given serious pharmacological consideration in relationship to the tobacco habit. Lewin (17) stated. “The decisive factor in the 

effects of tobacco, desired or undesired, is nicotine . . . and it matters little 

whether it passes directly into the organism or is smoked.” Support for this 

statement is based mostly on rationalizations from smoking behavior. analoPT 

to other habits involving pharmacological agents and. to a much lesser extent, 

on established scientific fact. The latter may be summarized brielly as 

follows: 

1. Only plants with active pharmacological principles have been employed 

habitually by large populations over long periods; e.g., tobacco (nicotine) ; 

coffee, tea, and cocoa (caffeine) ; betel nut morsel (arecoline) ; marihuana 

(cannibinols) ; khat (pseudoephedrine) ; opium ( morphine) ; coca leaves 

(cocaine) ; and others (see Lewin, 17). 

2. Denicotinized tobacco has not found general public acceptance as a 

substitute (16, pp. 531-532). 

3. Chewing tobacco and using snuff, although providing oral gratification, 

also furnish nicotine for absorption to produce systemic effects (34). 

4. Many but not all smokers can detect a reduction in nicotine content of 

cigarettes (9) . 

5. The administration of nicotine mimics the subjective effects of 

smoking (13). In uncontrolled experiments Johnston administered nicotine 

hypodermically, intravenously, or orally to smokers and non-smokers. Nonsmokers found the effects “queer,” whereas many smokers, including Johnston himself, claimed the subjective effects to be identical to those obtained 

by inhaling cigarette smoke and found that the urge to smoke was greatly 

reduced during nicotine administration. 

In spite of the anecdotal nature of most of this information, the facts are 

that nicotine is present in tobacco in significant amounts, is absorbed readily 

from all routes of administration, and exerts detectable pharmacological 

effects on many organs and structures including the nervous system. The 

classical pharmacological characterization of nicotine-cellular stimulation 

followed by depression which is noted in isolated tissue and organ systemshas been invoked to explain the widely differing subjective responses of 

smokers, many of whom describe the effects as stimulating (“smoking relieves 

the depression of the spirits”), while others obtain a soothing and tranquilizing effect (16, p. 533). 

Wilder (33) summarized the literature by noting “. . . observations that 

cigarette smoking obviously serves a dual purpose: it will mostly pick US UP 

349 
when we are tired or depressed and will relax and sedate us when we are 

tense and excited.” In order to ascribe such biphasic effects solely to the 

direct action of nicotine it would be necessary to discount psychological responses and alterations in mood from all other types of stimuli associated 

with smoking or the use of tobacco, an obvious impossibility. Although 

Knapp and Domino (15) have shown nicotine in small amounts to exert 

potent arousal effects in the electroencephalogram in animals, this evidence 

is difficult to interpret as it relates to smoking in man. A consensus among 

modern authors (27) appears to be that smoking, and presumably nicotine, 

exert a predominantly tranquilizing and relaxing effect. The act of smoking 

is of such complexity that the difficulties associated with objective analysis 

of whether smoking induces pleasure by creating euphoria or by relieving 

dysphoria renders objective analysis virtually impossible. The anecdotal 

literature suggests that sedation plays a more important subjective role in 

pipe and cigar smoking than with cigarette smoking. Since most pipe and 

cigar smokers do not inhale, this suggests that bronchial and pulmonary 

irritation from cigarette smoke after inhaling may contribute an important 

sensory input to the central nervous system which could modify the sedative 

effects of nicotine. so that some individuals would describe the experience as 

stimulating rather than sedative. Heavy cigarette smokers who inhale often 

describe the act as a pleasant sensory experience which constitutes for them 

one of the prime drives to continue to smoke. Freedman (10) used the term 

“pulmonary erotism.” Mulhall ( 19 ) and Robicsek i 22) have commented on 

this concept. An interesting psychoanalytical approach by Jonas (14)) 

which postulates central nervous system counterirritation to constant pulmonary irritation from smoking, is based upon this concept. If pulmonary 

irritation is a pleasure factor it probably is not related to nicotine alone but 

to other irritants in smoke and could represent a non-specific increase in 

afferent sensory discharge from the whole respiratory tract. A gap in knowledge exists in this area. F ur th ermore, until carefully controlled experiments 

with nicotine are conducted in man, the literature will be burdened further 

with anecdote and hypothesis rather than fact. 

DISTINCTION BETWEEN DRUG ADDICTION AND DRUG HABITUATION 

Smokers and users of tobacco in other forms usually develop some degree 

of dependence upon the practice. some to the point where significant emotional disturbances occur if they are deprived of its use. The evidence indicates this dependence to be psychogenic in origin. In medical and scientific 

terminology the practice should be labeled habituation to distinguish it clearly 

from addichm, since the biological effects of tobacco, like coffee and other 

caffeine-containing beverages: betel morsel chewing and the like, are not 

comparable to those produced by morphine, alcohol, barbiturates, and many 

other potent addicting drugs. In fact. to make this distinction, the World 

Health Organization Expert Committee on Drugs Liable to Produce Addiction 

(35) created the following definitions which are accepted throughout the 

wcrld as the basis for control of potentially dangerous drugs. 

350 
Drug Addiction 

Drug addiction is a state of periodic 

or chronic intoxication produced by 

the repeated consumption of a drug 

(natural or synthetic). Its characteristics include: 

1) An overpowering desire or need 

(compulsion) to continue taking the drug and to obtain it 

by any means; 

2) A tendency to increase the dose; 

3) A psychic (psychological) and 

generally a physical dependence on the effects of the drug; 

4) Detrimental effect on the individual and on society. 

Drug Habituation 

Drug habituation (habit) is a condition resulting from the repeated 

consumption of a drug. Its characteristics include: 

1) A desire (but not a compulsion) 

to continue taking the drug 

for the sense of improved wellbeing which it engenders: 

2) Little or no tendency to increase 

the dose; 

:H Some degree of psychic dependence on the effect of the drug, 

but absence of physical dependence and hence of an 

abstinence syndrome; 

4) Detrimental effects, if any, primarily on the individual. 

TOBACCO HABIT CHARACTERIZED AS HABITUATION 

Psychogenic dependence is the common denominator of all drug habits 

and the primary drive which leads to initiation and relapse to chronic drug 

use or abuse (25). Although a pharmacologic drive is necessary it does 

not need to be a strong one or to produce profound subjective effects in order 

that habituation to the use of the crude material becomes a pattern of life. 

Besides tobacco, the use of caffeine in coffee, tea, and cocoa is the best example in the American culture. Another example, the chewing of the betel 

morsel, exists on a world scale comparable to tobacco and involves several 

hundred million individuals of both sexes and of all races, classes, and 

religions (17). The morsel contains arecoline from the areca nut, an ingredient of the mixture. It is a very mild stimulant of the nervous system which 

is ordinarily no more detectable than nicotine subjectively. The morsel is 

chewed from morning to night, from infancy to death, and creates a craving 

more powerful than that for tobacco. As with tobacco, oral gratification 

plays an important role in this habit. 

Thus, correctly designating the chronic use of tobacco as habituation 

rather than addiction carries with it no implication that the habit may be 

broken easily. It does, however, carry an implication concerning the basic 

nature of the user and this distinction should be a clear one. It is generally 

accepted among psychiatrists that addiction to potent drugs is based upon 

serious personality defects from underlying psychologic or psychiatric disorders which may become manifest in other ways if the drugs are removed 

(32). 

Even the most energetic and emotional campaigner against smoking and 

nicotine could find little support for the view that all those who use tobacco, 

7 14-422 Q-64-24 351 
coffee, tea, and cocoa are in need of mental care even though it may at 

some time in the future be shown that smokers and non-smokers have different 

psychologic characteristics. 

RELATIONSHIP OF SMOKING TO USE OF 14~~~~~~~~ DRUGS 

TJndoubtedly, the smoking habit becomes compulsive in some heavy 

smokers but the drive to compulsion appears to be solely psychogenic sinrc, 

physical dependence does not develop to nicotine or to other constituents of 

tobacco nor does tobacco, either during its use or following withdrawal. 

create psychotoxic effects which lead to antisocial behavior. Compulsion 

exists in many prades. from the habit pattern of the cigarette smoker who 

subconsciously reaches into his pocket for a cigarette and may even light his 

lighter before he realizes that he is already holding a lighted cigarette in his 

lips, to the heroin addict who becomes involved in crime, sometime5 ill 

murder, in his search for drugs to satisfy his addiction. Clearly there ip a 

significant difference. not only in the personality involved but also in thr 

effects upon the user and his relationship to society. 

Proof of physical dependence requires demonstration of a characteristic 

and reproducible abstinence syndrome upon withdrawal of a drug or chemical 

which occurs spontaneously, inevitably, and is not under control of the sub. 

ject. Neither nicotine nor tobacco comply with any of these requirements 

(26). In fact, many heavy smokers may cease abruptly and, while retaining 

the desire to smoke, experience no significant symptoms or signs on withdrawal. On the other hand. it is well established that many symptoms and 

a few signs which may be observed objectively by others may occur following cessation of smoking, but no characteristic abstinence syndrome occurs 

(16, p. 539). Rather. a gamut of mild symptoms and signs is experienced 

and observed as in any emotional disturbance secondary to deprivation of 

a desired object or habitual experience. These may be manifest in some per. 

sons as an increased nervous excitability, such as restlessness, insomnia. 

anxiety, tremor, palpitation. and in others by diminished excitability, such 

as drowsiness, amnesia, impaired concentration and judgment, and diminished pulse. The onset and duration of these withdrawal symptoms arr 

reported by different authors in terms of days (20)) weeks (30)) or months 

(12, 28)) obviously an inconsistency if one attempts to relate these to nicotine 

d eprivation. In contrast to drugs of addiction, withdrawal from tobacco 

never constitutes a threat to life. These facts indicate clearly the absence of 

physical dependence. 

This view is supported further by consideration of the diversity of methods 

which are reported (16, pp. 540-546) to be successful in treatment of smoking withdrawal. Most methods have been based strictly on symptomatic 

treatment; for those who are depressed: stimulants such as caffeine, theebromine, and metrazol; and for those who are excited, sedatives, barbiturates. 

and the like. Hansel ( 11) treated his patients by stimulating them in the 

daytime with 10 to 15 mg of dextroamphetamine and putting them to sleep 

at night with a sedative. At least this treatment has the advantage that it does 

not interfere \\ith the usual patterns of diurnal and nocturnal behavior. 

