SMOI(ING and HEALTH 

REPORT OF THE ADVISORY COMMITTEE 

TO THE SURGEON GENERAL 

OF THE PUBLIC HEALTH SERVICE 

U.S DEPrl.RTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 
Public Health Service Publication No. 1103 

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

Washington. 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. 

iii 
COMMITTEE STAFF 

Professional Staff 

Eugene H. Guthrie, M.D., M.P.H. 

Staff Director 

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

Medical Coordinator 

Alexander Stavrides, M.D. 

Special Assistant to the Director 

Jack Walden 

Information Officer 

Mort Gilbert 

Editorial Consultant 

Helen A. Johnson 

Administrative Officer 

Jane Stafford 

Editorial Consultant 

Benjamin E. Carroll 

Biostatistical Consultant 

Secretarial and Technical Staff 

Helen Bednarek 

Mildred Bull 

Grace Cassidy 

Rose Comer 

Jacqueline Copp 

IV 

Alphonzo Jackson 

Jennie Jennings 

Martha King 

Sue Myers 

Irene Orkin 

Adele Rosen 

Margaret Shanley 

Don R. Shapland 

Elizabeth Welty 

Edith Waupoose 
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 

itseli 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 GEl\"ERAL 

v 
Table of Contents 

FOREWORD 

ACKNOWLEDGMENTS 

PART I INTRODUCTION, SUMMARIES AND 

CONCLUSIONS 

Page 

v 

IX 

Chapter 1 Introduction . . . . 3 

Chapter 2 Conduct of the Study 11 

Chapter 3 Criteria for Judgment 17 

Chapter 4 Summaries and Conclusions 23 

PART II EVIDENCE OF THE RELATIONSHIP 

OF SMOKING TO HEALTH 

Chapter 5 

Chapter 6 

Chapter 7 

Chapter 8 

Chapter 9 

Chapter 10 

Chapter ll 

Chapter 12 

Chapter 13 

Chapter 14 

Chapter 15 

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 . 

43 

47 

67 

77 

121 

259 

315 

335 

347 

359 

381 

vii 
ACKNOWLEDGMENTS 

During this study the AdYisory Committee on Smoking and Health has 

had the constant support of individuals. groups and institutions throughout 

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

the contributions of these indiYiduals involved considerable personaL pro· 

fessional or financial sacrifice. In e\·erv case the contributions lessened the 

burden of the Committee and increased the authoritY 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 following: 

ACKERMAN, LAUREN, :\1.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 \1edical Center, l'\ew York, N.Y. 

ALLEN, GEORGE V.-Presid~nt and Executive Director, The Tobacco Institut~, Inc., Washington, D.C. 

ALLING, D. W., 1\-i.D.-Statistician, :\ational Institute of Allergy and Infectious Diseases, U.S. Public Health Service, Bethesda, Md. 

AMERICAN CANCER SociETY, New York, 1\'.Y. 

AMERICAN TOBACCO Co., 1\'ew York, N.Y. 

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

Laboratory, Baptist Memorial Hospital, Jacksonville, Fla. 

ANDERVONT, HOWARD B., Sc. D.-Chief, 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, 1\'ew York, N.Y. 

ASHFORD, THOMAs_P., M.D.-Instructor in Surgery, College of Medicine, 

University of Utah, Salt Lake City, nah. 

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

AVERBACH, OsCAR, M.D.-Senior Medical Investigator, Veterans Administration Hospital, East Orange, N.J. 

BAILAR, Jom; C. III, :M.D.-Head, Demography Section, Biometry Branch, 

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

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

RF:ARMAI\, JACOB E., Ph. D.-Professor of Rio~tatistics. Universit\ of :\'linnesota School of Public Health, Minneapolis, Minn. 

RF:EBE, GILBERT W., Ph. D.-Statistician, National Acadernv of Sciences, National Research CounciL Washinf[ton, D.C. . 

IX 
BELL, FRANK A., Jr.,-Program Director for the Engineer Career Develop· 

ment Committee, Office of the Chief Engineer, U.S. Public Health Service, 

Washington, D.C. 

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

Mayo Clinic, Rochester, Minn. 

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

National Health and Welfare, Ottawa, Canada. 

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

Washington, D.C. 

BoeKER, 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 AC'ID WILLIAMSON ToBACCO CoRP., Louisville, Ky. 

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

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

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

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

Public Health Service, Bethesda, Md. 

C.<\NADIA:"' 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, Lours M.-Program Planning Officer, National Cancer Institute, 

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

CASTLEMAN, BENJAMIN, M.D.-Department of Pathology, Massachusetts 

General Hospital, Boston, Mass. 

CHADWICK, DOC'IALD R., M.D.-Chief, Division of Radiological Health, U.S. 

Public Health Service, Washington, D.C. 

CLARK, KE!'iC'IETH, Ph. D.-Consultant, Office of Science and Technology. 

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

CoBB, Smli"EY, M.D.-Program Director, Survey Research Center, University 

of Michigan, Ann Arbor, Mich. 

CoMROE, Juuus H., M.D.-Professor of Physiology 'and Director of the 

Cardiovascular Research Institute, University of California, San Francisco. 

Calif. 

CooN, 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. 

CoR:'<iFIELD, ] !'ROME-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 Universitv 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, Roswell 

Park Memorial Institute, Buffalo, N.Y. 

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

Federal Trade Commission, Washington, D.C. 

DoLL, RICHARD, M.D.-Director, Medical Research Council's Statistical 

Research Unit, University College Hospital Medical School, London, 

England 

*DoRN, HAROLD F.-Chief, Biometrics Research Branch, National Heart 

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

DOYLE, JosEPH T., M.D.-Director, Cardiovascular Health Center, Albany 

Medical College, Union University, Albany, N.Y. 

DUNHAM, LuciA J., M.D.-Medical Officer, Laboratory of Pathology. !\ationa! Cancer Institute, U.S. Public Health Service, Bethesda, Md. 

EBERT, RICHARD V., M.D.-Professor and Head, Department of J\ledicine, 

University of Arkansas 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, }AMES 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, American Cancer Society, 

Inc., New York, N.Y. 

*GILLIAM, 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, JoHN. M.D.-Head. Air Pollution Medical Studies, California 

Department of Public Health, Berkeley, Calif. 

"Deceased. 

XI 
GOLDSTEI'\', HYMAN, Ph. D.-Chief. Biometrics Branch, National Institute of 

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

Md. 

GRAHHf, SuoN. M.D.-Associate Cancer Research Scientist, Roswell Park 

Memorial Institute, Buffalo, N.Y. 

GREENBERG, BER'IARD 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, WILLIAM-Chief, Biometrv Branch, National Cancer Institute, 

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

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

Cambridge, Mass. 

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

HALMSTAD. DAVID---Actuary, The ~ational Center for Health Statistics, U.S. 

Public Health Service, Washington, D.C. . 

HAMMOND, E. CuYLER, Sc. D.-Director, Statistical Research Section, Medi· 

cal Affairs Department, American Cancer Society, Inc., New York, N.Y. 

H.<\MPERL, H., M.D.-Director of the Pathology Institute, University of 

Bonn, Bonn, Germany. 

HARTWELL, JoNATHAN L., Ph. D.-Chief, Research Communications Branch, 

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

HAYDEl\", RoBERT G., Ph. D.-Research Psychologist, Behavioral Sciences 

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

Service, Washington, D.C. 

HEIMAN:>~. HARRY, M.D.-Chief, Division of Occupational Health, U.S. 

Public Health Service, Washington, D.C. · 

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

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

Washington, D.C. 

HELLER, JoHl\" 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, KHHERI'>E, M.D.-Medical Director, Laboratory of Pathology, 

J\ational Cancer Institute, l'.S. Public Health Service, Bethesda, Md. 

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

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

HIGGI'>S, IA'i T. T .. M.D.-Professor of Epidemiology and Microbiology, 

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

HocHBADI, GoDFREY, Ph. D.-Chief, Behavioral Sciences Section, Division 

of Community Health Services, L.S. Public Health Service, Washington. 

D.C. 

HocKETT. RoBERT C., Ph. D.-Associate Scientific Director, Tobacco Industry Research Committee, New York, N.Y. 

HoR:'>I, D.niEL, 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, DiYision of Air 

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

HuEPER, WILHELM C., M.D.-Chief, Environmental Cancer Section. :\ationa! Cancer Institute, l'.S. Public Health Service, Bethesda, )\fd. 

IPSEN, JoHANNES, Ph. D.-Professor of Medical Statistic~. Henrv Phipps Institute, University of Pennsylvania. Philadelphia, Pa. 

ISBELL, HARRIS, M.D.-Professor of Clinical PharmacologY. l'niversity of 

Kentucky Medical School, Lexin~ton, Ky. 

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

Accident Prevention, U.S. Public Health Service, W a~hington. D.C. 

}ANTS, ZELDA-Statistician, National Cancer Institute, LS. Public Health 

Service, Bethesda, Md. 

JosiE, G. H., Sc. D., M.P.H.-Chief, Epidemiolo;ry Divi~ion. 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. 

KANNEL, 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, f..Iassachusetts Eye and Ear 

Infirmary, Harvard University Medical SchooL Boston, :\lass. 

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, A VIVA-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. L.S. Public 

Health Service, Bethesda, Md. 

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

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

KREYBERG, LErv, 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, PAULS., Ph. D.-Professor and Chairman of Department of Phar· 

macology, Medical College of Virginia, Richmond, V a. 

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

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

LEUCHTENBERGER, CECILIE, M.D., Ph. D.-Professor, Eidgenossische Technische Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland 

xiii 
LEUCHTENBERGER, RuDOLF, M.D.-Professor Eidgenossische Technische 

Hochschule, Institut fiir Allgemeine Botanik, Zurich, Switzerland 

LEVI"', 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, be., New York, N.Y. 

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

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

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

Hospital, Boston, Mass. 

LITTLE, CLARENCE CooK, M.D.-Scientific Director, Tobacco Institute Re· 

search Committee, New York, N.Y. 

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

MANOS, NICHOLAS E.-Statistician, Division of Occupational Health, U.S. 

Public Health Service, Washington, D.C. 

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, }AMES }., 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. AN'i-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, EDMO:"'D A., M.D.-Attending Physician, The Moore Clinic, The 

Johns Hopkins l!niversity Hospital, Baltimore, Md. 

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

University Medical School, Chicago, Ill. 

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

0RCHIN, MILTON, Ph. D.-Professor of Chemistry, University of Cincinnati, 

Cincinnati, Ohio. 

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

PAFFENBARGER, RALPHS., 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, ]OHN A., 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 

Mf,dicine, 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 College, 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-Special 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. 

SELIGMAN, ARNOLD M., M.D.-Chairman, Department of Surgery, Sinai Hospital, Baltimore, Md. 

XV 
SELTSER, RAYMOND, l\1.D.-The Johns Hopkins University School of Public 

Health, Baltimore, Md. 

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

Peabody Museum, Harvard University, Cambridge, Mass. 

SHAPIRO, HARRY, :\1.D.-Curator of Anthropology, American Museum of 

~atural History, New York, N.Y. 

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

Chicago, Ill. 

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

College of Virginia, Richmond, Va. 

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

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

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

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

SPIEGELMAN, MoRTIMER-Associate Statistician, Metropolitan Life Insurance 

Company, New York, N.Y. 

STALLONES, REVEL, 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., l\1.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, SHERMAN LEO"'ARD--Sociologist, San Francisco Field and Training 

Station, P.S. Public Health Service Hospital, San Francisco, Calif. 

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

Center, University of Chicago, Chicago, Ill. 

ToBACCo hsnn~TE, INc .. Washington, D.C. 

ToBACCO hsTITUTE RESE.\.RCH CoMMITTEE, New York, N.Y. 

Tm<t~HATA, GEORGE, Ph. D., D.P.H.-Chief of Epidemiology, St. Jude Research Hospital, Institute of Biology and Pediatrics, Memphis, Tenn., and 

Assistant Professor of Preventive Medicine, University of Tennessee, College of l\fedicine, 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, CLAUDE G.-Director, Tobacco Policy Staff, Agriculture Stabilization and Conservation Service, United States Department of Agriculture, 

Washington, D.C. 

XVI 
VINCENT, WrLUAM ].-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.A.-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 1., 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. 

ZERZAVY, FRED M., :'VI.D.-Department of Maternal and Child Health, The 

Johns Hopkins School of Public Health, Baltimore, Md. 

ZuKEL, WILLIAM, 1'\LD.-Associate Director, Collaborative Studies, 1\'ational 

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

714-422 0-64-2 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' such a presentation. This 

Part includes: (a) an introduction comprising. among other items. a chronology especially pertinent to the subject of this study and to the establishment and activities of the Committee, ( b I a short account of ho"- the study 

was conducted, (c) the chief criteria used in making judgments. and I d) 

a brief overview of the entire Report. 

HISTORICAL NOTES AND CHRONOLOGY 

In the early part of the 16th centurv, soon after the introduction of 

tobacco into Spain and England by explorers returning from the !'lew World. 

controversy developed from differing 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 proportionately. 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 sixty-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 general; coronary artery disease in particular), and to the non-cancerous (nonneoplastic) diseases of the lo\\ er respiratory tract 1. especially chronic 

bronchitis and emphysema). The next important basic date for starting 

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

great variety of investigations have been carrier! out. Manv of the chemical compounds in tobacco and in tobacco smoke have been isolated and 

tested. Numerous experimental studies in lower animals have been made 

hy exposing them to srnoke and to tars. gases and \·arious e<mstituPnts in 

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

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

expose them to possibly noxious agents over the prolonged periods under 

strictly controlled conditions that would 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. 

Among 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 value for the work of this Committee. These are ( 1) retrospective studies which deal with data from the personal histories and medical 

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

studies, in which men and women are chosen randomly or from some 

special group, such as a profession, and are followed from the time of their 

entry into the study for an indefinite period. or until they die or are lost 

on account of other events. 

Since 1 <):)9 there have been 29 retrospective studies of lung cancer alone 

which ha1e varving 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. At this time, also. the critical 

counterattack upon retrospective studies and upon conclusions drawn from 

them was launched by unconvinced individuals and groups. The same tvpes 

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

discussed further in Chapter :-t Criteria for Judgment. and in other chapters, 

especially Chapter 8. Mortality. and Chapter 9, Cancer. 

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

accumulated evidence were issued hy a number of organizations. These 

included the British \ledical Research Council: the cancer societies of Der.-

mark. 1'\orwav. Sweden. Finland. and the ~etherlands: the American Cancer 

Society: the American Heart Association: the Joint Tuberculosis Council of 

Great Britain: and the Canadian "\ational Department of Health and Welfare. 

The consensus. puhlich· declan~d. was that smoking is an important health 

hazard. particularlv 11 ith respec-t to lung cancer and cardiovascular disease. 

Earlv in 1%t the Tobacco lndustrv Research CommitteE' IT.I.R.C.i was - -

established by representati\ es of tobacco manufacturer~. growers, and warehousemen to sponsor a program of research into questions of tobacco use 

and health. Since then. under a Scientific Director and a Scit>ntific Ad,·isory 

Board composed of nine scientists who maintain their respt>ctive institutional 

affiliations. tht> Tobacco I ndustn Research Committee has conducted a 

grants-in-aid program. collectt>d information, and issued reports. 

The (J .S. Public Health Service first became officially engaged in an 

appraisal of the a\ ailable data on smoking and health in June. 19.'i6. when, 

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

6 
the subject was established jointly hv the National Cancer Institute. the 

National Heart Institute. the American Cancer Socieh. and the American 

Heart Association. After appraising Hi indepenclent ,-tudies carried on in 

five countries over a period of 18 Years. this group concluded that there is 

a causal relationship between excessive smokin~ of cif!art>ttes and lung cancer. 

Impressed bv the report of tht> Studv Committee and hv othPr new evidence. Surgeon General Lernv E. Burnev issued a statenwnt on J uh 12. I 057. 

reviewing the matter and declarinf': that: '"Tht> Publie Health Senict> ft>els 

the weight of tht> evidt>nce is increasingh· pointin~ in one dirt>ction: that 

excessive smoking is one of the rausativt> factors in lung cancer.·· A~ain. 

in a special article entitlt>rl "Smoking anrl Lung Cancer--A Statemt>nt of the 

Public Health Service."' publisht>d in tlw Journal of the .-\nwrican \1edical 

Association on Novemht>r 21L 19.')<). Surgeon Ge1wral Burne\· rt>ferrt>d to 

his statement issued in 1 9SI and rt>itt>ratt>d the belief of the Puhlic Health 

Service that: "The weight of t>vidence at prest>nt implicates smokin~ as the 

principal factor in the increased incidence of lung canr·t>r."" and that: '·Cigarette ;;moking particularh· is associated with an increast>d chance of developing lung cancer." These quotations state the position of the Public 

Health Service taken in 19S7 and 19.S9 on tht> qut>,tion of mwking and 

health. That position ha,: not changt>d in the sucreeding vears. during 

which several units of tht> Senire conducted extensive imesli)!ations on 

smoking and air pollution. anrl the St>rvirt> maintaint>d a constant scrutinv 

of reports and publications in this field. 

ESTABLISHMENT OF THE C0\1MITTEE 

The immediate antecedents of the estahli,hnwnt of the Surgeon General's Advisory Committee on Smoking and Health hegan in mid-19(Jl. 

On June 1 of that year. a letter was sent to the President of tht> l'nited States, 

signed by the presidents of the American Cancer Sociel\-. the American 

Public Health Association. the American Heart Association. and the National Tuberculosis Association. It uqred the formation of a Presidential 

commission to study the "widespread implications of the tobacco problem." 

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

with Surgeon General Luther L. Tern. \\ho shorth thereafter proposed to 

the Secretary of Health, Education. and Welfare the formation of an advisory committee composed of "outstanding experts who would asse's available knowledge in this area [smoking vs. health] and make appropriate recommendations . . . " 

On April 16. tht> Surgeon General sent a more detailed propo~al to the 

Secretary for the formation of the ad\·isory group. callinf! for re-evaluation 

of the Public Health Sen-ice position taken by Dr. Burne\ in the Journal 

of the American Medical Association. Dr. Terrv felt the net>d for a nt>w 

l'lok at the Senice"s po,.ition in the light of a numiwr of significant dt>wloplllents since 19.')() whirh emphasized the need for further action. Ht" listed 

these as: 

7 
l. New studies indicating that smoking has maior adverse health effects. 

2. Representations from national voluntary health agencies for action on 

the part of the Service. 

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

London. 

4. Action of the Italian Government to forbid cigarette and tobacco ad. 

vertising; curtailed advertising of cigarettes by Britain's major tobacco 

companies on TV; and a similar decision on the part of the Danish tobacco 

industry. 

5. A proposal by Senator Maurine Neuberger that Congress create a 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 gastrjc and duodenal ulcers." 

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

an expert committee to undertake a comprehensive review of all data on smok. 

ing and health. The President later in the same day at his press conference 

acknowledged the Surgeon General's action and approved it. 

On 1 uly 2~. 1962. the Surgeon General met with representatives of the 

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

.\merican 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. 1\'o 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 1 uly 27 compiled a list of more than 

150 scientists and physicians working in the fields of biology and medicine, 

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

with capacity to evaluate the elements and factors in the complex relation-

,hip between tobacco smoking and health. During the next month. these 

lists were screened by the representati,·es of organizations present at the 

July 27 meeting. Any organization could veto any of the name,.: on the 

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

the names of anv persons who had taken a puhl ic 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 The 

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

Stanhope Bavne-Jones. M.D .. LL.d .. f Retired). Fonner Dean. Yale School 

,f Medicine f 193-'i-40 1. former President. Joint Administrative Board. Cornell Cniversity. New York Hospital Meclical Center i 1947-52 I : former 

President. Societv of American Bacteriologi!'ts 1 1929 I. and American Society 

of Pathologv and Bacteriologv 119401. Field: 1'\ature and Causation of 

Di,ease in Human Populations. 

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

,-taff. 

Walter J. Burdette. 'l.D .. Ph. D .. Head of Department of Sur~ny. UniIPrsity of nah School of Medicine. Salt Lake City. Fields: Clinical &: 

Experimental Surgery; Genetics. 

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

Fit>ld: Mathematical Statistics. with Special Application to Biological 

Problems. 

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

l-niversitv of Pittsburgh. Field: Experimental and Clinical Pathology. 

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

Harvard University. Field: Chemistrv of Carcinogenic Hydrocarbons. 

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

Director of Pathology Laboratorie~, Francis Delafield Hospital, New York, 

\.Y. Field: Cancer Biology. 

John B. Hickam, M.D., Chairman, Department of Internal Medicine. Uni1 nsity of Indiana, Indianapolis. Fields: Internal Medicine. Physiology of 

f :arcliopulmonary Disease. 

Charles LeMaistre. M.D., Professor of Internal Medicine, The eniversitv 

of Texas Southwestern Medical School. and Medical Director. Woodla" n Ho~­

l'ital. Dallas. Texas. Fields: Internal Medicine, Pulmonary Diseases, 

l'n·ventive Medicine. 

Leonard M. Schuman, M.D .. Professor of Epid!'miology, l"niversity of 

\linnesota School of Public Health, Minneapolis. Field: Health and. Its 

Ht>lationship to the Total Environment. 

1

. :laur~ce H. Seevers. M.D., Ph. D .. Chairman. Department of Pharmacology. 

rnverSity of Michil!an, Ann Arbor. Field: Pharmacology of Anesthesia 

and Habit-Forming Drugs. 

P Ch_airman: Luther L. Terry, M.D .. Surgeon General of the United States 

ubhc Health Service. 

9 
Vice-Chairman: James M. Hundley. \LD .. Assistant Surgeon General for 

Operations, United States Public Health Service. 

Staff Director 

Eugene H. Guthrie. M.D., \LP.H. 

Public Health Service 

lO 

Medical Coordinator 

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

Public Health Service 
Chapter 2 

Cond net of the Study 
Chapter 2 

CONDUCT OF THE STUDY 

The work of the Surgeon General's AdvisorY Committee on Smoking and 

Health was undertaken. oq!anized. and pursued with independencP. a deep 

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

of the task. Thl' Committt'e's constant dt'~irt> 11 as to earn out in its 011 n 

way. with the bt'st obtainablt' advice and coopt'ration from experts outside 

its membership. a thorou;:rh and objectiw revit>w and evaluation of available 

information about the effects of thl' us!' of various forms of tobacco upon the 

health of human beings. It desired that the Report of its studies and judg· 

ments should be unquestionably the product of its labors and its authorship. 

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

and associates of the supporting staff. and from sewral organizations and 

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

and individuality has been produced. It is emphasized, hm,·ever. 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 9-10, 1962, 

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

into unanticipated explorations. At first an encyclopedic approach was 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 reason· 

able length of time, and certainly not under the urgencies of the existing 

situation. The final plan was to give particular attention to the cores of 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 

disease categories. 

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

topical divisions of the study were: 

• Tobacco and tobacco smoke, chemical and physical characteristics 

(Chapter 6 I . 

• Nicotine, pharmacology and toxicology (Chapter 7). 

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

ing habits, and other factors (Chapter 8). 

• Cancer of the lungs and other organs; carcinogenesis; pathology, and 

epidemiology I Chapter 9). 

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

bronchitis and emphysema. with some consideration of the effects of 

air pollution !Chapter 10). 

• Cardiovascular diseases. particular] y coronary artery diseases I Chapter 

111. 

• Other conditions. a miscellanv including gastric and duodenal ulcer, 

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

• Characterization of the tobacco habit and beneficial effects of tobacco 

(Chapter 13). 

• Psycho-social aspects of smoking (Chapter 14). 

• Morphological constitution of smokers I Chapter 15). 

As the primary dutv 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 ~ational 

Library of 1\ledicine. .\s the annotated monograph by Larson, Haag, and 

5ihette-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 

sourcf'. thf' National Librarv of Medicine was requested to compile a bibliog· 

raphv I by 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 

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

Library of 1-Iedicine 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 study by members of the Committee. In addition, the members drew 

upon the libraries and bibliographic services of those institutions in which 

thev held academic 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 manufacturing cigarettes and other tobacco 

products were invited to submit statements and any information pertinent to 

the inquiry. The replies which were receiYed 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 contracts. many con· 

ferences, seminar-like meetin~s. consultations. visits and correspondence 

made available to the Committee a lar~e 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 ahme. the Committee at its first meeting formed subcommittees with much overlapping in 

membership. These subcommittees were the main forces en~aged 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 genrnouslv at the request of the Committee. 