352 
In contrast to addicting drugs, the tendency to continue to increase the dose 

of tobacco is definitelv self-limiting because of the appearance of nicotine 

toxicity. Undoubtedly there is a considerable variation among individuals 

in inherited capabilities to tolerate nicotine. In some individuals this may 

completely deprive them of the pleasure of using tobacco 130). Although 

some tolerance is also acquired with repeated use. this is not sufficient to 

permit the nervous system to be exposed to ever-increasing nicotine concentrations as is the case with addicting drugs. This in itself mav militate against 

the development of the adaptive changes in nerve cells which create physical 

dependence. 

It is a well-known fact among smokers and other users of tobacco that 

certain toxic effects such as nausea and vomiting. which accompanv the 

initial use of tobacco, disappear with repeated use. This tolerance is only 

relative and excessive use may at any- time initiate these signs and symptoms 

even in the heavy smoker or other user (6). 

Acquired tolerance may take two forms: 

(a) A low grade tissue tolerance in mucous and pulmonary membranes 

to the irritants in tobacco or tobacco smoke (8). This probably involves 

adaptive changes in cell membranes. similar to those which occur with other 

local irritants, and a reduction in sensory nervous input permitting more 

prolonged exposure to those irritants without unpleasant subjective 

manifestations. 

(b) Sp eci fi c or g an t o 1 erance to nicotine which is also relatively low grade 

and comparatively short-lived. This tolerance, which may permit the administraton of nicotine in quantities several times larger than those which 

would induce toxic signs and symptoms initially (13)) varies with age (17), 

sex (30), and duration of exposure. Differences in metabolic disposition 

are not enough to account for tolerance (7. 29, 31). Animal studies indicate 

considerable tolerance to small but little if any to convulsant or lethal doses 

(2, 4). 

Another form of adaptation to tobacco wfhich is psychologic in origin is 

also common to many other drug habits. It might better be termed toleration than tolerance; the user “puts up with” symptoms of irritation and 

nicotine toxicity which are unacceptable to the novice. Many smokers accept 

persistent cough, bouts of nausea, and other unpleasant manifestations of 

irritation and toxicity. 

Much controversy concerns the relationship of smoking to other drug habits 

especially to those agents which are addicting like alcohol, the opiates, and 

others. Since the motivating factor in the habitual use of drugs of any type 

is the desire to change the status quo in order to achieve pleasure, to relieve 

monotony, to abolish tension or grief, etc., it is not unusual that many individuals in search of such gratification will habitually rely on several substances. Attempts to establish cause and effect relationships among the 

several habits have not been meaningful. A more plausible explanation is 

that the personality characteristics which lead to the search for change may 

find mild expression in smoking, coffee and moderate alcohol drinking, and in 

an exaggerated form by abusing the narcotic and stimulant drugs of addiction. 

353 
MEASURES FOR CURE OF TOBACCO H.ABIT 

Measures directed at the cure of the tobacco habit have heen designed 

l~rincipall\ to modifv or abolish the psj-chogenic. sensory. or pharmacologic 

drives ( 18. pp. .i-10-%1 I. 

In the psvchotheral)rutic area these include psychoanalytic technics, 

hvpnotiam. antismokin, ~7 campaigns hased upon fear of health consequences, 

religion. group ps!-chotherapy (similar to Alcoholics Anonymous), and 

tranquilizing or stimulant drues. 

Modification of tobacco taste by astringent mouthwashes (silver nitrate 

and copper sulfate I. hitters I quinine, quassia I. local anesthetics (benzocaine 

lozenges I. substitution of o&r tastes (essential oils and flavors), and production of a dq mouth iatropine or stramonium) are all measures which 

ha\,e heen aimed at diminishing the sensory drives. 

Administration of oral lobeline. a substance from Indian tobacco, with 

Meak nicotine-like actions as a nicotine substitute has had rather extensive 

trial I 5. 21: 36 )$ and commercial preparations are available. Carefully 

controlled studies have failed to establish the \-alue of lobeline (1, 18, 24). 

Of the methods cited above, those which deal with the psychogenic drives 

have been the more successful since ultimate realization of the goal involves 

the firm mental resolve of the individual to stop smoking. There is no 

acceptable evidence that this goal can be achieved solely by modifying 

sensory drives or using tobacco substitutes. 

The habitual use of tobacco is related primaril! to psychological and social 

drives, reinforced and perl)etuated hy the pharmacological actions of nicotine on the central nerl-ou’: system, the latter being interpreted subjectively 

either as stimulant or tranquilizin g dependent upon the individual response. 

‘iicotine-free tobacco or other plant materials do not satisfy the needs of those 

who acqtlire the tobacco habit. 

The tohacro hahit should he characterized as an hnbitrtn~ior7 rather than 

an nrlt/ic/ion. itI c~onf~lrnlit\~ with acceljted World Health Organization definition5. since onc’e estahlishrd there is little tendency to increase the dose; 

l)sychic hut not ljh! sical dependence is de\elol)ed: and the detrimental effects 

are primaril!- on thy indi\ itlual rather than society. Ko characteristic abstil:en(.e’s:\tldrclmc is dr\eloped uljon withdrawal. 

Acquired tolerance. r\-et\ though comparati\-elv low grade. is important 

in Ir\errolning nausea and other mild signs of nicotine toxicity and is a 

factor in continued 11s~ of tobacco. 

Discontinuation of snloking. although ljosressing the difficulties attendant 

upon extinctiotl of an\ conditioned rellex. is accoml)lished best by reinforcirl= factors which interruljt the l~s.\chogeuic drives. Nicotine substitutes or 

supplementary medications have not been pro\-en to be of major benefit iI1 

breaking the habit. 

354 
BENEFICIAL EFFECTS OF TOBACCO 

Evaluation of the effects of smoking on health would lack persl)ecti\-e if no 

consideration was given to the possible benefits to be derived from the 

occasional or habitual use of tobacco. A large list of possible phvsical benefits 

can be compiled from a fairly large literature. much of which is based upon 

anecdote or clinical impression. 

Even in those circumstances where a substantial body of fact and experience supports the attribute, the purported benefits are comparatively inconsequential in a medical sense. Examples are: (a) maintenance of good 

intestinal tone and bowel habits (23) _ and (b) an anti-obesity effect upon 

reduced hunger and a possible elevation in blood sugar (3). Insofar as 

these are supported by fact they represent tangible assets and cannot be 

totally dismissed. On the other hand. it would be difficult to support the 

position that these attributes would carry much weight in counter-balancing 

a significant health hazard. 

But it is not an easy matter to reach a simple and reasonable conclusion 

concerning the mental health aspects of smoking. The purported benefits 

on mental health are so intan$ble and elusive. so intricately woven into the 

whole fabric of human behavior, so subject to moral interpretation and 

censure, so difficult of medical evaluation and so controversial in nature that 

few scientific groups have attempted to study the subject. 

The drive to use tobacco being fundamentally psychogenic in origin has the 

same basis as other drug habits and in a large fraction of the American population appears to satisfy the total need of the individual for a psychological 

crutch. 

An attempted evaluation of smoking on mental health becomes more 

realistic if one is willing to confront the question. ridiculous as it may seem. 

What would satisfy the psychological needs of the 70,000,OOO Americans who 

smoked in 1963 if they were suddenly deprived of tobacco? Clearly there 

is no definitive answer to this question but it may be illuminated by analogy 

with the past. 

Historically, man has always found and used substances with actual or 

presumed psychopharmacologic effects ranging in activity from the innocuous 

ginseng root to the most violent poisons. In China, traditions and custom 

endowed the ginseng root with remarkable health-giving properties. The 

strength of this belief was so strong and the supply so short that the root 

often became a medium of exchange. The value of the root increased in 

direct proportion to its similarity in appearance to the human figure. 

The remarkable aspect of this situation is that the ginseng root is historically the world’s most renowned placebo, since science has failed to establish that it contains any active pharmacologic principle. 

It would be redundant to recount here all of the potent substances at the 

other end of the scale. It will suffice to note that this human drive is so universal and may be so powerful that man has always been willing to risk 

and accept the most unpleasant symptoms and signs-hallucinations and 

delusions, ataxia and paralysis, violent vomiting and convulsions, poverty 

and malnutrition, destructive organic lesions; and even death. 

355 
If the thesis is accepted that the fundamental nature of man will not change 

significantly in the foreseeable future. it is then safe to predict that man will 

continue to utilize pharmacologic aids in his search for contentment. In the 

best interests of the public health this should be accomplished with substances which carry minimal hazard to the individual and for society as a 

whole. In relating this principle to tobacco it may be reemphasized that the 

hazard. serious as it may be, relates mainly to the individual, whereas the indiscriminate use of more potent pharmacologic agents without medical supervision creates a gamut of social problems which currently constitutes a major 

concern of government as indicated by the recent (1962) White House Conference on Narcotic and Drug Abuse (32). 

SUMMARY 

Medical perspective requires recognition of significant beneficial effects of 

smoking primarily in the area of mental health. 

These benefits originate in a psychogenic search for contentment and are 

measureable only in terms of individual behavior. Since no means of quantitating these benefits is apparent the Committee finds no basis for a judgment 

which would v eigh benefits versus hazards of smoking as it may apply to the 

general population. 

REFERENCES 

1. Bartlett, W. A.. Whitehead, R. W. The effectiveness of meprobamate and 

lobeline as smoking deterrents. J Lab Clin Med 50: 278-81, 1957. 

2. Behrend. A.. Thienes, C. H. The development of tolerance to nicotine 

by rats. J Pharmacol Exp Ther 48: 317-25, 1933. [Abstract] J 

Pharmacol Exp Ther Proc 42: 260, 1931. 

3. Brozek, J., Keys, A. Changes in body weight in normal men who stop 

smoking cigarettes. Science 125: 1203, 1957. 

4. Dixon. W. E., Lee, W. E. Tolerance to nicotine. Quart J Exp Physiol 

5: 373-83, 1912. 

5. Dorsey, J. L. Control of the tobacco habit. i\nn Intern Med 10: 62% 

31: 1936. 

6. Edmunds, C. W. Studies in tolerance, l-nicotine and lobeline. J Pharmacol Exp Ther 1: 27-38, 1909. 

7. Edmunds, C. W.. Smith. M. I. Further studies in nicotine tolerance. 

J Pharmacol Exp Ther 8: 131-2, 1916. Also: J Lab Clin Med 1: 

315-21, 1915-16. 

8. Farrell. H. The billion dollar smoke. A working truth in reference to 

cigarettes and cigarette smoking. Nebraska Med J 18: 226-8, 1933. 

9. Finnegan, J. K.. Larson, P. S., Haag, H. B. The role of nicotine in the 

cigarette habit. Science 102: 94-6, 1945. 

10. Freedman, B. Conditioned reflex and psychodynamic equivalents in 

alcohol addiction. An illustration of psychoanalytic neurolom, with 

rudimentary equations. Quart J Stud Alcohol 9: 53-71, 1948. 
11. Hansel, F. K. The effects of tobacco smoking upon the respiratory tract. 

South M J 47: 745-9, 1954. 

12. Head, J. R. The effects of smoking. Illinois Med J 76: 83-287, 1939. 

13. Johnston, L. Tobacco smoking and nicotine, Lancet London 2: 742, 

1942. 

14. Jonas, A. D. Irritation and counterirritation. i\ hypothesis about the 

autoamputative property of the nervous system. New York Vantage 

Press, 1962. 368 p. 

15. Knapp, D. E., Domino, E. F. Action of nicotine on the ascending reticular activating system. Int J Neuropharmacol 1: 333-51, 1962. 

16. Larson, P. S., Haag. H. B., Silvette, H. Tobacco: Experimental and 

Clinical Studies. Baltimore, The Williams & Wilkins Company, 1961. 

932 p. 

17. Lewin, L. Phantastica: Narcotic and stimulating drugs: Their use and 

abuse. London, Kegan Paul, Trench, Truhner, 1931. 335 p. 

18. Miley, R. A., White, 1’. G. Giving up smoking. Brit Med J 1: 101, 

1958. 

19. Mulhall, J. C. The cigarette habit. Trans Amer Laryng Assn 17: 192- 

200, 1895. Also: Ann Otol 52: 714-21, 1943; and N Y Med J 62: 

686-8, 1895. 

20. Ochsner, A. Smoking and cancer: A doctor’s report. N Y J Messner, 

1954. 86 p. 

21. Rapp. G. W., Olen, A. A. Lobeline and nicotine. Amer J Med Sci 230: 

9, 1955. 

22. Robicsek, M. U. H. Eine neue Therapie der Nikotinsucht oder dieKunst, 

das Rauchen zu lassen. Fortschr Med 50: 1014-5, 1932. 

23. Schnedorf, J. G., Ivy, A. C. The effects of tobacco smoking on the 

alimentary tract. An experimental study of man and animals. 

JAMA 112: 898-904, 1939, 

24. Scott, G. W., Cox, A. G. C., Maclean, K. S., Price, T. M. L., Southwell, N. 

Buffered lobeline as a smoking deterrent. Lancet 1: 54-5, 1962. 

25. Seevers, M. H. Medical perspectives on habituation and addiction. 

JAMA 181: 92-8, 1%2. 

26. Seevers, M. H., Deneau, G. A. Tolerance and dependence to CNS drugs. 

In: Root, W. S., Hoffman, F. G. eds. Physiological Pharmacology, 

N Y Acad Press, 1963. p. 565640. Vol. 1: Nervous system. 

27. Silvette, H., Larson, P. S., Haag, H. B. Medical uses of tobacco past and 

present. Virginia Med Monthly 85: 472-84, 1958. 

28. Swinford, O., Jr., Ochota, L. Smoking and chronic respiratory disorders. Results of abstinence. Ann Allerg 16: 4X-8, 1958. 

29, Takeuchi, M., Kurogochi, Y., Yamaoka, M. Experiments on the repeated injection of nicotine into albino rats. Folia Pharmacol Jap 50: 

669, 1954. 

30. Von Hofstatter, R. Uber Abstinenzerscheinungen beim Einstellen des 

Tabakrauchens. Wien med Wschr 86: 42-3, 73-6, 1936. 

31. Werle, E., Muller, R. Uber den Abbau von Nicotin durch tierisches 

Gewebe. II. Biochem 308: 355-8, 1941. 

32. White House Conference on Narcotic and Drug Abuse. Sept. 27-28, 

1962. Proc Govt Print Off, 1963. 330 p. 

357 
33. Wilder. J. Paradox reactions to treatment. New York J Med 57: 

3348-52. 1957. 

34. Wolff. W’. 4.. Giles. W. E. St u d ies - on tobacco chemistry. Fed Proc 9: 

24G, 1950. 

35. World Health Organization. Expert Committee on Addiction-Produci,,,, 

Drugs. Se\,enth Report. 15 p. 

r I Its Techn Rep Ser NO. 116, I9.j:. , 

36. Wright. 1. S.. Littauer, D. Lobeline sulfate, its pharmacology and uw 

in the treatment of the tobacco habit. JAMA 109: W-54, 193;. 

358 
Chapter 14 

Psycho-Social Aspects 

of Smoking 
Contents 

Pap. 

INTRODUCTION .................... 36 I 

DEMOGRAPHlC FACTORS ............... .?(,I 

Age ......................... :I6 I 

Smoking by Socioeconomic Level ............ 36_ 

Occupation ...................... 36” 

Education ...................... 363 

Sex.. ....................... 363 

Race. ........................ 363 

Marital Status .................... 361 

Religion ....................... 364 

Rural versus Urban .................. 361 

Summary. ...................... 361 

PERSONALITY AND SMOKING. ............ 30; 

Extroversion and Introversion. .............. 30-l 

Neuroticism ...................... 306 

Psychosomatic Manifestations. ............. 36; 

Psychoanalytic Theory ................. 36: 

Summary. ...................... 3hH 

TAKING UP SMOKING ................. 36H 

Parents’ Smoking Patterns ............... 36’3 

Intelligence and Achievement .............. 331 

Some IIypotheses on the Heginning of Smoking ...... 3: I 

Status Striving .................... 3;’ 

Rebellion Against Authority .............. 373 

Smoking as a Response To Stress and as a Tension Release . . :3,:\ 

DISCONTINUATION .................. 374 

SUMMARY ....................... 376 

CONCLUSION ...................... 3;; 

REFERENCES. ..................... 3:; 

360 
Chapter 14 

INTRODUCTION 

The smoking habit has been found to be linked with several demographic 

variables (such as age: sex: socioeconomic level, etc.), with a number of 

general behavioral patterns (such as degree and kind of participation in a 

variety of social activities). with psychological characteristics (such as intelligence, school achievement. etc.). and with certain personality variables 

isuch as intro- and extroversion. gregariousness. feelings of inferiority. need 

for status, etc.). 

A brief general discussion will be followed by a review of empirical evidence linking demographic characteristics with smoking. Certain psychological-personality variables will then be considered, followed by a review of 

what is known about the beginning of the smoking habit and about its discontinuation. Finally, general conclusions will be drawn about the present 

state of knowledge. 

The term “smoking,” unless otherwise specified, refers throughout to cigarette smoking only, because almost all research in the area has dealt only 

with cigarette smoking. 

DEMOGRAPHIC FACTORS 

A clear and authoritative demographic description of smokers is not readily 

available from any one study on the subject. The considerable differences in 

the characteristics of the smoking population as reported by various studies 

can probably be explained by one or more of the following factors: 

1. Samples were drawn from populations differing in geographical location and in a number of other population characteristics. 

2. Data in the several studies were collected during different years between the 1930’s and 1962. Therefore, some differences in reported data could be due to time trends. 

3. Methods of gathering information differed among the studies. 

4. Data were analyzed and/or grouped in different ways. 

Nonetheless certain trends seem to be well established. 

AGE 

As far as is known from actual data, few children smoke before the age 

of 12. probablv less than five percent of the hors and less thar: one t’ercent 

of the girls. b rom age 12 on. however, there is a fairlv regular increase 

in the prevalence of smoking. At the 12th grade level, ‘between 40 to S5 

361 
percent of children have been found to be smokers. By age 25, estimate, 

of smoking prevalence run as high as 60 percent of men and 36 !lerce,,; 

of women. There is a further increase up to 35 and 40 years after Ichich a 

drop is observed. In the 65 and over age group, prevalence of smoking in 

only approximately 20 percent among men and four percent among ~~-olllt’,, 

These distributions are based on cross-sectional rather than longitudi,,,,; 

data and may be subject to considerable change over the years as each F,.r,. 

eration of smokers carries its own smoking pattern into higher age bracktqc, 

It is also conceivable that increased public attention to possible hazarll. 

of smoking within the last few years has led to some decrease m the numl,,., 

of smokers, a decrease not evenly distributed among the several age erou,,., 

Since these statistics were collected several years ago. they may not r+,.t 

current age distributions. More recent but limited data suggest that th,s,.(. 

has been an increment in smoking prevalence at all age levels since the earl\ 

fifties (7, 13, 23, 26, 31 j. 

Horn (11) estimates that 10 percent of later smokers “develop the halsit 

with some degree of regularity” b f 

their high school years. 

e ore their teens and 65 percent duril,; 

It seems. then. that the )-ears from the early tefLtl, 

to the ages of 18-20 are significant years in exposing people to their first 

smoking experiences. 

SMOKING BY SOCIOECONOMIC LEVEL 

Empirically, socioeconomic level is usually determined by means of one 

or several separate and measurable variables such as income, educatic,,,. 

occupation and type of residence. 

Despite the use of different determinants of class status. there is rathrr 

consistent evidence that smoking patterns are related to socioeconomic lr\~l 

in that the lower or working classes contain both more smokers and earlier 

starters. This has been found in America as well as in England (3,4.10.2?. 

27). 

As to separate class-linked variables. income does not seem to be relatrfl 

in a consistent manner to prevalence of smoking either in England I 391 

or in the U.S.A. (261. There does appear to be some tendency to\tar(l 

fewer male smokers among those with a yearly income below $2.000 iax of 

19561 and. in the older groups only. \vith an annual income over $.S.n00. 

On the other hand, income does relate positively to the quantity of cigarettrconsumed. 

OCCUPATION 

Almost as many different ways of classifving and grouping occupations 

have been used as there ar? studies dealing with this variable. making conlparisons extremely difficult. Moreover. most groupings are not \er! 

meaningful since the\- used broad and rotnprehensive job clasaificationwhich obscure some of the most important orcul)ational characteristics. 

For example. the category “professional” encotnpasses (as do other rategories) a tremendous range of occupations. These vary widely amon? 

362 
themselves with respect to many characteristics that may be significantly 

associated with smoking habits. For these and other reasons it is not surprising that data reported on the relationship between occupation and 

cigarette smoking are anything but easy to interpret. Nonetheless. if occupation is used merely as a class-index, these data are in accord with those 

obtained in reference to other socioeconomic indices: whitecollar, professional, managerial and technical occupations contain fewer smokers than 

craftsmen, salespersons, and laborers. 