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

formulations of conclusions were made bv 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 

exe~utive session, it had the advantage of attendance at its meetings of ob-

>ervers from other Federal agencies. There were representatives from the 

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

Federal Trade Commission, Department of Commerce. Department of Agriculture. and the Food and Drug Administration. Sen·ing as more than observers and reporters to their agencies, when they were present or by 

written communication, they 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 196.3, 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 0-64-3 15 
Chapter 3 

Criteria for Judgtnent 
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, setting 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 implicit 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 
epidemiolol!ic 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 jud~ments 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 

Yigorously 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 Aristotle, 

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

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

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

may be stated briefly as follows: 

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

a host ( ,~ariable man) and a complex agent (tobacco and its products, partie20 
ularly those formed by combustion in smoking). The probe 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 mi~Zht: a l improve his well· 

heinll. b l let him proceed normally, or c) 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 publications and reports and throu!!h consultation with \\~ell informed persons. 

2. When a relationship or an association betweE:n 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 while a factor could he a source of variation. not all 

sources of variation are causes. It is recof!nized 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. i.e .. without it the other factors I as 

genetic susceptibility) 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 studv. and it is capable of convey· 

ing the notion of a significant, effectuaL relationship between an agent and 

an aswciated disorder or disease in the host. 

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

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

Although various disciplines and fields of scientific knowledge were repre· 

sented among the membership, all members shared a common conception 

of the multiple etiology of biological processes. ~o member was so naive 

as to insist upon mono-etiology in pathological processes or in vital phenomena. All were thorou!!hly 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 AND 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 ~icotine . . 

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 

Smoke ............ . 

Characterization of the .Tobacco 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 . . . . . . . 

l'lon-Neoplastic Respiratory Diseases, Particularly 

Bronchitis and Pulmonary 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 

Tobacco 

Chronic 

Page 

25 

26 

28 

29 

30 

30 

31 

31 

31 

32 

32 

32 

33 

33 

33 

34 

34 

35 

37 

37 

37 

37 

37 

37 

38 

38 

38 

39 

39 

39 

39 

39 

39 

39 

40 

I. Deaths from selected disease categories, United States, 1962 26 

2. Expected and observed deaths for smokers of cigarettes only 

and mortality ratios in seven prospective studies . . . . . 29 

24 
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 l. 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 27,000 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 1940, to 396,000 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 I.-Deaths from selected disease categories, United States, 191 

__________ c_.a_u_se_o __ f_dea_th_· _________ 1 __ T_ot_a __ l_ -~ale~~-~~ 

Degrnf'rative anr! arteriosclerotic heart disea&"t inc1uding coronary 

disease (420, 422)_------------------------------------------------- 577,918 348,604 2 Hypertensive heart disease (44(}-3)__________________________________ 62.176 26, 6.>4 Cancer of lung (162-3) _ __ _ __ __ __ __ __ __ ___ __ ____ __________ ______ _____ 41, 376 35. 312 

Cirrho,is of liwr (581 )_ __________________________ ------------- ______ 21, 824 14, 329 Bronchitis and emphysema (5G2, 527.1)______________________________ 15,104 12,937 Stomach and duodenal ulcers (51(}-1)________________________________ 12.228 8, R1n Can orr of h!adrler (181)_ __ ____ ____ __ _ __ ___ __ ______ _________ __ ___ __ __ 8, 081 5, 57.1 Cancer of oral caYity (140-8) _ __ _______ ____ __ __ __ __ ____ __ __ __ __ __ __ _ f\, 481 t, 920 Cancer of csophaom (].10) ___ ____ ____ __ __ __ __ ______ ____ __ __ __ __ __ __ 5, O~S 3, 973 

Cancrroflarynx (Jf,Jl_ ------------------------------------------- 2,417 2,172 

----1----1-- All aho\·r C'ausrs ____ _ 

All other causes _____________ -------------------------------------

All causes __________ __ 

•International Statistical Classification numbers in pn.rentheses. 

7.52,603 4fo3, 312 

1,004,027 531,477 

2 

4 1----1---

1, 7.16, 720 994, 7~9 

Nearly 70 million people in the United States consume tobacco regul; 

Cigarette consumption in the United States has increased markedly sine€ 

turn of the Century, when per capita consumption was less t!:lan 50 cigan 

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 1 

and to a peak of 3,986 in 1961. The 1955 Current Population Su 

~howed that 68 percent of the male population and 32.4 percent of the fe1 

population 18 years of age and over were regular smokers of cigare 

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

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

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

which reached a peak of 2~;2 lbs. per person in 1910, fell to a little r 

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

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

The background for the Committee's study thus included much ger 

information and findings from previous investigations which associated 

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

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

to assess the nature and magnitude of the health hazard attributabl 

smoking. 

KINDs oF EviDENCE 

In order to judge whether smoking and other tobacco uses are lll]Ul 

to health or related to specific diseases, the Committee evaluated three 1 

kinds of scientific evidence: 

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

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 tob 

and smoke, though not carcinogenic themselves, promote cancer prodw 

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

contained in tobacco smoke produce experimentally the kinds of non 

cerous damage seen in the tissues and cells of heavy smokers. This incl 

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 studie3 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-

of this Chapter, and in Chapter 3. 

The experimental, clinical, and pathological evidence, as well as d~ 

from population studies, is highlighted in Section B of this Chapter, whi 

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

this evidence is presented in detail. 

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

the results of the seven prospective population studies which, as noted abo· 

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

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

which are involved. 

EviDENCE FRoM THE CoMBINED REsULTS OF PROSPECTIVE 

STUDIES 

The Committee examined the seven prospective studies separately as w 

as their combined results. Considerable weight was attached to the c< 

sistency of findings among the several studies. However, to simplify prest 

tation, only the combined results are highlighted here. 

Of the 1,123,000 men who entered the seven prospective studies and w 

provided usable histories of smoking habits (and other characteristics su 

as age), 37,391 men died during the sttbsequent months or years oft 

studies. No analyses of data for females from prospective studies 1 

presently available. 

To permit ready comparison of the mortality experience of smokers a 

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

smokers compared with non-smokers, and mortality ratio. After adjustme1 

for differences in age and the number of cigarette smokers and non-smoke 

an expected number of deaths of smokers is derived on the basis of deal 

among non-smokers. Excess deaths are thus the number of actual (observe 

deaths among smokers in excess of the number expected. The mortal 

ratio, for which the method of computation is described in Chapter 

measures the relative death rates of smokers and non-smokers. If the a1 

adjusted death rates are the same, the mortality ratio will be l.O; if the de! 

rates of smokers are double those of non-smokers, the mortality ratio ~ 

be 2.0. (Expressed as a percentage, this example would be equivalent t< 

100 percent increase.). 

Table 2 presents the accumulated and combined data on 14 disease ca 

gories for which the mortality ratio of cigarette smokers to non-smokers ll 

1.5 or greater. 

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

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

nearly 70 percent higher than for non-smokers. (This ratio includes de1 

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

shown.) 

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

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

diseases: cancer of the lung (10.8), bronchitis and emphysema (6.1), c: 

28 
TABLE 2.1-Expected and observed deaths for smokers of cigarettes only and 

mortality ratios in seven prospective studies 

Underlying cause of death 

rsn('('r of I lUll: (162-3) '----- ------------------------------------ _: __ _ !tronchitis and emphysema (502, 521.1)------------------------------

r,n<'<'r of larynx (161) ----------------------------------------------- flrsl conC<'r (140-8) _____ --------------.-----------------·-·---------- ranrer of esopha!ffiS (!50)----------- ________ ---------------------- __ Stomach and duodenal ulcers (540, 541) ____________________________ _ 

nther circulatory diseases (451-681 ___ ------- _ ----------------------. r;rrhosis of liver (581) _______________ -------- _. --------------------

l'snm of bladder (181). _______________ ------------------·-·--------

l'oronary artery discaSt> (420\_. -------------------------------------

<'ther heart diseases (421-2, 430--4) ____ --------------- _ ---------------

l!yrertensive heart (440-3) ____ -------------------------------------- rh·nrr~] arteriosclerosi., (150)~ ----------------- _______ -- ------------- riUlr<'T of kidney (180) _________________ --------.--------------------

All ('!!USeS'----------------------------------------------·----------

'-~brid•erl from Table 2'i, Chapter 8. Mortality. 1 International Statistical Classification numbers in parentheses. 1 lnrludes all other causes of death as well as those hsted ab<n·e. 

Expected 

deaths 

170.3 

89.5 

14.0 

37.0 

33.7 

105.1 

254.0 

169.2 

111.6 6, 430. 7 526.0 

40\l. 2 

210.7 

79.0 15, 653. n 

Observed 

deaths 

1, 833 

546 

75 

152 

1\3 

294 

649 

379 

216 

11,177 

8f\8 

631 

310 

]2') 

23, 223 

Mortal!ty 

ratio 

10.8 

6.1 

5.4 

4.1 

3.4 

2.51 

2.6 

2. 2 

1.9 

1.7 

1. 7 

1.5 

1.5 

1. 5 

1.68 

rer 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 

roronary 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 

neath 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 10 to 

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

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

40 or more, it is 120 percent higher. 

. Cigarette smokers who stopped smoking before enrolling in the seven stud-

~es have a death rate about 40 percent higher than non-smokers, as against 1

0 percent higher for current cigarette smokers. Men who began smoking 

before age 20 have a substantia1ly higher death rate than those who began 

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

~makers, 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. 

f In two studies which recorded the degree of inhalation. the mortality ratio 

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

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

29 
at the earlier ages ( 40-50) represented in these studies, and declines w 

increasing age. 

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

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

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

8moking more than 5 cigars daily, death rates are slightly higher. Tht 

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

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

!<orne degree. The death rates for pipe smokers are little if at all higt 

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

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

Excess Mortality 

Several of the reports previously published on the prospective stud 

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

of cigarette smokers among the principal causes of death. The hazard m1 

be measured not only by the mortality ratio of deaths in smokers and nc 

»mokers, 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, wi 

lung cancer uniformly in second place. For all seven studies combim 

coronary artery disease (with a mortality ratio of l. 7) accounts for 45 p1 

cent of the excess deaths among cigarette smokers, whereas lung cane 

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

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

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

blood vessels, other than coronary artery Q.isease, 14 percent; cancer si1 

other than lung, 8 percent; and chronic bronchitis and emphysema, 4 perce1 

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

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

interest to public health authorities and the medical profession. 

AssociATIONS AND CAUSALITY 

The array of information from the prospective and retrospective studies 

smokers and non-smokers clearly establishes an association between cigare 

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

2 provide an approximate index of the relative strength of this associati( 

for all causes of death and for 14 disease categories. 

In this inquiry the epidemiologic method was used extensively in t 

assessment of causal factors in the relationship of smoking to health amo 

human beings upon whom direct experimentation could not be impost 

Clinical, pathological, and experimental evidence was thoroughly consider 

and often served to suggest an hypothesis or confirm or contradict ott 

findings. When coupled with the other data, results from the epidemiolo! 

30 
studies can provide the basis upon which judgments of causality may be 

made. 

It is recognized that no simple cause-and-effect relationship is likely to exist 

between a complex product like tobacco smoke and a specific disease in the 

variable human organism. It is also recognized that often the coexistence of 

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

factors may play a determinant role; that is, without it, the other factors 

(such as genetic susceptibility) seldom lead to the occurrence of the disease. 

THE EFFECTS OF SMOKING: PRINCIPAL FINDINGS 

Cigarette smoking is associated with a 70 percent increase in the age· 

!<pecific 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 mountinl! 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 lung cancer in men; the ma~mitude 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 10-fold risk of developing 

lung cancer and heavy smokers at least a 20-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 hnmchitis 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. 

714-422 0-64-4 31 
Cardiovascular Diseases 

It is established that male cigarette smokers have a higher death ra 

from coronary artery disease than non-smoking males. Although t 

causative role of cigarette smoking in deaths from coronary disease is n 

proven, the Committee considers it more prudent from the public heal 

viewpoint to assume that the established association has causative meani1 

than to suspend judgment until no uncertainty remains. 

Although a causal relationship has not been established, higher mortali 

of cigarette smokers is associated with many other cardiovascular diseas1 

including miscellaneous circulatory diseases, other heart diseases, hypt 

tensive heart disease, and general arteriosclerosis. 

Other Cancer Sites 

Pipe smoking appears to be causally related to lip cancer. Cigare1 

smoking is a significant factor in the causation of cancer of the laryn 

The evidence supports the belief that an association exists between tobac' 

use and cancer of the esophagus, and between cigarette smoking and cane 

of the urinary bladder in men, but the data are not adequate to deci, 

whether these relationships are causal. Data on an association betwe 

smoking and cancer of the stomach are contradictory and incomplete. 