Unemployed have been found to be somewhat more likely to smoke than 

employed (23) . 

According to Lilienfeld (19). smokers change jobs significantly more 

often than non-smokers. Specific data as to reasons for such changes are 

not given, however, making this variable difficult to interpret. Repeated 

job changes may be indicative of neurotic traits as the author proposes, but 

they may also be due to other reasons which create psychological pressures 

to which smoking is one possible response. 

EDUCATION 

The relationship between smoking and education is unclear. Lilienfeld 

(19) failed to find educational differences between smokers and non-smokers 

in his 1956 probability sample of adults in Buffalo, New York. Matarazzo 

and Saslow (23) also concluded that educational attainment, in terms of 

highest grade completed, does not differentiate smokers from non-smokers. 

Hammond (8): on the other hand. reported a curvilinear relation among 

men between 45 and 79 years of age. S ma k ers were under-represented 

among those who never attended high school and among college graduates. 

and over-represented in all the categories between. 

Because of the strong relationship between education and occupation, 

the trends found in regard to occupation may reflect those found in regard 

to education: those occupations normally associated with high education 

show, by and large, a smaller prevalence of smokers. 

SEX 

Fewer women smoke than men and their smoking is almost entirely 

restricted to cigarettes. However, the proportion of women smokers has 

increased faster than that of men smokers in recent years. Horn (11) 

reports that a recent American Cancer Societv survev showed an increase 

since their 1955 survey of five percent (from 3?i to 36 percent). Salber and 

Worcester (28) suggest on the basis of a sample of senior students at 

Newton, Mass., high schools that “women. particularly Jewish women. may 

soon overtake men in the number who smoke.” 

RACE 

The proportion of smokers is roughly the same among whites and nonwhites (7) and relations of smoking to sex and age also were comparable 

363 
in the t\vo groups. But many more heavy smokers (more than one pack 

per day) were found among whites: as compared with non-whites, in the 

case of both men and women. Since. as was reported earlier, income H’as 

found to relate to amount, though not to prevalence, of smoking. this racial 

difference could reflect economic differences between whites and non-whites, 

MARITAL STATUS 

Smoking (of any kind’) is most prevalent among the divorced and widowed 

and least among those who have never been married, except that amol,g 

persons over 45. nerer-marrieds are as likely to be smokers as the marrictl, 

(7). 

RELIGION 

There is evidence of lower smoking rates within some religious sects which 

condemn smoking (161 and among persons who hold devout religious beI& 

For example, less smoking was found among Harvard students who werp 

religious and whose parents were devout; and non-smokers seem morp 

inclined to attend church than smokers 13, 22, 37). Both Horn (111 and 

Straits and Sechrest (37 ) report over-representation of smokers amr)t~F 

Catholics, a church in which more tolerance is shown towards smoking than 

among some Protestant churches. 

As in all such correlational studies it is impossible to say whether there 

is a direct causal link between religion and abstention, or whether POIW 

. . . . other factors account both for the rellglous convlctlons and the abstenti~l~l 

from smoking. 

RURAL VERSUS URBAN 

There are proportionally fewer smokers in rural than in urban areas. 1)~ 

the smallest percentage of smokers is within the rural farm population. The 

rural non-farm population is more like the urban population with only 

slightly fewer smokers than in the latter. No relationship of smoking to size 

of community has been established. No convincing interpretation can 1~8 

offered in view of the lack of additional data. 

SUMMARY OF DEMOGRAPHIC FACTORS 

iKo single comprehensive theory to explain smoking is suggested by thpy* 

demographic data taken by themselves. In fact. the only known attempt at 

formulating a theory I+ hich is. at least partly. related to or based on suc~h 

data revolves around a hypothesis relating smoking, or not-smoking. to 

introjected culture standards linked to social class norms in our societ! 

(21,22). 

Nonetheless, there are many. though not always clear, relationships ht.- 

tween smoking and a variety of social and economic variables. Taken al- 
together, there emerges the picture of smokin, w as a behavior that has over 

many years become tied closely to man\- of the complexities of our present 

society. There can he no doubt that smoking as a habit is determined in 

some measure by a variety of such social forces as are reflected in demographic data of the kind reviewed ahove. But it will he some time before 

the specific interrelations can be disentangled. 

Since man is not a passive target of such forces but an active participant, 

no possible explanation can omit consideration of the way in which he reacts 

to and, in turn, creates such forces. in short. a consideration of personality 

factors. 

PERSONAI,ITY AND SVOKING 

All research studies on the relation hetls.reen smokin? and personality 

select one or several. more or less distinct personalitv traits or characteristics 

for scrutiny. For example. they mav try to test h!-l)othrFes on the interrelation between smoking and introversion. smoking and nruroticism. smoking 

and anxiety. etc. A few students have tripd to describe personality e)-ndromes by a synthesis of several such traits. .4t the present state of knowledge. however. it is more fruitful and more valid to speak not in terms of a 

“smoker personality.” but rather in terms of discrete personality characteristics which may he found to he associated with smokers. 

Certain difficulties are encountered in reconciling findings from the several studies. Sometimes authors use identical terms even though there is 

some doubt that they refer to the same concept. For example. the term 

“neuroticism” in one study ma\- refer to a personality trait as measured by 

certain psychological tests. in another to a classification of observed so-called 

nervous behavior. When data from studies using the one are at variance 

with data from studies using the other. it is dimcult to say whether these 

studies really are yielding contradictor-v findings. or whether differences in 

such data are due to the fact that they reflect different variables. In addition. psychological techniques for the assessment of personality are still of 

uncertain validity. some possibly of little or no value. For example. in a 

number of studies the investigators have made up a priori scales. tests or 

questionnaires without any reported attempts at estahlishinp their reliahility 

or validity. 

EXTROVERSION AND INTROVERSION 

One of the best-designed studies (1. 61 was rarrird out in England using 

representative samples and objective techniques using question$ previousl? 

developed by Epsenck and claimed by him to “have been found to be . . . 

reasonably valid measures of three personality traits, extroversion. neuroticism, and rigidity.” (6). If one accepts the author’s claim that the questionnaire really did measure these traits. a very significant rrlationqhip was found 

between extroversion and smoking. Heavy- smokers were more extroverted 

than medium smokers; these were more extroverted than light smokers and 

365 
ex-smokers; and both non-smokers and pipe smokers were least extroverted 

Two consecutive studies with different representative samples yielded th; 

same results, and the association of smoking with extroversion lvas als,, 

supported by several other investigators, such as McArthur et al (221 a,,,] 

Schubert (341. Another study by Straits and Sechrest (371 using the S,,,.i,l 

Introversion Scale from the Minnesota Multiphasic Personality Inventory (,,, 

a rather small and probably biased sample did not support this finding, 

The general picture which emerges from Eysenck’s study and from others 

is one of smokers tendmg to hve faster and more intensely, and to be ,,,,~r,. 

socially outgoing. 

Several studies, using behavioral rather than psychological test data. ‘“,,- 

port this picture. Davis (41 describes young smokers as “more gregari,,,,< 

and socially advanced” than non-smokers. 

similar findings. 

McArthur et al (22) re,,,,n 

However, a compilation of actual participation of smokers and non. 

smokers, respectively, in a number of specific social activities as reported 11, 

several investigators (4, 13, 19, 30) yields conflicting data. Smoker< a&. 

reported to participate more in such social activities as dancing, courtship 

and fraternities-in line with what would be expected of extroverted irldi. 

viduals. As to participation in sports, findings in some studies favor the 

smoker, in others the non-smoker. Non-smokers were found by one investi. 

gator to show greater social participation in organizations and to hold more 

. . offices-activities more associated with extro- than with mtroversion. 

Smokers show greater interest in TV and movies, non-smokers in reading 

books. Studies and cultural activities are over-represented among nonsmokers. 

These conflicts in the data as collected do not necessarily reflect real conflicts, however. Some sports may be of a less gregarious or extroverted 

nature than others (for example, swimming or tennis as compared to football). Offices in college organizations also may range from president of a 

cultural club to class president. It is altogether possible that this rarrar 

can accommodate introverted as well as extroverted students. Lumping 

together heterogeneous activities under one broad descriptive term, as done 

in so many studies on smokers’ behavior, may obscure real relationships. 

In any case. M-hile the association between extroversion and smoking is 

fairly well supported by available evidence, less certainty exists as to the 

exact nature of this association. It is possible that extroversion is directl! 

related to smoking as a habit pattern, that is, that smoking is an expression 

of this kind of personality, as most authors seem to imply. It is equall! 

plausible that the extrovert. by virtue of his greater participation in various 

social activities. exposes himself more to social stimuli to pick up old 

re-enforce the smoking habit. He may also be more susceptible to social 

influence. 

NEUROTICISM 

Several studies. using a variety of methods. have investigated variables 

related more or less vagueI\ with u hat mav be subsumed under the term 

neuroticism. Such variables include neuroticism as a personality trait in366 
ferred from such varied indices as psychological tests, existence of anxiety 

states, “nervousness,” somatic symptoms, unusual restlessness in terms of 

job and residence, and others. 

Most studies support the contention that neuroticism, in this wide sense, 

is indeed associated with the smoking habit f 16. 18, 19,24,25). 

A few studies fail to demonstrate any relationship of smoking behavior 

with one or another of these neurotic characteristics. Straits and Sechrest 

(37) found no significant difference in anxiety as measured by Taylor’s 

Manifest Anxiety Scale (in contrast to Matarazzo who did). Eysenck et al. 

(l), using a neuroticism-scale. did not find any significant relationship of 

neuroticism either to tvpe or degree of smoking. He does suggest, however, 

that “inhaling may be more prevalent among the more neurotic and 

notionally disturbed.” 

‘The state of our knowledge in respect to the smoking-neuroticism svndrome can be best summarized this way: 

Despite the individual deficiencies of many of the studies, despite the 

great diversity in conceptualization and research methods used. and despite 

certain discrepancies in reported findings. the presence of some comparability between them and the relative consistency of findings lend support 

to the existence of a relationship between the smoking habit and a personality configuration that is vaguely described as “neurotic.” However, there 

are no acceptable studies that help decide how this relationship arises, to 

what degree (if at all) neuroticism leads to the beginning and/or to the 

continuation of smoking, or to what degree if at all: it accounts for habituation and resistance to discontinuation. 

PSYCHOSOMATIC MANIFESTATIONS 

In a study by Matarazzo and Saslow (23)) smokers report more psychosomatic symptoms than non-smokers in responses to the “Saslow Psychosomatic Screening Inventory.” However, differences were significant in 

only one of three groups tested. 

In the English study by Eysenck (1) heavy, medium and ex-smokers of 

cigarettes were found to have the largest number of psychosomatic disorders, 

non-smokers the least, light cigarette and pipe smokers being intermediate. 

None of these differences, however, were statistically significant. 

There is no persuasive evidence that smoking and psychosomatic ailments 

are associated to any important degree. 

PSYCHOANALYTIC THEORY 

Psychoanalysts have advanced the hypothesis that smoking, like thumbsucking, is a regressive oral activity related to the infant’s pleasure at his 

mother’s breast (36). It is claimed that male thumbsuckers are very likely 

to smoke and drink in later years. The frequently observed fact that those 

who stop smoking show increased food consumption, weight gains and use of 

chewing gum also supports the oral hypothesis. However: Kissen (15) argues 

that this could be explained in terms of purely physiological responses. 

7 14-422 O-64-25 367 
McArthur et al. (22) found a positive statistical relationship between the 

ability to stop smoking and the number of months of breast feeding. He also 

reports that thumb-sucking in childhood was more common among men who 

continued to smoke. The data provided are insufficient to assess these claims, 

but they do at least suggest that the oral hypothesis warrants further 

investigation. 

SUMMARY OF PERSONALITY AND SMOKING 

Some investigators have attempted to synthesize many of the differences 

in personality characteristics, as they have been found or suggested by a 

variety of studies, into a comprehensive “smoker personality.” What emerges 

in each case is an artifact. 

“While smokers do differ from non-smokers in a variety of characteristics, 

none of the studies has shown a single variable which is found exclusively 

in one group and is completely absent in the other” (23). Nor has any single 

variable been verified in a sufficiently large proportion of smokers and in 

sufficiently few non-smokers to consider it an “essential” aspect of smoking. 

“While this is true for aZZ of the variables . . . it is especially true for the 

variables measuring personality characteristics . . . a clear-cut smoker’s 

personality has not emerged from the results SO far published in the 

literature” (23). 

Nonetheless, there appear enough differences between smokers and nonsmokers to warrant the assertion that there are indeed different psychological 

dynamics at work. However, in what ways these differ, and to what extent 

these differences are cause, or effect, or both, is not yet known. 

TAKING UP SMOKING 

All available knowledge points towards the years from the early teens to 

the age of 20 as a significant period during which a majority of later smokers 

began to develop the active habit. For this reason, many studies have 

focused on smoking among youths, almost exclusively selecting high school 

and college students as their subjects. 

The trend to an inverse relationship between smoking and socioeconomic 

level is more pronounced when smoking among children is examined in the 

light of parents’ socioeconomic status. For example, Salber and MacMahon 

(27) report significantly fewer smokers among Newton, Mass., public school 

students (grades 7 through 12) in the upper than in the lower socioeconomic 

levels. Horn et al. (13) found a significant inverse positive relationship 

between parents’ education and children’s smoking behavior in students in 

the Portland, Oregon, high school system, although this relationship diminishes with grade, becoming negligible by the senior year. Several other 

studies, with more narrowly selected samples, yielded similar results. 

Smoking patterns among children could be influenced by their parents’ 

smoking patterns which, in turn, are affected by the latter’s social class-linked 

characteristics. On the other hand, the social class level of children them368 
selves is associated with a number of factors that could influence their 

behavior. For example, children from better homes may go to different 

schools, may show higher learning ability and motivation, may associate with 

different kinds of peers, may engage in different kinds of social activities, and 

so forth. All these factors could have a bearing on their smoking, independent of, or in addition to influences exerted by their parents. There can 

be little doubt that all of these observations must be considered in any attempt 

to answer the question of initiation of smoking. 

PARENTS’ SMOKING PATTERNS 

Horn et al. (13) found a strong association between parents’ and children’s 

smoking habits. There is a consistent increase in the number of high school 

smokers from their freshman to their senior years, regardless of sex or 

parental habits. But within each year there are significantly more smokers 

in families where both parents smoke than in families where neither parent 

smokes. Various combinations of smoking practices of father and mother 

respectively, also affect children’s habits differentially. Horn’s findings are 

supported by those of Salber and MacMahon (27) obtained from Newton, 

Mass., high school students. 

This congruity between parents’ and children’s smoking habits has led 

some investigators to ascribe, explicitly or implicitly, simple and direct 

causal properties to parents’ smoking behavior. It has even been asserted 

that the most effective way to diminish smoking radically among children 

would be to decrease smoking among their parents. However, such congruity could be due to several factors. Parents could exert direct and force 

ful influence on their children ; the attitudes and practices of smoking 

parents could create a general atmosphere of permissiveness in the home; 

conflict between parents’ exhortations and their actual behavior could influence children’s perception of the pros and cons of smoking. Selection of 

social associates on the basis of similar attitudes and behavior norms may 

lead to a social life on the part of the parents involving other families (and 

their children) who smoke, thus providing additional social smoking stimuli 

for their own children. Then, there is the availability of cigarettes in a 

home where parents smoke which could facilitate the child’s first steps towards smoking. Finally, the possibilities of similarity in personalities of 

parents and children cannot be ruled out. 

Even in families where neither parent smokes there is a striking increase 

with age in smoking among children. Moreover, congruity between the two 

generations diminishes with each year from freshman to senior year. That 

this trend of diminishing congruity continues into college is suggested by the 

findings of Straits and Sechrest (37) w h o report from a sample of 125 male 

college students that smokers are not more frequently from families in which 

both parents smoke. 

The most plausible (though not necessarily the only) interpretation is 

that, as children grow older, they themselves, as well as their relationship to 

the home, change. With approaching adulthood and its associated new 

social patterns, other influences supplant those of the parents. The children 

369 
spend increasing amounts of time away from their immediate families and 

their direct supervision and are increasingly exposed to other social influences. They begin to exert their independence more and more. In fact, 

as will be seen later, hypotheses to the effect that taking up smoking may 

be a symptom or an expression of strivin, 0 for self-assertion have been 

advanced and have received some support from various investigations. 

It is quite possible that parents’ influence affects the age at which children 

start smoking much more than it affects the ultimate taking or not taking 

up of the habit. 

With very few exceptions, the association between parents’ and children’s 

smoking behavior has been investigated only via inferences drawn from 

statistical relationships. Th e exceptions offer data that are mostly of doubtful validity (mainly because of unsophisticated techniques for eliciting selfreports by children or because of non-representative sampling) or are insufficient for the derivation of any even moderately firm conclusions. No study 

employing appropriate and intensive methods on adequate samples has heen 

found which examined the nature of the psycho.social dynamics. Therefore, 

all interpretations of the association between parents’ and children’s smoking 

habits must remain on the level of hypotheses, no matter how suggestive 

the data may appear to be. 

INTELLIGENCE AND ACHIEVEMENT 

Children’s intelligence does not seem to be related to whether they take up 

smoking or not. Earp (5)) Matarazzo et al (24)) Kissen (15), and Matarazzo and Saslow (23) all failed to find significant correlations between intelligence measures and prevalence of smoking. 

Salber et al (32) report that among boys from the Newton, Mass. public 

schools, non-smokers in every grade have “a higher mean IQ than discontinued smokers who, again, have higher mean IQ’s than smokers . . . the 

trend in girls, though similar in direction, is less marked.” However, no 

statistical tests are reported and an approximate check on the reported data 

by means of several t-tests does not support the authors’ contention. 

In the same study a high relationship was found between achievement 

scores obtained from school grades and non-smoking, and the authors conclude that ‘?he difference in smoking habits results from differences in academic achievement rather than intelligence.” Earp (5) found that more 

smokers than non-smokers among Antioch College students failed to graduate. 

Lynn (20) claimed that non-smoking adolescents make higher grades (but 

scholastic averages according to age were found sometimes to favor the 

smokers). Horn et al. (13) present evidence that there is a higher proportion 

of smokers among high school students who are older than the modal age of 

their classmates. The authors describe such students who are older than their 

classmates as students who “tend to be scholastically unsuccessful” implying 

that under-achievement may relate to their smoking. However, since smoking 

is age-linked among high school students, statistical differences between older 

and younger students within any 

by their age differences. 

given school grade can be accounted for 

370 
Thomas (38) and Lilienfeld (19) f ound no differences between smokers 

and non-smokers in academic standing and in number of years of schooling 

completed, respectively. 

In general, the evidence seems somewhat to favor a moderate tendency 

towards less satisfactory achievements by smokers than by non-smokers. 

Again, the question of “why” is difficult to answer. It is most unlikely 

that smoking itself could be responsible. It is possible that whatever accounts 

for poorer classroom performance may also account for the higher smoking 

prevalence. It is also possible that smoking is an effect of frustration, or 

of other psychological reactions to such failure to maintain high scholastic 

standards. 

SOME HYPOTHESES ON THE BEGINKING OF SMOKING 

Davis (4) deduces from responses to the question “how did you come 

to start?” two factors that explain the beginning of smoking: a sociabilityimitative and a wish-for-adult-status factor. Support for this hypothesis 

is seen in the similarity between parents’ and children’s smoking habits. 

Other studies (2, 3, 5, 13) also support it. 

Despite this agreement amon g several studies, at least along general lines, 

and despite the plausible, common-sense nature of the hypothesis, it is not 

an altogether satisfying one. First, evidence is derived largely from selfreports. These may or may not reflect valid insight on the part of the 

respondents. Second, the similarity between parents’ and their children’s 

smoking behavior lends itself to such other, and perhaps more plausible, 

interpretations as have been presented earlier. Third, the explanations 

for first smoking, such as “curiosity,” “saw others smoke” or “someone 

offered me a cigarette” (reported by investigators) come to mind easily 

and this may account for the frequency with which children offer them 

rather than other possible explanations requiring both deeper insight and 

more introspective efforts. 

Considering that during adolescent years the problem of becoming an 

adult is universal and that smoking has probably become a very pervasive 

symbol of adulthood in our society, the hypothesis fails to explain why so 

many children, under the very same circumstances fail to become smokers. 

A collection of self-inspective reports from smokers, even though probably 

representing valid reasons for those respondents who give them, is not 

sufficient to explain why these respondents, but not others, become smokers. 