THE ToBAcco HABIT AND NICOTINE 

The habitual use of tobacco is related primarily to psychological a1 

social drives, reinforced and perpetuated by the pharmacological actio 

of nicotine. 

Social stimulation appears to play a major role in a young person's ea1 

and first experiments with smoking. No scientific evidence supports t 

popular hypothesis that smoking among adolescents is an expression 

rebellion against authority. Individual stress appears to be associated mo 

with fluctuations in the amount of smoking than with the prevalence of smc 

ing. The overwhelming evidence indicates that smoking-its beginnin 

habituation, and occasional discontinuation-is to a very large extent p~ 

chologically and socially determined. 

Nicotine is rapidly changed in the body to relatively inactive substanc 

with low toxicity. The chronic toxicity of small doses of nicotine is lc 

in experimental animals. These two facts, when taken in conjunction wi 

the low mortality ratios of pipe and cigar smokers, indicate that the chror 

toxicity of nicotine in quantities absorbed from smoking and other metho 

of tobacco use is very low and probably does not represent an importa 

health hazard. 

The significant beneficial effects of smoking occur primarily in the ar 

of mental health, and the habit originates in a search for contentment. Sin 

no means of measuring the quantity of these benefits is apparent, the Co1 

mittee finds no basis for a judgment which would weigh benefits agair 

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 table:! 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 AND ToBAcco 

SMOKE 

Condensates of tobacco smoke are carcinogenic when tested by application 

to the skin of mice and rabbits and by subcutaneous injection in rats (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 substam;:es, 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 carcinogenic 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,i) 

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 
contain various polycyclic aromatic hydrocarbons proven to be carcinog1 

in many species of animals. Some of these hydrocarbons are also pre! 

in tobacco smoke. It is reasonable to assume that these can be carcinogt 

for man also (Chapter 9, pp. 146-148). 

Genetic factors play a significant role in the development of pulmon 

adenomas in mice. It is possible that genetic factors can influence the srr 

ing habit and the response in man to carcinogens in smoke. However, tt 

is no evidence that they have played an appreciable role in the great incH 

of lung cancer in man since the beginning of this century (Chapter 9, p. 19 

Components of the gas phase of cigarette smoke have been shown to J 

duce various undesirable effects on test animals or organs. One of th 

effects is suppression of ciliary transport activity, an important cleans 

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 

social drives, reinforced and perpetuated by the pharmacological acti 

of nicotine on the central nervous system. Nicotine-free tobacco or ot 

plant materials do not satisfy the needs of those who acquire the toba, 

habit (Chapter 13, p. 354) . 

The tobacco habit should he characterized as an habituation rather t1 

an addiction. Discontinuation of smoking, although possessing the diffi< 

ties attendant upon extinction of any conditioned reflex, is accomplished l 

by reinforcing factors which interrupt the psychogenic drives. Nicol 

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 tracl 

and bronchi of cigarette smokers, with or without lung cancer, than of n 

smokers and of patients without lung cancer. These epithelial changes 

(a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance of atypi 

cells with irregular hyperchromatic nuclei. The degree of each of 

epithelial changes in general increases with the number of cigarettes smok 

Extensive atypical changes have been seen most frequently in men who smol 

two or more packs of cigarettes a day. 

"'omen cigarette smokers, in general, have the same epithelial changes 

men smokers. However, at given levels of cigarette use, women appear 

show fewer atypical cells than do men. Older men smokers have more atypi 

cells than younger men smokers. Men who smoke either pipes or cig 

have more epithelial changes than non-smokers, but have fewer changes tl 

cigarette smokers consuming approximately the same amount of tobac 

Male ex-cigarette smokers have less hyperplasia and fewer atypical c1 

than current cigarette smokers. 

It may be concluded, on the basis of human and experimental eviden 

that some of the advanced epithelial hyperplastic lesions with many atypi 

34 
cells, as seen in the bronchi of cigarette smokers, are probably premalignant 

(Chapter9,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) have also shown a definite increase, although 

to a much lesser degree. The histological typing of lung cancer is reliable, 

but the use of the ratio of histological types as an index of the magnitude of 

increase in lung cancer is of limited value I Chapter 9, pp. 173-175). 

Functional and Pathological Changes.-Cigarette smoke produces signif. 

icant funtional alterations in the trachea, bronchus, and lung. Like several 

other agents, cigarette smoke can reduce or abolish ciliary motility in experi· 

mental animals. Postmortem examination of bronchi from smokers shows 

a decrease in the number of ciliated cells, shortening of the remaining cilia, 

and changes in goblet cells and mucous glands. The implication of these 

morphological observations is that functional impairment would result. 

In animal experiments, cigarette smoke appears to affect the physical 

rharacteristics of the lung-lining layer and to impair alveolar I 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 

<moke, 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 

;moke produces significant functional alterations in the upper and lower 

1irways 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 

rt 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 

han that for non-smokers. The death rates increase with the amount smoked. 

cor groups of men smoking less than 10, 10-19, 20-39, and 40 cigarettes 

tnd over per day, respectively, the death rates are about 40 percent, 70 per-
cent, 90 percent, and 120 percent higher than for non-smokers. The rati, 

the death rates of smokers to non-smokers is highest at the earlier ages ( 

50) represented in these studies, and declines with increasing age. The s. 

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 mort< 

ratio of cigarette smokers to non-smokers was substantially higher for 1 

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 n 

tality ratio for a given amount of smokin!! was greater for inhalers than 

non-inhalers. Cigarette smokers who had stopped smoking prior to en 

ment in the study had mortality ratios about 1.4 as against L7 for cur 

cigarette smokers. The mortality ratio of ex-cigarette smokers incre1 

with the number of years of smoking and was higher for those who sto:p 

after age 55 than for those who stopped at an earlier age (Chapter 8, p. ~ 

The biases from non-response and from errors of measurement that 

difficult to avoid in mass studies may have resulted in some over-estima 

of the true mortality ratios for the complete populations. In our judgm 

however, such biases can account for only a part of the elevation in mort< 

ratios found for cigarette smokers (Chapter 8, p. 96). 

Death rates of cigar smokers are about the same as those of non-smol 

for men smoking less than five cigars daily. For men smoking five or n 

cigars daily, death rates were slightly higher ( 9 percent to 27 percent) 1 

for non-smokers in the four studies that gave this information. There iss, 

indication that this higher death rate occurs primarily in men who have l 

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 

all higher than for non-smokers, even with men smoking 10 or more pip< 

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 I 

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 Death.-ln the combined results from the s« 

prospective studies, the mortality ratio of cigarette smokers was particul 

high for a number of diseases. There is a further group of diseases, inclw 

some of the most important chronic diseases, for which the mortality r 

for cigarette smokers lay between 1.2 and 2.0. The explanation of 

moderate elevations in mortality ratios in this large group of causes ~s 

clear. Part may be due to the sources of bias previously mentioned o 

some constitutional and genetic difference between cigarette smokers 

non-smokers. There is also the possibility that cigarette smoking has s 

general debilitating effect, although no medical evidence that clearly supp 

this hypothesis can be dted (Chapter 8, p. 105) . 

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

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

cancer uniformly in second place (Chapter 8, p. 108). 

36 
For cigar and pipe smokers combined, there was a suggestion of high 

mortality ratios for cancers of the mouth, esophagus, larynx and lung, and 

for stomach and duodenal ulcers. These ratios are, however, based on small 

numbers of deaths (Chapter 8, p. 107). 

CANCER BY SITE 

Lung Cancer 

Cigarette smoking is causally related to lung cancer in men; the 

magnitude of the effect of cigarette smoking far outweighs all other 

factors. The data for women, though less extensive, point in the 

same direction. 

The risk of developing lung cancer increases with duration of 

smoking and the number of cigarettes smoked per day, and is 

diminished 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, but much less than for cigarette 

smokers. The data are insufficient to warrant a conclusion for 

each group individually (Chapter 9, p. 196). 

Oral Cancer 

The causal relationship of the smoking of pipes to the develop· 

ment of cancer of the lip appears to 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 (Chapter9, 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 . 

stomach cancer (Chapter 9, p. 229). 

NoN-NEoPLASTIC REsPIRATORY DisEASES, PARTICULARLY CHRO 

BRoNCHITIS AND PuLMONARY EMPHYSEMA 

Cigarette smoking is the most important of the causes of chr< 

bronchitis in the United States, and increases the risk of dying fr 

chronic bronchitis. 

A relationship exists between pulmonary emphysema and 

arette smoking hut it has not been established that the relatiom 

is causal. The smoking of cigarettes is associated with an increll 

risk of dying from pulmonary emphysema. 

For the bulk of the population of the United States, the imJ 

lance of cigarette smoking as a cause of chronic hronchopulmoJJ 

disease is much greater than that of atmospheric pollution 

occupational exposures. 

Cough, sputum production, or the two combined are consiste1 

more frequent among cigarette smokers than among non-smok 

Cigarette smoking is associated with a reduction in ventilat 

function. Among males, cigarette smokers have a greater pr• 

Ience of breathlessness than non-smokers. 

Cigarette smoking does not appear to cause asthma. 

Although death certification shows that cigarette smokers IJ 

a moderately increased risk of death from influenza and pneumo 

an association of cigarette smoking and infectious diseases is 

otherwise substantiated (Chapter 10, p. 302). 

CARDIOVASCULAR DISEASE 

Smoking and nicotine administration cause acute cardiovascular ef 

similar to those induced by stimulation of the autonomic nervous sys 

but these effects do not account well for the observed association bet' 

cigarette smoking and coronary disease. It is established that male ciga 

smokers have a higher death rate from coronary disease than non-smo 

males. The association of smoking with other cardiovascular disorde 

less well established. If cigarette smoking actually caused the higher d 

rate from coronary disease, it would on this account he responsible 

many deaths of middle-aged and elderly males in the United States. 0 

factors such as high blood pressure, high serum cholesterol, and exce~ 

obesity are also known to be associated with an unusually high death 

from coronary disease. The causative role of these factors in coro 

disease, though not proven, is suspected strongly enough to be a m 

reason for taking countermeasures against them. It is also more prude 

assume that the established association between cigarette smoking and 4 

38 
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 or· 

ganic lesion) has been related to pipe and cigar smoking by clini· 

cal impressions. The association has not been substantiated by 

epidemiological or experimental studies (Chapter 12, p. 342). 

Cirrhosis of the Liver 

Increased mortality of smokers from cirrhosis of the liver has 

been shown in the prospective studies. The data are not sufficient 

to support a direct or causal association (Chapter 12, p. 342). 

Maternal Smoking and 1nfant 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 morpholog· 

•cal differences between smokers and non-smokers, hut is too 

lneager 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 sLdies 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-smoker" to consider it an "essential" aspect of smoking. 

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 existence of predisposing constitutional or 

hereditary factors (Chapter 14, p. 3 77). 

40 
PART II 

Evidence of the 

Relation Between Srnoking 

and Health 
=:hapter 5 

Consumption of 

Tobacco Products in 

the United States 
List of Tables 

Page 

TABLE l. Tobacco products: Consumption per capita, 15 years 

and over, United States, 1900-1962 . . . . . . . 45 

TABLE 2. Filter tip cigarettes: estimated output and percentage 

distribution . . . . . . . . . . . . . . . . . . 46 

44 
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 Cnited States, including overseas members of the Armed 

Forces, who consume tobacco on a regular basis is close to 70 million ( l). 

Consumption of tobacco products per capita, IS 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.'J8. Per capita cigar consumption remained steady at slightlv over 100 in the first two decades of the century, 

but 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 during 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 

Yt'ar .\11 tobacco, Cigarettes, 

pounds nun1ber Cigars, \Pipe tobacco, 

numher I pounds 

Chewing 

tobacco, Snuff, pounds pounds 

-------------[-----[-------- ------[----------- liKX)- 7. 42 ~~~ i 

Ill 1.63 4. 10 0. 32 1910 ------------- 8. 59 113 2. 58 3. 99 .50 1920 8. 6li 611 117 1.96 3. 06 .50 1930 . s. 88 I, 365 72 L87 LOO . 46 1940 .. 8. 91 I, 828 56 2. 05 LOO -38 19.'iL 

1159 I 3, 322 50 -94 -78 -36 11100 -------------- 10.97 3,888 57 .59 -51 .29 19m ------------ 11. 15 3, 986 56 _59 I -51 .27 1962 ------------ 10.85 3, 958 55 561 .50 .26 

Source: Department of Agriculture, Economic Rrs('arch St>rvice. 

Starting in 1950, 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. In 1956 the figure had reached 

2i.6 percent. 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 1962 ( 31 (Table 2). 

45 
TABLE 2.-Estimated output of filter-tip cigarettes and percentage of total 

cigarette production, United States, 1950-1962 

Year 

1950 _________________ _ 1951. ________________ _ 

1952 _________________ _ 

1953.----------------- 1954 _________________ _ 

1955 _________________ _ 

19.06 __________________ 1 

Filter-tip 

cigarettes 

(billions) 

2. 2 3.0 

5. 6 12.4 

36.9 

77.0 

116.9 

Percent of 

total 

0. 6 0. 7 

1.3 

2. 9 

9.2 

18.7 

27.6 

Year 

1957 _________________ _ 

1958' ----------------- 1959 __ ---------------- 1960 _________________ _ 196L ________________ _ 1962 _________________ _ 

Filter-tip 

cigarettes 

(billions) 

168.3 

213.0 

238.8 

258.0 

277.1 

292.5 

•Data from 1958 through 1962 are official estimates from Censu.<? of .•. \I.anufacfurer.~. 

Source: U.S. Department of Agriculture, Economic Research Service. 

REFERENCES 

Percent of 

total 

38.0 

45.3 

48.7 

50.9 

52.5 

54.6 

1. 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 

714-422 0-64-5 

Chemical and Physical 

Characteristics of Tobacco 

and Tobacco Smoke 
Contents 

CHEMISTRY OF TOBACCO . . . 

COMPOSITION OF CIGARETTE SMOKE . 

COMPOUNDS OF THE PARTICULATE PHASE OTHER 

THAK 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 .. 

CARCINOGEI\"IC HYDROCARBOKS AKD HETEROCYCLICS IN TOBACCO SYIOKE . . . . . . . . . . 

COCARCINOGENS . . . . . . . . . . 

Page 

49 

50 

51 

Sl 

Sl 

.)2 

52 

"? 

::~_ 

S3 

5~ 

51 

5~ 

55 

55 

55 

58 

MECHAI\"ISM OF THE FORMATIO-" OF CARCI~OGE~S. 59 

THE GAS PHASE . . . . . . . . . . 60 

EFFECTS 0~ CILIARY ACTIVITY . 61 

PESTICIDES A~D ADDITIVES 61 

SUMMARY. . . 62 

REFERENCES . . 63 

List of Tables 

TABLE I. Major classes of compounds in the particulate phase 

of cigarette smoke . . . . . . . . . . . . . . 51 

TABLE 2. Carcinogenic polycyclic compounds isolated from 

cigarette smoke . . . . . . . . . . . . . 56 

TABLE 3. Polycyclic hydrocarbons isolated from tobacco 

smoke . . . . . . . . . . . . . 58 

TABLE 4. Some gases found in cigarette smoke . . . 60 

48 
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 Nicotiana tabacum is now the chief source 

of smoking tobacco and is the only species cultivated in the Lnited 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. :\1any 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, 

myosmine, and anabasine. These nitrogen-containing substances are all 

Nicotine Nornicotine Myosmine Anabasine 

basic and hence extractable with acid. Seven members of a second group 

of compounds fairly distinctive to tobacco have been isolated and characterized (l962-63)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: 

H,c 

HaC......_ /CHa 

c 

Isoprenoid tobacco 

CH3 

OH 

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 C, and methyl groups at C., Ca, and C12 (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 is a 

concentrated aerosol with millions or billions of particles per cubic centimeter 

\ 25, 30). The median size of the particles is about 0.5 micron (l ) . 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. The large quantities of material required for 

investigation of the chemical components are prepared on smoking machines 

{ 25) in which large numbers of cigarettes are smoked simultaneously in a 

fashion designed to simulate average smoking habits, and a yellow-brown 

condensate known as tobacco tar is collected in traps cooled to the temperature 

of dry ice ( -70° C.) or liquid nitrogen ( -196° C.). The tar thus contains 

all of the particulate phase of smoke as well as condensable components of the 

gas phase. The amount of tar from the smoke of one cigarette is between 

3 and 40 mg., the quantity varying according to the burning and condensing 

conditions, the length of the cigarette, the use of a filter, porosity of paper, 

content of tobacco, weight and kind of tobacco. 

An important factor determining the composition of cigarette smoke is the 

temperature in the burning zone. While air is being drawn through the 

cigarette the temperature of the burning zone reaches approximately 884° C. 

and when the cigarette is burning without air being drawn through it the 

temperature is approximately 835 ° C. ( 42). The smoke generated during 

puffing, when air is being drawn through the cigarette, is called main-stream 

smoke; that generated when the cigarette is burning at rest is called side-

!>tream smoke. At the temperatures cited extensive pyrolytic reactions occur. 

Some of the many constituents of tobacco are stable enough to distil unchanged, but many others suffer extensive reactions involving oxidation, 

dehydrogenation, cracking, rearrangement, and condensation. The large 

number and variety of compounds in tobacco smoke tar is reminiscent of the 

composition of the tar formed on carbonization of coal, which in many cases 

is conducted at temperatures lower than those of a burning cigarette. It is 

thus not surprising that some 500 different compounds have been identified 

in either the particulate phase of cigarette smoke or in the gas phase. 

In one study (50) regular cigarettes ( 70 mm. long, about 1 g. each) without filter tips produced 17-W mg. of tar per cigarette. In another investigation ( 4-3) 17 4-,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 

70-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 was 

condensed in a series of three glass traps cooled in liquid air. The condensate 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 I or a fluorescence spectrum in good agreement over the entire range 

with that of an authentic sample and include one or more of the following: 

Rf value observed in a paper chromatogram I-H) ; order of elution from 

alumina; mass spectrometry. 

COMPOUNDS OF THE PARTICULATE PHASE 

OTHER THAN HIGHER POL YCYCLICS 

This brief summary is based largely on the comprehensive review by 

Johnstone and Plimmer of the Medical Research Council at Exeter l;nilrrsity, England (241. It should be noted that water constitutes 27 percent 

,f the particulate phase. The major groups of compounds included are 

-ho11 n in Table l. 

ALIPHATIC AND ALICYCLIC HYDROCARBONS 

-\!most all of the possible hydrocarbons, C, through C,, saturated and 

un,;aturated, straight-chain and branched-chain, have been reported to be 

pre,.en, in tobacco smoke. Intermediate, normally liquid paraffins are present. All the C26 through C,3 n-alkanes have been identified, as well as the 

C, and C2 u-C:, 3 isoparaffins. 

T IBLE l.-Major classes of compounds in the particulate phase of cigarette 

smoke 

I Percent in CJas.< particu1'"''"~ 

X umber of compounds Toxic action on lung 

TERPENES AND IsoPRENOID HYDROCARBONS 

·~ ls~pren~, the basic unit of the terpenes and of higher terpenoids has been 

· t>ntdied 111 cigarette smoke ( 34) as have its dimers, dipentene and 1,8-prnenthadiene. The triterpene squalene, consisting of six isoprene units 

~~~ shown to be present in smoke ( 4 7) is of interest because of the possi1 11Y of its being cyclized to polycyclic compounds and because of its ready 

51 
HaC 

CHa 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 (cancer-causing), at least under certain conditions 

of administration I 12). Phvtadienes, products of the dehydration of the 

diterpene alcohol phvtol, are also present in smoke and subject to air oxidation to hydroperoxides. 

CH, CHa CH, CHa 

CH,OH 

HaC 

Phytol 

ALcOHOLs AND 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 lO lbs. of flue-cured aged tobacco 

(0.44 percent). Grossman et a! ( 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. 

'\fany 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, ,8-sitosterol, and y-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 polycyclic 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 
HaC 

HaC 

HaC 

HaC 

CHa 

~ 

Isoprene 

CHa 

Solanesol 

+ 

Dipentene 

(major product) 

CHa 

HaC;O 

HaC 

HaC ~ 

CHa 

HaC;O 

HaC I 

HaC 

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 

Dipalmityl ketone 

A ems 

16' 

CHa 

A large number of volatile and nonvolatile acids of low molecular weight 

are present in tobacco smoke. Fatty acids of chain length cl3 to CB are 

reported to constitute l 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 PoL YPHENOLs 

Since the phenols and polyphenols present in tobacco leaf play an im. 

portant role in the curing and smoking quality of tobacco, a great deal of 

investigative work has been done on the estimation, separation, and identifi. 

cation of complex tobacco phenols such as rutin and chlorogenic acid. The 

presence of simple phenols in tobacco smoke was established as early as 

1871. The phenol content of smoke became of increasing importance with 

HO 

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 addition 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 

polycyclic heterocyclic compounds have also been identified in smoke (45) 

and will be discussed later since the three polycyclic compounds are carcinogenic. A pentacyclic compound related to xanthene, namely 1,8,9-perinaphthoxanthene, has been identified in smoke ( 45). 

1,8, 9-Perinaphthoxanthene 

AMINO Acms 

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 1,_g. of metallic constituents, which are mainly potassium (90 

percent 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.--1- 1'-g. in 

the smoke of one cigarette. The inorganic compounds are most likely 

chlorides, but metals themselves may be present. 

Apparently berdlium is present in tobacco in trace quantities, but is not 

'olatilized in the smoking process I 43 I. Nickel is present in cigarettes in 

trace amounts and may occur in main-stream smoke to a small extent, 

probably a,; the chloride I 311. Spectrographic analysis has shown the 

presence of chromium in smokr at a le\el of lPss than 0.06 ,ttg. per cigarette. 

This level appears too low to represent a hazard ( 48). 

NoNCARCINOGENic AROMATIC HYDROCARBONS 

The aromatic hydrocarbons present in tobacco smoke have received 

an enormous amount of attention since some of them are carcinogenic. 

l\Joncarcinogenic hYdrocarbons of smoke containing one to three rings 

include benzene. toluene and other alkylbenzenes, acenaphthene, acenaphthylene. fluorrne. anthracene. and phenanthrene. Hydrocarbons of established carcinogenicity to mice all contain from four to six condensed rings. 

However, no less than 27 hydrocarbons containing four or more condensed 

rings which have been tested for carcinogenicity with negative results have 

been isolated from tobacco smoke tar. As methods of separation and 

identification improve, it is almost certain that additional hydrocarbons will 

he 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 a!. in seeking to identify the active substance 

m 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 I. The hydrocarbon was recognized as different from the carcinogen of coal tar because its fluorescent spectrum did not match the characteristic three-banded spectrum of the tars. In 1933 Cook and co-workers ( 11) 

isolated the coal tar constituent respomihle for the characteristic fluorescence 

and identified it as benzo \a) pyrene. lt is one of the most potent of all 

the carcinogens now known. 

55 
TABLE 2.--Carcinogenic Polycyclic Compounds Isolated From Cigarette 

Smoke 

Compound Structure 

1. Benzo(a)pyrene 

2. Dibenzo(a,i)pyrene 

3. Dibenzo(a,h)anthracene 

4. Benzo(c)phenanthrene 

5. Dibenz(a,j)acridine 

6. Dibenz(a,h)acridine 

7. 7H-Dibenzo(c,g)carbazole 

56 

Carcino- Amount reported 

genicity l'g/ 1000 cigarette:, 

++++ 

++++ 

++ 

+ 

+ 

+ 

+ 

16 

(ave. of 10 reports) 

O.o2-10 

(2 reports) 

4 

(1 report) 

not stated 

2.7 

(1 report) 

0.1 

(1 report) 

0.7 

(1 report) 
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 1 and its supplement) prepared by J. L. Hartwell (16) of the 

i\ational 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 1 + + + + ) , potent ( + + +) , moderately carcinogenic ( + + ) , or weakly carcinogenic ( + ) (31). l\lany other such compounds studied are reported in the Hartwell survey and in another by Arthur 

D. Little, Inc. (31). The rating assigned to dibenzo(a,i) 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 

<;arcinogenicity are: benzo (j) fluoranthene and dibenzo ( a,1) pyrene. 

Identification of benzo (a) pyrene is reported in 19 separate investigations; the amount given in the table per 1000 cigarettes ( 70 mm. long, 

weighing about LO g. each) is the average of 10 values selected on the 

basis of the quality of criteria used for identification ( 31). Compounds 

I, 2, 3, 4, and benzo U) 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. Wynder and Hoffman (50) investigated this 

point by adding a known amount of radioactive ("-labelled 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 35-40 percent of carcinogen during processing. The amount of benzo(a)pyrene given in Table 2 thus should be 

multiplied by a factor of 1.5 to give the estimated true amount. Probably 

the amounts of 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 

[,.~. P<'T 1000 ~- or tobacco consumed] 

--------------------------------,-------,------,-----_ 

II ydrorar bon Ci~arettrs Ci~ars I Pipes 

-----~------------~-------------l~--------1-------'~------_ 

Benzo(a.)[)yrPne ____________________ --------------------

Acenaphthylen!' ............... _ ...................... _ .... __ 

~~~~~~~:::::::::::::::::::::::::::::::::::::::::::::::::::1 

COCARCINOGENS 

9 

.';() 

109 

125 i 

I 

~4 

16 

119 

176 

8.1 

2111 1,100 

75.1 

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 potentiating action of croton oil is due to the presence of fatty acids and 

their esters. A further observation of possible importance is that some poly· 

cyclic hydrocarbons, though very weak or inactive as carcinogens, are capable 

of initiating malignant growth under the influence of a promoter. Thus 

henz (a) anthracene, identified in cigarette smoke, is very weak or inactive in 

initiating malignant growth by itself, but initiates carcinogenesis under the 

influence of croton oil as promoter (15). 