In order to have greater confidence in this hypothesis, it is necessary to 

know whether non-smokers do not also have the “wish for adult status”; 

whether, if they do, they do not see smoking as appropriate symbolic 

behavior; if they do not see it as such a symbol, why some do and others do 

not; and if non-smokers do see it as such a symbol, why do they not take 

up smoking. 

As to “imitation,” it is less an explanation than a description of what 

occurs. In somewhat more dynamic terms, one might think of it as conforming behavior in the sense that conformity with the behavioral norms of one’s 

social reference groups may be a means for gaining social acceptance. 

Although the hypothesis has a persuasive ring and has some suggestive 

371 
evidence, all that can be said is that these two factors, imitation and desire for 

adult status, may play a role in inducing some, and perhaps many. c,hil] 

to take up smoking. 

( WI1 

STATUS STRIVING 

Some students of smoking behavior have looked at the dvnamir> ,,f 

“striving for status” in a broader sense, as a manifestation of InterrPlnted 

basic psycho-social needs. T o b e accepted by one’s reference persons. I’artir. 

ularly one’s peer groups, to develop self-esteem and an acceptable self.imapr. 

and to cope with painful feelings of inadequacy, are such basic psycho-social 

needs. Of these, striving for adult status is only one aspect. It is entire]\ 

possible that, if smoking is related to the latter, it may be more in terms ,;f 

keeping abreast of one’s peers than in terms of deliberately wanting to be 

an adult. 

Horn (11) points out that there emerges from a variety of studies a 

“syndrome of intercorrelated measures that seem to have in common thP 

failure to achieve peer group status or satisfaction.” The reference is to 

such reported findings as that smoking is more frequent among students who 

are older than their classmates, fall behind their peers in scholastic standing, 

become drop-outs, and choose easier over more demanding curricula. This 

relation between under-achievement and smoking has generally been inter. 

preted in terms of compensation. 

Salber et al. (32) suggest, “it may be that children who do not achieve 

this desirable state (good standing with family and peers) because of poor 

academic grades, find in taking up smoking a way of demonstrating their 

maturity and achieving acceptance in a peer group whose values are somewhat different from those of the academically more successful student.” In 

a wider sense, Horn (11) regards smoking as a “compensatory behavior, a 

symptom of other problems of emotional health.” 

Other authors have found evidence of greater participation of smokers in 

sports (although this evidence is not entirely consistent), of smokers’ more 

daring war records, of their poorer disciplinary records, and of impulsive. 

rebellious behavior, especially on the part of heavy smokers 120, 22, 33i. 

The findings from anthropometric studies of students’ physiques which detected an association between physical masculinity and non-smoking (351 

has also been cited as support for this interpretation. 

Once again there is considerable evidence to render the hypotheses 

advanced very plausible but not altogether satisfactory. A number of questions can be raised. First of all, the evidence that scholastic underachievement may be to some measure responsible for smoking ias is more or less 

strongly implied by some authors) is not very impressive. For example, in 

all studies reviewed, the fact that a student does not perform as well as his 

peers in the classroom is accepted as prima-facie evidence that he feels psy 

chologically frustrated or socially deprived. The underlying assumption is 

that children generally see scholastic achievement as an important goal to 

strive for, and that even partial failure to achieve this goal is sufficiently disturbing to them to lead to compensatory behavior. This assumption is open 

to question especially among population groups in whose hierarchy of values 

372 
the pursuit of intellectual goals does not rank very high. Many children 

from lower socio-economic levels (who contribute considerably to the ranks 

of “underachievers” and among whom smoking is more prevalent), may be 

among those who ascribe relatively little importance to competing successfully with their peers in classroom performance. NG studies have demonstrated that there is a relation between smoking and underachievement as a 

psychological variable. 

The evidence concerning greater participation of smokers in sports is, as 

stated earlier, not consistent. Nor is the evidence on each of the other variables that are presumed to be indicative of status deprivation or status 

striving. 

Other questions can be raised. Even if smokers do participate in more 

sports, do engage in more dating and courtship behavior I 1) and generally 

do manifest more “masculine behavior.” why need this be interpreted as 

“compensatory” behavior rather than a reflection of actual masculinity? If 

these behaviors are mere demonstrations of masculinity, why should smoking 

be taken up as an additional, certainly less self-evident, demonstration of 

masculinity? Why is it that smoking, a habit acquired increasingly by 

women, should persist in carryin g with it such a pervasive symbolic meaning 

of masculinity? And again there is the troublesome question as to why 

some, but not so many others, choose this particular means of giving evidence 

of their masculinity? 

At present, there is persuasive, but not convincing evidence that smoking 

among adolescents may in many cases be related to needs for status among 

peers, self-assurance, and striving for adult status. 

REBELLION AGAINST AUTHORITY 

Since a need for independence, a striving for adult status and more 

stature among one’s peers in an adolescent are associated with rebellion 

against authority, the hypothesis relating smoking with such rebellion is a 

logical extension of the foregoing hypothesis. 

While rebellion may play a role, perhaps an important one, there is not 

much evidence for it. Claims in the literature are at best based on circumstantial, suggestive evidence, linked to conclusions by a chain of questionable 

assumptions. 

SMOKING AS A RESPONSE TO STRESS AND AS A TENSION RELEASE 

Stress seems to be related to smoking, as it does to a score of other habits. 

There is some evidence that the experience of stressful situations contributes 

to the beginning of the habit, to its continuation, and to the number of 

cigarettes consumed (4, 14, 22). Kissen (15) concludes that “cigarette 

consumption increases in relation to the occurrence of some emotionally 

stressful situations. Such situations therefore appear to play a part in perpetuating smoking. The interpretation of what is emotionally stressful 

may depend on its particular significance to the individual, that is: it may 

depend on the personality traits of the individual.” 

373 
A plausible case can be made that the experience of stress together with 

social situations favorable to smoking can provide the trigger to initial 

experiments with smoking as well as a mechanism to reinforce the habit 

once estabhshed. 

Considerable evidence lends credence to this hypothesis. “Nervous” 

traits, anxiety, and over-reaction to environmental stimuli have been found 

to be very prevalent among smokers as compared to non-smokers. Under. 

achievement, that is failure to live up to one’s expected norms, may produce 

stress if the experience is relevant to a person’s needs and values. Cartwright et al. (3) found that men often tended to start smoking when the, 

took their first wage-earning job. This could be due to the tensions and 

anxieties associated with the event, together with new social influences and. 

perhaps, the new-found freedom from home restraints. The same explana. 

tion could be advanced for the observed increase in initial smoking amona 

young men in military service (7). 

More direct, but possibly less reliable, is evidence from self-reports of 

smokers. With great consistency, investigators have reported that smokers 

state they tend to smoke, or to smoke more, under temporary stress-pro. 

ducing experiences. As McArthur et al. (22) point out, such short-lived 

fluctuations in response to brief stress episodes would not be detected by 

survey methods that elicit information on smoking behavior at only one 

point in the smokers’ lives or even, as in McArthur’s case, at yearly inter. 

vals. Here again different and more intensive research methods are called for. 

Existence of an association between stress and tensions on the one hand. 

and smoking behavior on the other can probably be accepted with a reasonable degree of confidence. It should be noted, however, that stress, as here 

used, is defined in terms of an inner psychological-physiological response to 

certain external events. The fact that a number of people may be exposed 

even simultaneously to the same stressful life situation does not necessarily 

mean that all of them experience stress or experience it to the same extent and 

in the same way. Whether they do, in what way: and to what extent depends. 

among other things, on the psychological meaning that the situation has for 

them. This, again, points to the need to supplement broad correlational 

studies with research that more specifically examines constellations of the 

several interdependent variables within and without the individual. 

Furthermore, the role of smoking relative to the tension which presumably 

evokes it is not at all clear. Is smoking merely an expression of tension or 

does it serve as a reducer of psychic tension? If the fatter, is it effective, 

that is, would tension actually be less while smoking a cigarette than while 

not doing so? No research has apparently dealt with this problem. 

DISCONTINUATION 

Consideration of factors involved in discontinuation of smoking may help 

understand the nature of the habit itself.* 

*Because the present chapter is concerned only with psycho-social aspects, discussion 

of methods of discontinuance or their relative effectiveness has been dealt with elsewhere 

(see Chapter 13). 

374 
Even less is known about discontinuance than about beginning of smoking. 

However. there is good evidence that it is related to the beginning of the habit, 

its nature, and its duration. 

The rate of smokers who discontinue has consistently been found to be 

highest among those who start late in life, have smoked the least number of 

years: and whose average cigarette consumption has been smallest (7, 11: 16, 

22). 

Most frequent reasons for discontinuing given by children who had been 

fairly regular smokers but had quit, were lack of enjoyment and dislike for 

smoking. Interestingly, these reasons differ from reasons given by children 

who have never smoked for not taking up smoking. These latter are more 

along health, aesthetic and moral lines (29). 

Among adult smokers who quit (the 1955 census data list about 11 percent, a rate that has probably increased in the intervening years), the most 

frequent reasons given were “various health considerations, the expense, 

moral reasons, and a test of one’s will power” (9, 16). Relatively few 

people refer to publicity about lung cancer (17). but this may he changing 

with increased public attention to this issue. Also, the surprising lack of 

reference to fear of disease among respondents may be a function of certain 

inhibitions to admitting such a negative motive for what is generally regarded as an intelligent and desirable thing to do. 

A study carried out in 1957 by Lawton and Goldman (17) yielded some 

interesting results that throw some light on the effects of intellectual elements 

in relation to discontinuation of smoking and at the same time raise some 

puzzling questions. 

Two groups of scientists, matched for age and sex: and for the scientific 

nature of their interests formed the subjects. One consisted of 72 wellknown lung cancer scientists, the other of experimental psychologists. 

Significantly fewer of the cancer specialists than of the psychologists were 

smokers, and the same difference existed in respect to the number of persons 

in each group who believed cigarette smoking to be a cause of lung cancer. 

But there was no difference in respect to the number of persons in the two 

groups who had discontinued smoking within the past five years, nor in 

respect to the number of smokers who expressed dissatisfaction with their 

smoking habits, Most interesting, however, was the finding that when those 

in the two groups who believed smoking to be a cause of cancer were compared, it was the psychologists who expressed more dissatisfaction with their 

own smoking, and who exhibited a significantly lower prevalence of smoking, 

a higher rate of attempted discontinuations, and a higher rate of deliberately 

diminished amount of cigarettes consumed. 