If more were known about the possible cocarcinogenicity of the many 

inactive components of tobacco smoke, some of the apparent discrepancy 

between isolation and bioassay data might disappear. It is possible that some 

of the carcinogenicity of smoke is due to hydroperoxides formed from un· 

saturated 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 dibenzo ( a,i) pyrene per 1000 

cigarettes (Table 2) is 0.021-'!L and another is lO,ug. 

However. it is not necessarv 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 bioassays suggest that cigarette smoke 

probably contains components which, acting in a manner as yet undescribed, 

are involved in the induction of tumors in mice. 

Assessment of all conceivable synergistic effects presents a gigantic problem 

for exploration. Tobacco smoke contains considerable amounts of phenols 

and fatty acids, both of which, as previously mentioned, enhance the activity 

of known carcinogens. Cellulose acetate filters now in use remove 70--80 

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 ( 44) reports formation of 

benzo (a) pyrene and pyrene on pyrolysis of stigmasterol, a smoke comCHa 

HO 

Stigmasterol Benzo(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 nontohacco cigarettes made from vegetable fibers and 

spinach resulted in formation of benzo (a) pyrene (50). 

Hurd and co-workers (22) by careful experimentation have elaborated 

plausible mechanisms for the formation of polycyclic aromatics by pyrolysis 

of materials of low molecular weight at temperatures in the range 800--900° C. 

Postulated radical intermediates are: 

- . (a) CHz=C=CH - CH2-C=CH 

(b) CH-CH=CH - CH=CH-CH 

- - (c) CH=CH-CH=CH 

These radicals can arise from propylene, toluene, picoline, or pyridine. A 

var~ety of polycyclic hydrocarbons can be generated by reaction of these 

radu:als with themselves or with other small radicals present in the heating 

zone. For example, dimerization of (b) should give benzene. 

59 
It thus appears that the pyrolysis of many organic materials can lead to 

the formation of components carcinogenic to mice. Cigarette paper con. 

sists essentially of cellulose. Pyrolysis of cellulose has been shown to produce 

benzo (a) pyrene. The observation 12) 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 GAS PHASE 

The gas phase accounts for 60 percent of total cigarette smoke. Hobbs 

et al. 134, 35 '1 found that 98.9 mole percent of the gas phase is made up of 

the following seven components: 

\'itrogen ____________________________ _ 

Oxygen _____________________________ _ 

Carbon-dioxide ______________________ _ 

Carbon-monoxide ____________________ _ 

Hydrogen ___________________________ _ 

Argon ______________________________ _ 

~ethane ____________________________ _ 

73 mole percent 

10 

9.5 

4.2 

I. 

0.6 

0.6 

98.9 

The approximately one percent of the gas phase not accounted for by the 

seven major constituents contains numerous .compounds, no less than 43 

of which have been identified as present in trace amounts. Some of these 

are listed in Table 4 (I). 

TABLE 4.-Some gases found in cigarette smoke 

1 I Concentra- I Safe lew! for : 1 Compound i tion industrial I Toxic action on lung 

------1----l rxposur=-:._, _____________ _ 

I (ppm) ! (ppm) 

g~~~~~ ~;~'~f,i,~dl'. _ _ _ ::::: 1 ~~::~ 1_ 100 

?\of ethane, t>th:.:uw, propa1w, hut ant', etc_ S7, 000 ! ,!)()() 

AcPtyiPn<', PI il;-lt•rw, propyll'ne, etc_... :n, IXJO .\, 000 

Formal<lrhv•h• 30 .\ 

Acetaldt>hv'd•• _ 3, 200 200 Acro!Pin _ _-_ _ 100 o. 5 

~fetilanol 700 ·. Aceton!' I, 100 ! 

Methylt•thyl ketont• 500 I 

Ammoo~ - Xitrogpn llio\idt·------- 200 

2110 

250 

!Oil 

5 

I 

Unknown _ '-'one 

X one 

::'\ont\ 

Irritant 

Irritant 

Irritant 

Irritant 

Irritant 

Irritant 

Irritant 

~ll'thyl :\itritt•_______ 200 ······--------

Irritant 

t:'nknov.·n HydrogPTl SJllfidt> 40 rrritant Hyt.!rogPn C'yanidt•-- 1.600 Methyl C'illoridt• _____________ I, 200 

20 

10 

100 

Rpspiratory enzyme poison t:'nknown 

*The Yalues listed refl'r to time--weighted a\·eragp concentrations for a normal work day. 

60 
EFFECTS ON CILIARY ACTIVITY* 

An important line of investigation was opened up by the report by Hildin~ 

( 18) that cigarette smoke is capable of inhibiting the transport activity of 

ciliated cells such as found in the respiratory tract. It has been suggested 

i 10. 11) that failure of ciliary function to provide a constantly moving 

stream of mucus enables environmental carcinogens to reach the epithelial 

cells. Kensler and Battista 128) describe development of a method of 

bioassay for inhibition of ciliary transport activity involving exposure of 

the trachea of a rabbit to the test material. The smoke from a regular 

cigarette was found to inhibit transport activity by 50 percent after exposure 

to two or three puffs. Several commercial filter cigarettes gave essentially 

the same result. The fact that these filters lower the phenol content by 

70 to 80 percent and trap about 40 percent of the particulate phase suggested 

that neither phenolic nor particulate materials are responsible for the 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 following 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 to· 

hacco 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"03 per million, with an average value 

of 13.9 ppm. ( 6). Cogbill and Hobbs ( 8) found that main-stream smoke 

of cigarettes containing 7.1 11-g. of arsenic per cigarette contains 0.031 pg. per 

puff. This amount would be equivalent to 0.25 p.g. of arsenic per cigarette 

( 8 puffs), and hence a smoker consuming 2.5 packs of such cigarettes per 

day might inhale 12.5 11-g. 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 f-!g. of arsenic per 10 cubic meters, which is an approxi· 

mate daily intake per person ( 38). 

Extensive Federal efforts to discourage the use of arsenicals for the control 

of tobacco hornworms on the growing tobacco crop resulted in a sharp de-

•This topic i!\ discussed more ful]y in Chapter 10. 

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 

As20a (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, endrin, 

dieldrin, Guthion, aldrin, heptachlor, Diazinon, Dylox, Sevin, and chlordane 

( 42a) . Trace amounts of TDE and endrin have been detected in commercial 

cigarettes and cigarette smoke. Guthion and Sevin residues were detected 

in main-stream cigarette smoke at 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 conlamination 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 hecause 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 established to 

be carcinogenic. They are shown in Table 2. The over-all carcinogenic 

potency of tobacco tar is many times the effect which can be attributed to 

substances isolated from it. The difference may be associated in part with 

the presence in tobacco smoke of cocarcinol!"ens, 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 oqrans, one of which is 

suppression of ciliary transport activity in trachea and bronchi. 

62 
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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 Chern 9(3): 193-7, 1961. 

5. Campbell, J. M., Lindsey, A. J. Polycyclic hydrocarbons in cigar smoke. 

Brit J Cancer ll : 192-5, 195 7. 

6. Carey, F. P., Blodgett. G., Satterlee, H. S. Preparation of samples for 

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7. Clemo, G. R. Some aspects of the chemistry of cigarette smoke. Tetrahedron 3: 168-74, 1958. 

8. Cogbill, E. C., Hobbs, M. E. 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 Chern Soc 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. 

II. Fieser, L. F., Fieser, M. Topics in organic chemistry. New York, 

Reinhold, 1963, p. 43-56. 

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13. Grossman, J. D., Deszyck, E. J., Ikeda, R. M., Bavley, A. A study of 

pyrolysis of solanesol. Chern lndustr 1950-1962. 

14. Guthrie, F. E., McCants, C. B., Small, H. G., Jr. Arsenic content of 

commercial tobacco, 1917-1958. Tobacco Sci 3: 62--4, 1959. 

15. 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. Survey of compounds which have been tested for carcinogenic activity, Federal Security Agency, Public Health Service 

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17. Hilding, A. C. On cigarette smoking, bronchial carcinoma and ciliary 

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714-422 0-64-6 63 
deciliated islands in the respiratory epithelium. Ann Othol 65: 116--

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Hl. Hilding, A. C. On cigarette smoking. bronchial carcinoma and ciliary 

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the deposition of tar in the bronchial tree and removal by ciliary action. 

New Eng J Med 25-!: 1155-60, 1956. 

19. Holsti. P. Tumor promoting effects of some long chain fatty acid!' in 

experimental skin carcinogenesis in the mouse. Acta Path Microbiol 

Scand -!6: 51-8, 1959. 

20. Homburger, F., Tregier, A. Modifying factors in carcinogenesis. Progr 

Exp Tumor Res 1: 311-28, 1960. 

21. Hurd, C. D., Macon, A. R. Pyrolytic formation of arenes. -!.Pyrolysis 

of benzene, toluene and radioactive toluene. J .\mer Chern Soc 84: 

4524-6, 1962. 

22. Hurd, C. D., Macon, A. R., Simon, J. 1., Levetan, R. V. Pyrolytic formation of arenes. l. Survey of general principles and findings. J Amer 

Chern Soc 84: 4509-15, 1962. 

23. Hurd, C. D., Simon, J. I. Pyrolytic formation of arenes. 3. Pyrolysis 

of pyridine, picolines and methylpyrazine. J Amer Chern Soc 84: 

4519-24, 1962. 

24. Johnstone, R. A. W., Plimmer, J. R. The chemical constituents of tobacco and tobacco smoke. Chern Rev 59: 885-936, 1959. 

25. Keith, C. H., Newsome, J. R. Quantitative studies on cigarette smoke. 

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May 29, 1957. 

26. Keith, C. H., Newsome, J. R. Quantitative studies on cigarette smoke. 

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144 (14) : 26-31, Apr 5, 1957. 

27. Kennaway, E., Lindsey, A. J. Some possible exogenous factors in the 

causation of lung cancer. Brit 1\led Bull 14: 124-31, 1958. 

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29. Kosak, A. I., Swinehart, J. S., Taber, D., Van Duuren, B. L. Stigmasterol in cigarette smoke. Science 125: 991-2, 1957. 

~0. Langer, G., Fisher, N. A. Concentration and particle size of cigarettesmoke particles. AM.\ Arch lndustr Health 13: 372-8, 1956. 

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64 
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65 
Chapter 7 

Pharmacology and 

Toxicology of 

Nicotine 
Contents 

Page 

GENERAL PHARMACOLOGIC ACTION OF NICOTINE ON 

~ERVE CELLS . . . . . . . . . . . . . . . . . 69 

EFFECTS ON THE CENTRAL NERVOUS SYSTEM 69 

CARDIOVASCULAR EFFECTS. . 70 

GASTROINTESTINAL EFFECTS. 71 

DISTRIBUTION Al\"D FATE. 71 

CHRONIC TOXICITY . 73 

SUMMARY . . 74 

REFERENCES. . . . . 75 

Figure 

FIGURE I. Summary diagram of routes for the metabolism 

of nicotine in mammals . . . . . . . . . . . . . . . . . 72 

68 
Chapter 7 

GE\"ERAL PHAR"\1ACOLOGIC ACTION OF NICOTINE ON 

~ERVE CELLS 

The pharmacology and chronic toxicity of nicotine. in dosage comparable 

to the amounts that man may absorb from 5moking or other use of tobacco. 

are pertinent to an evaluation of health hazard. 

The most notable action of nicotine involves a direct effect on sympathetic 

and parasympathetic ganglion cells ( 18 I . This usually occurs as a transient 

excitation, followed by depression, or even paralysis 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 acetylcholine and concomitant reduction 

in the intensity of postganglionic discharge~. Similar effects occur at the 

neuromuscular junction, resulting in a curariform action in skeletal muscle 

with adequate doses 1 16). In the central nervous system, as in ganglia, 

primary stimulation is succeeded bv depre~sion. Furthermore. nicotine like 

acetylcholine discharges epinephrine ft:om the adrenal glands and other 

chromaffin tissue ( 20) ; it also releases antidiuretic hormone from the 

posterior pituitary by stimulating the supraopticohypophyseal system ( 3). 

:\icotine also augments various reflexes by excitation of chemoreceptors in 

the carotid body I 10). 

The pharmacological respon5e 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 excitability 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 suggests 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). Very little of the reported work involves human 
experimentation, and most of it is with doses much larger than are associated 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 animals 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 

ongm. Nausea and emesis are more pronounced in the novice smoker hut 

may occur even in heavy smokers with excessive use of tobacco. Electroencephalographic ( EEG) studies in the intact rabbit ( 21) indicate that nicotine, 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 ( lO to 

20 p.g/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. These effects did not appear to be related to 

fluctuations in blood pressure or to catecholamine or serotonin levels. 

In a study of electrical activity (as measured by 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 l 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 ( l) 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. 

CARDIOVASCULAR EFFECTS 

The cardiovascular effects of nicotine are described in Chapter 11, Cardiovascular Diseases. 

70 
GASTROINTESTINAL EFFECTS 

\1ost but not all experimental and clinical evidence supports the popular 

1 iew that smoking reduces appetite 16, ll p. 2711. This reduction has been 

attributed both to direct effects on gastric secretions and motility and to 

reflexes arising from local effects on the taste buds and mucous membranes 

in the mouth. The unpredictable and temporary elevation of blood sugar 

is probably too small to contribute significantly ( 17, p. 326 I. Nicotine 

effects on the hypothalamus. comparable to the appetite reduction produced 

f,v other stimulants like amphetamine, and psychological mechanisms may 

play significant roles ( 23 I. Hun:rer contractions are inhibited hut :rastric 

movements of digestion do not appear to he influenced sitmifiranth hv 

moderate smoking ( 41 . 

\ausea, often associated with vomiting. is In far the most common 

"mptom related to the gastrointestinal tract. This effect probably ori:rinates centrally in the medullary emetic chemoreceptor trigg-er zone 114 I. 

It is now generally agreed that nicotine stimulates peristalsis but the 

mechanism is a complex one. probabh im olving locaL central and reflex 

actions. Schnedorf and I\)' f 21 I found "ide individual variation in gastro· 

intestinal passage time in medical student smokers and non-smokers but 

gained the impression that smoking tends to augment motility of the colon. 

These effects are probably related to actions on the parasympathetic ganglia 

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 alternatinl! patlt'rns between the two extremes. The only consistency is that s\mptoms 

attributable to nicotine effects on the gastrointestinal tract are very common. 

DISTRIBUTION AND FATE 

\'icotine is actively and rapidly metabolized by man and other mammals, 

tht 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 

terhnics. Nicotine is a rather unstable molecule which in neutral or alka· 

li11e conditions undergoes a variety of changes. A review of the current 

<·oncepts of the known and suggested pathways for the metabolism of 

nicotine is shown in Figure l ( 18 1. The main intermediate appears 

10 _ be 1- )-cotenine which yields y-(3-pyridyll-y-methylamino butyric 

and. Cotenine has low toxicity and lacks the potent pressor activity of 

nicotine. 

Dogs receiving 150 mg/kg/ day orally for 108 days exhibited no weight 

In,~ or other objective signs ( 2). Man has ingested 500 mg orally at 8-hour 

lfl!t>rvals for 6 days without untoward effects. No evidence has been pre-

-ented that the other known metabolites of nicotine carry any significant 

' 1 stemic toxicity. 

71 
SUMMARY DIAGRAM OF ROUTES 

FOR THE METABOLISM OF NICOTINE IN MAMMALS 

(Some hypothetical intermediates are shown in brackets.) 

l) ~-[~H ~~;,, l_) '~~ 'oo11 ]-[~II] l) ~~; ,'oH 

NicoliiH' •Hydroxynicotine• llydruxycotinintJ 

y~(::I·Pyridy I )-y-methylam inobutyric Acid Cotinine Cotinine Mf'thonium Ion 

l.somethylnicutinium Ion •Ketuamide• y-(3-Pyridyl)-y•oxo-hutyric Acid 3-Pyridylacctic Aid 

FIGURE l. 

Sour<'e: McKennis, Herbert H., Jr. (18) 
CHRONIC TOXICITY 

Evaluation of the chronic toxicity of tobacco smoke may be considered 

in several categories: (a) the systemic toxicity of nicotine or its congeners, 

1 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-l\eoplastic 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) _ which is greatly in excess 

of any human smoking exposure. Even though some authors ( ll) observed 

weight loss and degenerative vascular changes in rats under these severe 

conditions, others I 221 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 

I 8, 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 

~igns 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 which 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 •mall amount of snuff is placed in the ,.:roove between the lt>t>th and tht> lower lip 

or beneath the ton11ue and held tht>re from 30 minutes to several hours. 

73 
absorbed I cW-60 mg) from 6 cigars uninhaled equals that from 30 cigarettes inhaled ( 19) . Chewing tobacco may yield 8 to 87 mg in 6 to 8 hours 

12~); in chewinf! snuff, 20-60 mg of nicotine (7). 

The following variables play a role in the amount of nicotine absorbed 

(l7,p.81: 

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: 

l. 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 ( ? ) ; 

ll. Agglomeration of smoke particles (more important in cigarettesmoking). 

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, there are no useful mortality statistics 

in those who chew, 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. The predominant actions are central stimulation 

and/ or tranquilization which vary with the individual, transient hyperpnea, 

74 
peripheral vasoconstriction usually associated with a rise in systolic pressure, 

suppression of appetitite, stimulation of peristalsis and. with larger dos~s. 

nausea of central origin which may be associated with vomiting. 

Nicotine is rapidly metaholized by man and certain other mammals. The 

primary pathway through ( - l·cotenine to y-13-pyridyl) -y-methylaminobutyric acid is described in detaiL The known metabolites have very low 

toxicity. 

The rapidity of degradation to non-toxic metabolites, the resu Its 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 

I. Bickford. R. G. Physiology and drug action: An electroencephalographic analysis. Fed Proc 19: 619-25, 1960. 

2. Borzelleca, ]. F., Bowman. E. F .. McKennis. H .. Sr. Studies on the 

respiratory and cardiovascular effects of I - ) -cotenine. ] Pharmacal Exp Ther 137: 3] 3, 1962. 

3. Burn. ]. H., Truelove, L. H., Burn. I. The antidiuretic action of nicotine and of smoking. Brit Med ] l: 403-6. 1945. 

't. 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.]. 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. 

rQueries and minor notes] JAMA ll9: 534, 1942. 

1. Gaede. D. Sur wirkung des schnupftabaks. Naunyn Schmiedeberg 

Archiv Exp Path, 130-45, 1944. 

3. Haag, H. B., Weatherby, J. H., Fordham, D., Larson, P. S. The effect 

on rats of daily-life span exposure to cigarette smoke. Fed Proc 5: 

181, 1946. 

9. Hauser, H., Schwarz, B. E., Roth, G .. Bickford, R. G. Electroencephalographic changes related to smoking. Electroenceph Clin 1'\europhysiol 10: 576, 1958. 

10. Heymans, C .. Bouchaert. ]. ]., Dautrebande, L. Sinus carotidien et 

reflexes respiratories. 3. Sensibilite des sinus carotidiens aux substances chimiques. Action stimulante respiratorie reflexe du sulfure 

de sodium, du cyanure de potassium, de Ia nicotine et de Ia labeline. 

Arch lnt Pharmacodyn 40: 54--91, 1931. 

II. 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 ~ystem. Int J Neuropharmacol 1: 333-51, 1962. 

n. Kuchle. H. J .. Loeser, A., Meyer, G., Schmidt, C. G., Strurmer, E. Ta. 

hakrauch. Ein beitrag zur wirkung von tabakfeuchthaltemittein. Z 

Ges Exp Med 118: 554--72, 1952. 

l L Laffan. R. J ., Borison, H. L. Emetic action of nicotine and lobeline. 

J Pharmacal Exp Ther 121: 468-76, 1957. 

15. Lambiase. M .. Serra, C. Furno e sistema nervoso. l. Modificazioni 

dell'attivita elettrica corticale da fumo. Acta Neurol (Napoli) 12: 

175-IJ.), 1957. 

16. Langley, 1. 1\'. 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 Advisorv 

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. .\ccion de Ia nicotina sobre Ia secreciiin 

de adrenalina y nos adrenalina de la sangre venosa suprarrenal del 

perro. Rev Soc Argent Bioi 28: 219-24, 1952. 

21. Schnedorf, ). G., Ivy, A. C. The effect of tobacco smoking on the alimentary 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. 

2:{. 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 85 

Mortality Ratios by Amount Smoked . 85 

Mortality Ratios at Different Ages 87 

Age at Which Smoking was Started . . 89 

Mortality Ratios by Duration of Smoking 90 

Inhalation of Smoke . . . . 91 

Ex-Cigarette Smokers . . . . . . . . 92 

Ex-Cigar and Pipe Smokers. . . . . . 94 

EVALUATION OF SOURCES OF 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 . . . 108 

Cigarette Smokers . 108 

Cigar Smokers 112 

Pipe Smokers . . . 112 

~Iortality 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 

FIGURE l. Death rates (logarithmic scale) plotted against age 

for current cigarette smokers and non-smokers, U.S. veterans 

Page 

study . . . . . . . . . . . . . . . . . . . . . . . 88 

TABLE 1. 

TABLE 2. 

TABLE 3. 

TABLE 4. 

TABLE 5. 

TABLE 6. 

TA.BLE 7. 

TABLE 8. 

TABLE 9. 

TABLE 10. 

TABLE ll. 

TABLE 12. 

TABLE 13. 

TABLE 14. 

TABLE 15. 

TABLE 16. 

TABLE 17. 

TABLE 18. 

List of Tables 

Outline of prospective studies of smoking and mortality. 

Mortality ratios of current smokers by type of 

smoking .................. . 

Mortality ratios for current smokers of cigarettes only, 

by amount smoked . . . . . . . . . . . . . . 

Mortality ratios for current smokers of cigars only, by 

amount smoked . . . . . . . . . . . . . . . . 

Mortality ratios for current smokers of pipes only, by 

amount smoked . . . . . . . . . . . . . . . . 

Mortality ratios by age group for current smokers of 

cigarettes only, men in 25 States . . . . . . . . . 

Increase in natural logarithm of death rate per l ,000 

man-years for each 5-year increase in age, 6 prospective studies . . . . . . . . . . . . . . . . . . 

Mortality ratios by age at which smoking was started 

and by amount smoked for current smokers of 

cigarettes only . . . . . . . . . . . . . . . . . 

Mortality ratios for current smokers by type of smoking 

and by length of time smoked . . . . . . . . . . 

Mortality ratios for smokers of cigarettes only by 

inhalation status and amount of smoking . . . . . 

Mortality ratios for ex-smokers and current smokers of 

cigarettes . . . . . . . . . . . . . ·. . . . . . 

Mortality ratios for ex-smokers of cigarettes only by 

number of years since smoking was stopped and by 

amount smoked . . . . . . . . . . . . . . . . 

Mortality ratios for ex-cigarette smokers by number 

of years of smoking, U.S. veterans study ..... 

Mortality ratios for ex-smokers of cigars only and 

pipes only and for current cigar and pipe smokers . 

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 . . . . . . . . . . . . . . . . . . 

Percentages of usable replies in five studies . . . . . 

Mortality ratios for cigarette smokers by populationsize of city . . . . . . . . . . . . . . . . . . 

Age-adjusted death rates per 1,000 (over approximately 

22 months) for variables that may be related to 

mortality .................. . 

714-422 0-64-7 

83 

85 

86 

86 

87 

87 

89 

89 

90 

91 

93 

93 

93 

94 

95 

96 

99 

100 

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 

,;tudies) 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 ....... . 

TABLE 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 . . . . 

TABLE 29. Mortality ratios in respondents and computed values 

for the complete population . . . . . . . . . 

TABLE 30. Proportions and death rates for Berkson's example . . 

80 

Page 

102 

105 

106 

106 

106 

107 

108 

109 

114 

ll5 

ll6 

ll6 
Chapter 8 

PROSPECTIVE STUDIES OF MALE POPeLATIONS 

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, 

Buell and Breslow ( 8) . 