There is no readily available convincing explanation for this finding, 

but it does demonstrate that the smoking habit is linked with so many 

aspects of a person’s psychological make-up that mere intellectual awareness 

of risks involved, even among those with rather intimate and intensive contact with the subject, is insufficient to overcome other dynamic factors 

involved. 

On the other hand, Horn (12) related that among several approaches 

used to modify high school children’s smoking habits, the “remote” approach 

involving a logical appeal to the intelligence of the boys and girls proved 

375 
to be the relatively most effective one. There was evidence, according to 

Horn, that “this approach was most effective among those who smoked in 

emulation of their parents, and less SO among those who smoked for the 

more emotionally tinged reasons of compensation or rebellion.” Unfortu. 

nately, it is not entirely clear from the description of the study how trust. 

worthy was the identification of the motives underlying these children’s 

smoking. Yet, these results agree logically with the position that there is 

no single cause or explanation of smoking, but that smokers may start. 

continue, and discontinue smokin g in response to different inner needs and 

external influences, social and other. 

SUMMARY 

Scientific investigations into the psycho-social aspects of smoking are 

relatively recent and, except for a few large-scale and systematic studies, 

leave much to be desired from the standpoint of methods and conceptions. 

However, evidence from a few sound studies, and converging evidence from 

many studies, none of which could stand up by itself under exacting scrutiny, 

permit the following statements concerning the relationship between psychosocial characteristics and smoking behavior: 

1. As far as is known from actual data, few children smoke before the age 

of 12, probably less than five percent of the boys and less than one percent of 

the girls. From age 12 on, however, there is a fairly regular increase in the 

prevalence of smoking. At the 12th grade level between 40 to 55 percent of 

children have been found to be smokers. By age 25, estimates of smoking 

prevalence run as high as 60 percent of men and 36 percent of women. There 

is a further increase up to 35 and 40 years after which a drop is observed. 

In the 65 and over age group. prevalence of smoking is only approximately 

20 percent among men and 4 percent among women. 

2. Smokers and non-smokers differ in a number of demographic characteristics but no single comprehensive theory to explain smoking is suggested by 

the demographic data taken by themselves. 

3. Although smokers are different from non-smokers psychologically and 

socially, there are many differences among smokers and among non-smokers, 

so that some smokers may be like some non-smokers. 

4. Smoking appears to be not one behavior but a range of psychologically 

diverse behaviors each of which may be induced by a different combination 

of factors and may serve different needs. Therefore no single explanation 

can suffice. 

5. Social stimulation appears to play a major role in a young person’s 

early and first experiments with smoking. 

6. There is suggestive evidence that early smoking may be linked with 

self-esteem and status needs although the nature of this linkage is open to 

different interpretations. 

7. No scientific evidence supports the popular hvpothesis that smoking 

among adolescents is an expression of rebellion against authority. 

376 
8. No differences in intelligence between smoking and non-smoking children have been found, but smokers are more frequent among those who fall 

behind in scholastic achievements. 

9. No smoker personality has been established but certain personality factors have been reported to be associated with smoking, among them extroversion, neuroticism, and a disproportionate prevalence of psychosomatic 

manifestations. 

10. Stress appears to be less associated with prevalence of smoking than 

with fluctuations in amount of smoking. 

11. The cultural milieu seems to have a strong influence, a permissive cultural climate tending to promote and a rejecting or outright prohibitive one 

to inhibit smoking. 

12. Less is known about discontinuation than about beginning of smoking. 

although there is good evidence that it is related to the beginning of the habit, 

its nature, and duration. 

CONCLUSION 

The overwhelming evidence points to the conclusion that smoking-its 

beginning, habituation, and occasional discontinuation-is to a large extent 

psychologically and socially determined. This does not rule out physiological 

factors, especially in respect to habituation, nor the existen,ce of predisposing 

constitutional or hereditary factors. 

REFERENCES 

1. A Report on Personality Factors and Smoking. Part 2. [Eysenck supv] 

Prepared by Mass-Observation Ltd. August 1962. 27, 24 p. 

2. Bothwell, P. W. The epidemiology of cigarette smoking in rural school 

children. Med Offr 102: 125-32,1959. 

3. Cartwright, A., Martin, F. M., Thompson, J. G. Distribution and development of smoking habits. Lancet 2: 725-7; 1959. 

4. Davis, R. Cigarette smoking motivation study. Research Services, 

London, 1956. 

5. Earp, J. R. The student who smokes. Yellow Springs, Antioch 1931. 

64 P. 

6. Eysenck, H. J., Tarrant, M., Woolf, M., England, L. Smoking and 

personality. Brit Med J 1: 1456-60, 1960. 

7. Haenszel, W., Shimkin, M. B., Miller, H. P. Tobacco smoking patterns 

in the United States. Public Health Monog No. 45: 1-111, 1956. 

8. Hammond, E. C. Report to the Surgeon General’s Advisory Committee 

on Smoking and Health. 

9. Hammond, E. C., Percy, C. Ex-smokers. N Y J Med 58: 29569,1958. 

10. Heath, C. Differences between smokers and nonsmokers. AMA Arch 

Intern Med 101: 377-88,1958. 

377 
11. Horn, D. Behavioral aspects of cigarette smoking. J Chronic Dis 16. 

383-95. 1963. 

12. Horn. D. Modifying smoking habits in high school students. Children 

7: 63-5. April l%O. 

13. Horn. D.? Courts, F. A., Taylor. R. M., Solomon: E. S. Cigarette smokina 

among high school students. Amer Public Health 49: 1497, 1959, 

14. Kissen, D. M. Emotional factors cigarette smoking and relapse in pul. 

monarp tuberculosis. Health Bull 18: 38-44, 1960. 

15. Kissen. D. M. Psycho-social factors in cigarette smoking motivation. 

Med Offr 104: 365-72. 1960. 

16. Lawton. M. P. Psycho-social aspects of cigarette smoking. J Health 

Hum Behav 3: 163-70,1962. 

17. Lawton. M.. Goldman. A. Cigarette smoking and attitude toward the 

etiology of lung cancer. J Sot Psycho1 54: 235-48, 1961. 

18. Lawton, M., Phillips, R. The relationship between excessive cigarette 

smoking and psychological tension. Amer J Med Sci 232: 39742. 

1956. 

19. Lilienfeld, A. Emotional and other selected characteristics of cigarette 

smokers and nonsmokers as related to epidemiological studies of lung 

cancer and other diseases. J Nat Cancer Inst 22: 259-82, 1959. 

20. Lynn. R. M. A study of smokers and non-smokers as related to achievement and various personal characteristics. [Abstract J In: Res Prog 

No. 464, p. 164, 1948. 

21. McArthur, C. C. The personal and social psychology of smoking. In: 

James, G.. Rosenthal, T. eds. Tobacco and Health. Springfield, Ill., 

Thomas, 1961. p. 201-9. 

22. McArthur. C.. Waldron, E., Dickinson, J. The psychology of smoking. 

J Abnorm Sot Psycho1 56: 267-75. 1958. 

23. hlatarazzo, J. D.. Saslow, G. Psychological and related characteristics 

of smokers and non-smokers. Psycho1 Bull 57: 493-513,196O. 

24. Matarazzo. R. M.. Matarazzo, J. D.. Saslow, G., Phillips, J. S. Psychological test and organismic correlates of interview interaction patterns. J Abnorm Sot Psycho1 56: 329-38, 1958. 

25. Moodie. W. Smoking. drinking, and nervousness. Lancet 2: 188-9, 

1957. 

26. Sackrin, S.. Conover. A. Tobacco smoking in the U.S. in relation to 

income. L-SDA Market Res Rep Xo. 189, 1957. 

27. Salber, D.. MacMahon. 8. Cigarette smoking among high school students related to social class and parental smoking habits. Amer J 

Public Health 51: 1780-9, 1961. 

28. Salber, E., Worcester, J. Ch ange in women’s smoking patterns. Cancer. 

In press as of September 1963. 

29. Salber. E. J., Welsh. B.. Taylor, S. V. Reasons for smoking given by 

secondary school children. J Health Hum Behav 4: 118-29, NO. 2, 

Summer 1963. 

30. Salber, E. J., and others. Recreational activities and attitudes toward 

smoking: A study of school children. Pediatrics. In press as of September 1963. 

378 
31. Salber, E. J., Goldman, E., Buka, M., Welsh, B. Smoking habits of high 

school students in Newton, Mass. New Eng J Med 265: 969-74,1961. 

32. Salber, E. J., MacMahon, B. S mo k ing habits of high school students 

related to intelligence and achievement. Pediatrics 29: 780-7, 1962. 

33. Schonfeld, J. Special report to the Surgeon General’s Advisory Committee on Smoking and Health. 

34. Schubert, D. Volunteering as arousal-seeking. [Abstract] Amer 

Psycho1 15: 413, 1960. 

35. Seltzer, C. Masculinity and smoking. Science 130: 1706-7, 1959. 

36. Strachey, J., ed. Sigmund Freud three essays on the theory of sexuality. 

In: Inst Psycho-Analyt Lib. London, Hogarth, 1962. No. 57, p. l-130. 

37. Straits, B., Sechrest, L. Further support of some findings about the 

characteristics of smokers and non-smokers. J Consult Psycho1 In 

press, 1963. 

38. Thomas, C. B. Characteristics of smokers compared with non-smokers 

in a population of healthy young adults including observations on 

family history, blood pressure, heart rate, body weight, cholesterol, 

and certain psychologic traits. Ann Intern Med 53: 697-718, 1960. 

39. Todd, G. Statistics of smoking. 2d edition. Research Paper No. 1. 

The Tobacco Manufacturers’ Standing Committee. London, 1959. 

379 
Chapter 15 

Morphological 

Constitution of 

Smokers 
Contents 

PHYSIQUE OF SMOKERS Page 

................ 384 

SOMATOTYPE CLASSIFICATION ............ 38:( 

MASCULINITY ..................... 383 

BODY WEIGHT. .................... 384 

PROSPECTZVE STUDY ................. :I85 

CONCLUSION ...................... :<87 

REFERENCES. ..................... X8; 

382 
Chapter 15 

MORPHOLOGICAL CONSTITUTION OF SMOKERS 

PHYSIQUE OF SMOKERS 

Several studies deal with the relation of morphological constitution and 

smoking. In 1929 Diehl (2) reported a study of the physique of smokers 

as compared to non-smokers in a group of freshmen at the University of 

Minnesota. Measurements of height and weight were obtained at the time 

of the freshman entrance examination, and smoking habit was determined 

from a questionnaire item based simply on whether the student did or did 

not smoke. No significant differences were found in height, weight, and 

height/weight ratio between the 445 smokers and 441 non-smokers. However, the design of the study limits the reliability of the information. 

SOMATOTYPE CLASSIFICATION 

A more satisfactory but still limited study was reported by Parnell (4) 

in 1951. Using Sheldon’s somatotyping technique, Parnell contrasted the 

classifications of smokers and non-smokers of 308 Oxford undergraduates. 

In smokers the most frequent somatotypes were the dominant endomorphs 

and endomorphic mesomorphs; the least frequent was the dominant ectomorph, with the dominant mesomorph in the middle. For the non-smokers 

the most frequent somatotype was the dominant ectomorph, and the mesomorphic ectomorph; the least frequent were the endomorphs and the 

endomorphic mesomorphs, and again the dominant mesomorphs were in 

the middle. 

MASCULINITY 

In 1959 Seltzer (5 j presented information on the relationship between 

physical masculinity and smoking in a group of 247 Harvard College students 

who had been followed for more than 15 years for smoking habits, as well 

as other information. From the smoking data, the subjects were classified 

into three groups, non-smokers, moderate smokers and heavier smokers. 

When the subjects were sophomores, they were rated with respect to a bodybuild complex known as the masculine component, which referred to the 

element of masculinity as indicated by external morphological features. In 

measuring this element, the more the pattern of anatomical traits tends 

7 14-422 O-64-26 383 
toward the extreme masculine form, the stronger is the masculine component. 

the greater the departure from the extreme masculine type towards th; 

feminine build, the weaker is the masculine component. The results of this 

study showed a statistically significant association between the strength of 

the masculine component and smoking habits. More specifically, it was 

found that weakness of the masculine component is significantly more 

frequent in smokers than in non-smokers, and most frequent in heavier 

smokers. Furthermore, it was indicated that the subjects with weakness of 

the masculine component showed a constellation of personality and behavioral 

traits that were, for the most part, not inconsistent with the findings of 

Heath (3) in his study of the differences between smokers and non-smokers, 

Although these findings were suggestive, they were recognized by the author 

as being preliminary and tentative in nature and requiring further confirma. 

tion. Furthermore, the series on which these results were obtained was 

relatively small and represented a highly selected population. 

BODY WEIGHT 

Thomas (7)) in her study of precursors of hypertension and coronary 

artery disease in more than 1,000 students at The Johns Hopkins University 

School of Medicine compared the group of non-smokers with the group of 

smokers for body weight among other characteristics. The group of 297 

non-smokers included occasional smokers as well, and the 321 smokers included all smokers except non-smokers, occasional, ex-smokers, and unknown. 

Pipe, cigar, and mixed smokers were included in the smoker category. The 

relationship of body weight to smoking habits was analyzed on the basis of 

percentage of overweight and underweight calculated from standard tables. 

Thomas found the percentage distribution of overweight and underweight 

was similar for smokers and non-smokers except at the upper end of the 

distribution curve. There was an excess of smokers who were 30 percent 

or more overweight, and the subjects who were 4Q percent or more overweight 

were all regular smokers, The non-smokers had also a greater frequency 

of individuals with 10 percent or more underweight than the smokers. The 

difference between smokers and non-smokers with regard to this body weight 

classification was found to be statistically significant. The subjects were also 

compared for the ponderal index (height over the cube root of weight), with 

the smokers showing an excess of the unusually heavy body builds. 

In the introduction to her paper on the characteristics of smokers compared with non-smokers (of which the weight analysis was a part), Thomas 

wrote: “The finding that smokers, especially heavy smokers, have a higher 

mortality rate from coronary heart disease than do non-smokers makes it 

important to determine whether those who smoke are fundamentally different 

from those who do not smoke, or whether smokers and non-smokers are 

essentially alike. If alike, th en smokers and non-smokers may be considered 

as a single population with a uniform life expectancy. If, however, smokers 

have constitutional differences from non-smokers, the two groups might have 

384 
inherently different mortality rates, and one group could not serve as a 

control for the other in statistical studies.” After detailing the significant 

differences noted in her data between smokers and non-smokers, with regard 

to history of parental hypertension, heart rate, pulse pressure, body weight, 

and other variables, Thomas concluded that “It cannot be determined from 

the present data whether those individual characteristics which are more 

often found among smokers than non-smokers represent true constitutional 

differences or are due to the effects of smoking. The differences observed 

in the parental histories indicate that smokers and non-smokers have a 

somewhat different heritage, and suggest that at least some of the variations 

found in individual traits may be genetic in origin.” 

In a study of 167 adult male factory workers of Neapolitan parentage 

but of American birth and upbringingt Damon (11 reported on morphological correlates with smoking. The original series contained 213 volunteers 

but 46 dropped out for various reasons, and the age range was most 

extensive from 20 to 59 years of age. Damon’s non-smoker category consisted of subjects not currently smoking and had never been regular smokers. 

Cigar and pipe smokers were combined with cigarette smokers, and the 

statistical analysis was based on the biserial correlation coefficient. 

As a result of his analysis, Damon found that smoking was associated 

at the 5 percent level with bi-iliac/biacrominal breadth. subscapular skinfold, 

ectomorphy, and physical activity; and at the 1 percent level with weight, 

height/cube root of weight, endomorphy and somatotype group. Smokers 

of all grades had very similar levels of activity. On the other hand, the 

most active and the least active men smoked more than those of average 

activity-a finding which reflects a curvilinear regression of smoking on 

activity. Damon concludes: “The results show a consistent and significant 

tendency . . . for lean men to smoke more than stout or fat (but not muscular) men . . . higher cholesterol levels among smokers . . . contrary 

to findings previously reported, smokers in this series were no less masculine 

in physique, were no more active and consumed no mnre alcohol than 

non-smokers.” 

PROSPECTIVE STUDIES 

The most extensive study of morphology as related to smoking habits is 

Seltzer’s prospective study of 922 H arvard alumni 13 years out of college, 

whose physical characteristics were recorded when they were undergraduates (6) . The investigation was concerned with the morphological 

characteristics of different classes of non-smokers, cigarette smokers, pipe 

smokers, and cigar smokers, in a selected male population in order to ascertain 

the extent to which different smoking classes are phenotypically and genotypitally conditioned. The morphological material consisted of a series of 

anthropometric measurements taken in the fall of 1942 as part of the routine 

Harvard College medical examination. A total of 12 measurements were 

obtained of various parts of the body, from which 10 body ratios or indices 

were computed. When the morphologic data were collected, there was no 

385 
prior consideration or knowledge of their ultimate use in this correlative 

study with the subjects’ subsequent smoking histories. Information With 

respect to the smoking habits of these Harvard men was obtained in the fall 

of 1959 through the medium of a questionnaire (81 percent response). The 

questionnaire covered approximately 16 years of smoking history and the 

subjects at the time of completing the questionnaire averaged 35 years of 

age, a period of maximum lifetime smoking experience. 

. 

AS far as smoking 

categories are concerned, an attempt was made to obtam groupings as nre. 

cisely differentiated as possible. The primary ClaSSifiCatiOn separated the 

subjects into non-smokers and smokers. The non-smoker was defined as a 

person who had never smoked at all or had attempted an occasional smoke 

during his lifetime. Individuals who smoked occasionally but not every day 

were excluded from the non-smoker category. The smokers were subdivided 

into exclusive groupings of cigarette only, cigar only, and pipe only in 

accordance with the form of tobacco used. All who regularly used more than 

one form of tobacco were omitted from this particular classification. For 

the analysis of degree or rate of cigarette smoking, there was a breakdown 

into five subgroups from occasional to 2f packs a day. The prospective 

nature of the study, with the availability of the physical measurements made 

during the college years, had the special advantage of representing a level of 

morphological status undifferentiated by individual variations resulting from 

modes of habit, diet, physical activity, health and disease of the subsequent 

adult years. The analysis was divided into three parts: comparison of non. 

smokers and smokers, variations among smokers according to form of smok. 

ing, and variations among smokers as related to degree or rate of smoking. 

The comparison of 234 non-smokers and 688 smokers showed that the 

two groups were significantly differentiated both in morphologic dimensions and proportions. ln every instance, the smokers had larger mean 

dimensions than the non-smokers, and in all but one instance these differences 

were statistically significant. Smokers were consistently greater than nonsmokers in height, weight, and in the dimensions of the head, face, shoulders, 

chest, hip, leg, and hand. Similarly, the smokers of cigarettes only, pipes only, 

and cigars only had larger mean dimensions than those of the non-smoker 

category. In addition, in eight out of ten bodily indices or proportions the 

smoker types showed mean deviations from the non-smoker that were all 

in the same direction and indicative of the same trend. A consistent graded 

pattern of differentiation into a specific order of arrangement of non-smokers, 

cigarette only, pipe only, and cigar only smokers, in that order, was found. 

Thus, for example, in the case of weight, the cigarette only smokers were 4.37 

pounds heavier than the non-smokers, the pipe only smokers 6.59 pounds 

heavier, and the cigar only smokers 10.41 pounds greater mean body weight. 

Analysis of the data dealing with amount of cigarette smoking did not show 

a regular significant body build differentiation according to rate or degree 

of smoking, but there were suggestions of a positive linear trend from the 

lightest smoking category to the “1 to 2 packs daily” followed by a downward 

trend of the maximum “2f packs daily” smokers. 

Of all the morphological studies, this prospective study appears to present 

the best data available. Nevertheless, the Harvard students comprise a 

highly selected sample. 

386 
CONCLUSION 

The available evidence suggests the existence of some morphologic differences between smokers and non-smokers, but is too meager to permit a 

conclusion. 

REFERENCES 

1. Damon, A. Constitution and smoking. Science 134: 339, 1961. 

2. Diehl, H. S. The physique of smokers as compared to non-smokers. A 

study of university freshmen. Minnesota Med 12: 421, 1929. 

3. Heath, C. W. Differences between smokers and non-smokers. AMA 

Arch Intern Med 101: 377, 1958. 

4. Parnell, R. W. Smoking and cancer. Lancet 1: 963, 1951. 

5. Seltzer, C. C. Masculinity and smoking. Science 130: 1706, 1959. 

6. Seltzer, C. C. Morphologic constitution and smoking. JAMA 183: 

639,1963. 

7. Thomas, C. B. Characteristics of smokers compared with non-smokers 

in a population of healthy young adults, including observations on 

family history, blood pressure, heart rate, body weight, cholesterol 

and certain psychologic traits. Ann Intern Med 53: 697, 1960. 

387