( 6) Pensioners of the Canadian Department of Veterans Affairs, i.e., vet· 

erans of World Wars I and II and the Korean War. Best, Josie 

and Walker, 1961 (2). 

( 7) American men in 25 states, enrolled by volunteer researchers of the 

American Cancer Society, each of whom was asked to enroll about 

10 families containing at least one person over 45. Hammond, 

1963 (ll). 

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) . 

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 enrollment, age range, number of, months followed, total number of deaths, 

and the number of person-years of exposure. The number of subjects 

studied l usable replies) ranged from around 34,000 in the British doctors 

study to 448,000 in the n~w 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 I and the new American Cancer Society study 

1)1) 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 practi~ble 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. 

As regards type of smoking, cigarettes, cigars and pipes appear in all 

seven combinations. Since results for the "mixed" categories are difficult to 

interpret and sometimes involve relatively small numbers of subjects, the 

analysis here concentrates on the following types: 

Cigarettes only 

Cigarettes and other 

Cigars only 

Pipes only 

In some instances the last two categories have been combined when the 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 
co 

w 

Authors 

--· 

Subjects 

Number of usable replies 

Date of enrollment 

Age range 

Months followed 

Number of deaths 

Person-years of exposure 

TABLE I.-Outline of prospective studies of smoking and mortality 

Doll & Hill (5) Hammond & Dorn (6) Dunn, Linden, Dunn, Buell, Best, Josie, Walker Horn (10) Breslow (7) Breslow(~) (2) 

British doctors White men in 9 U.S. veterans California occu- California Ameri· Canadian pensioners States patlonal groups can Legion m£>m- (veterans and de- hers pendcnts) 

34,000 188,000 248,000 67,000 60,000 78,000 

Oct. 1951 Jan.-Mar. 1952 Jan. 1954 and Nov. 1953 and May-Nov. 1957 Sept. 1955-July, 1956 Jan. 1957. May 1957. 

35-75+ li0-{;9 30-75+ 35---<19 35-75+ 35-75+ ----- -· 

120 44 78 About 48 About 24 72 

4,534 11,870 24,519 1,714 1,704 9,070 

269,000 668,000 1,312,000 222,000 119,000 3S:l,OOO 

--- -

Hammond (11) 

Men in 25 States 

448,000 

Oct. 19511-Fcb. 1960. ---

35-89 

About 22 ~---- --·------

11,612 

820,000 

------· 
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 agespecific death rate for non-smokers is multiplied by the number of person. 

years in the group of smokers. This product gives an expected number of 

deaths, which represents the number of deaths of smokers that would be 

expected to occur if the age-specific death rate were the same as for non. 

smokers. These expected numbers of deaths are added over all age classes, 

and their total is compared with the total number of observed deaths in the 

smokers. The mortality ratio is the ratio (total observed deaths in the 

smokers)/ (total expected deaths) . A mortality ratio of l 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 l 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 agedistribution 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. These 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 

84 
should make adjustments so that the different groups of smokers being 

compared are equalized on all other relevant aspects of the practice. This 

can be done at best only partially. Most studies measured only some of the 

variables on which adjustment is desirable. When the data are 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 smokin? 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 

Type of smoking British 

dortors 

Men in 9 States 

Study group 1 

erans veterans States 

U.S. vet- I Canadian I Men in 25 

----------------------i-------l------l------

2l~::::m~~ ~~~-other~~:::::::::::::::::::: 

~~~so~;;::::::::::::::::::::::::::::::::: } 

1.44 

1. 05 

0.95 

1. 70 1. 45 . 

1. 05 1.101 

1.79 1.65 1.83 1.46 1.23 1.54 1.07 1.11 0.97 1. 06 , 1. 10 o. se 

1 The California occupational and Legion studies give mortality ratios of 1.78 and 1.58 respectively, for all cigarette smokers (current and ex-smokers). 

MoRTALITY RATIOs BY AMoUNT 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 

smoked 

Cigarettes per British Men in 9 u.s. California California Canadian Men in 25 day doctors States veterans occupa- LeJ(ion• veterans tionai• I 

Less than 10 ----- 1.06 1.33 1.35 1.44 } '1.30 { 1. 55 1()-20 _____________ 1. 31 1.66 I. i6 1. 79 1.68 21-39 _____________ 31.62 1.93 1.99 2. 2i '1.64 } 40 and OWL. '1.84 { --- • 2. 50 2. 20 2.22 1.83 11,85 

I 

•current and ex-cigarette smokers combined. 1 "Less than 10" is "less than 5" plus "about H"; "1(}-20" is "about I"; "21-39" is "about l~li". 

' Less than I pack. 3 20-34. 

• 35 plus. ' More than I pack. ' About I pack. ' More than I pack. 

States 

1. 45 1.75 

1.90 

2. 20 

TABLE 4.-Mortality ratios for current smokers of cigars only, by amount 

smoked 

Number per day Men in 9 U.S. vet- Canadian Men in 25 Over-all 

States erans veterans States results 

1-4________________________________________ 1.06 0.99 11.12 0.93 1.00 

5 or more .. -------------------------------- l. 20 I. 24 '1.26 1.10 1.20 

I 1-2. 

2 3 or more. 

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 ( lO or more per day) two studies show increases of 15 and 12 percent in death rates, but 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 death>; raises a doubt as to whether the difference from unity could be due to >;arnpling 

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 l4fo!ms. 

of tobacco daily. 

TABLE 5.-Mortality ratios for current smokers of pipes only, by amount 

smoked 

Pipes per day 

:o9or-more::::::::::::::::::::::::::::::::: I 

Men in 9 

States 

1.00 

1.15 

Study 

u.s. 

veterans 

1.03 

1.12' 

Canadian 

veterans 

I. 07 

1.01 

Men in 25 

States 

0. 92 

0. 76 

MoRTALITY RATIOs AT DIFFERENT AcEs 

Over-all 

ratio 

1.01 

I. 05 

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 

00-50 than for men over 70. This effect is illustrated in Table 6 from 

the study of men in ~5 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 the logarithm of the age-specific death rate is plotted against age, 

the resulting points lie reasonably close to a straight line. For the U.S. 

TABLE 6.-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 

4()--49 50--59 6(Hl9 7G--79 ~9 

I. 44 1.40 1.40 1.08 

1.94 \lll !.50 I. 65 

2.05 I. 48 I. 16 

2. 37 1.68 1.28 0. 58 

2.06 I. 70 1.47 I. 22 

E~~ ~~ ~~~~ ~ ~ ~ ~ ~ ~~~~~ ~ ~ ~~~~~ ~~ ~ ~ ~ ~~~~~ ~ ~~~ ~: ~ Allamounts _______________________________ l---2-.33-1-----1----

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, 

"' "' < 

UJ 

>-

z 

< 

~ 

0 

0 

0 

0 

"' UJ 

Q. 

UJ 

I-

< 

"' ::c 

I-

< 

UJ 

0 

88 

DEATH RATE (logarithmic scale) PLOTTED AGAINST AGE, 

PROSPECTIVE STUDY OF MORTALITY IN U.S. VETERANS 

AGE IN YEARS 

FIGURE 1. 
the slope is slightly less steep for the cigarette smokers than for the nonsmokers. This indicates that the mortality ratio is declining with increased 

age. 

Table 7 shows these slopes (increase in the natural logarithm of the death 

rate for each 5-year increase in age) computed from six of the studies. 

The salient features are as follows: ( l) 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.-/ncrease in natural logarithm of death rate per 1,000 man-years 

for each 5-year increase in age, 6 prospectivP studies 

I 

British 

doctors Men in 9 

States U.S. 

veterans California California · :\fen in 25 

Type of smoking ~f~~J.;"; Le~ion ' 1 States ' 

---------------1----1----1----1-----1-----

Non-smokers ---------------- .49\1 .489 .502 I .490 

Cigarettes by amount per day _____ 11 ____ 1 ___ ._4_48_ 1 ___ ._43_6_

1 

___ ._47_6_

1 

____ ._43_8 

. 593 .474 . 492 . 427 

1-9 ------------------------- . 5.16 . 484 . 490 I • 401 10-al._________________________ . 454 . 461 . 551 . 457 

2\-39 __ ----------------------- . 477 . 420 . 467 . 447 

40+-------------------------·- . 401 . 345 

. 567 

. 471 

.449 

~~~~::::::::::::::::::::::::} . 598 { . 466 

. 521 . 483 ------------ ------------ .458 ------------ ------------

1 "Cigarettes" includes .,cigarettes and other" and current and ex·smokers. ' First 10 months' experience. 

AGE AT WHICH SMOKING WAS STARTED 

. 445 

. 441 

. 40\ 

.401 

. 457 

. 458 

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 B.-Mortality ratios by age at which smoking was started and by 

amount smoked for current smokers of cigarettes only 

Age started to smoke 

U.S. veterans: 

Under aJ_ ----------------------------- al--24.---------------------------------

Me%~~~nr~~~,:::::::::::::::::::::::::: 15-!9. 

al--24.:: ::::::::::::::::::::::::::::::: 25 or over __ ·----------------------- ___ _ 

'1().19 cigarettes per day. ' al-39 cigarettes per day. 

Number of cigarettes per day 

1-9 lG-W 21-39 

1.60 1.89 2.16 1.40 1. 72 1. 87 1. 15 1.50 1. 47 

l. 79 1 2.23 '2. 21 1. 75 l 1.83 '2. 01 1. 25 l 1. 52 '1. 62 1.03 1 1.36 ' 1. 45 

40+ 

2. 45 2. 23 1.11 

2.\5 

2. 38 

1. 93 

1.56 

Over-all 

ratio 

1. 98 1. 72 1.39 

2.17 

1. 99 1. :;~ 

J. 34 

89 
For a fixed amount of smoking, the mortality ratios (with one exception) 

exhibit a consistent and rather striking increase as the age at which smoking 

was started decreases. This increase appears in all smoking groups of 

Table 8. For men who started smoking cigarettes under the age of 20 

the over-all death rate was about twice that for non-smokers, whereas fo; 

those who did not start until they were over 25 the death rate was only about 

35 percent higher. 

MoRTALITY RATios BY DuRATION OF SMOKING 

Three studies have some data available on the number of years during 

which the subjects had smoked. The comparison of mortality ratios for 

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.-111 ortality ratios for current smokers by type of smoking and by 

length of time smoked 

:'-!umber of years smoked 

Type of smoking U.S. veterans Canadian veterans Men in 9 States 

<15 I 15-24 25-34 35+ <15 I 15-29 30+ <25 25-34 35+ 

--~---- --1--------1----------

~: ~i : ~- ~ ;: ~ ;: ;; ;: ;; li ;: ~ ;· ~ :::~:~~: :::;:~~: ::::;:;~ Cigarettes only ____ _ 

Ci~arettes and other __________ _ 

1.01! 1.34 0.97 1.07 1.36 0.93 1.09 ------------------------

1 

Cigars only ______ _ Pipesonly _______ _ 

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 ( lO) found no 

trend with duration for men smoking more than a pack a day, but the other 

two studies show an upward trend for this group of smokers. 

For cigar smokers the only groups showing an increase in death rates over 

non-smokers are those smoking for the longest period (Table 9). The in· 

creases of 12 percent for the 35 years or over group in the U.S. study and of 

90 
31 percent for the 30 years or over group in the Canadian study are both 

statistically significant. 

For pipe smokers no trend with duration of smoking is discernible. The 

two figures which stand out ( 1.34 in the U.S. study and 1.36 in the Canadian 

study) are both based on relatively small numbers of deaths. 

INHALATION OF SMOKE 

In two of the studies the suhjects 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 1-9 cigarettes 

daily. With the very heavy smokers (40+) the figures in Table 10 suggest 

that the mortality ratio may remain the same for non-, slight, and moderate 

inh::lers. The ratios of 2.05 (non·) and 1.97 (slight) are, however, based 

on only 26 and 41 deaths, respectively. 

TABLE 10.-Mortality ratios for smokers of cigarettes only by inhalation 

status arui amount of smoking 

Cigarettes per d3y 

Degree or inhalation Over·all 

------------------------I---~-~ ___ 1 ___ ~_~_I9 ______ ~ __ 9 __ 1 ___ w __ + ___ 1 _____ __ 

I 

ratio 

~fen in 25 States: 

'~~:~~:.::••!:!:•:•!:::!!···· 1.29 

1.29 

1.61 

1.88 

1.05 

1.35 

; t-mounts are lifetime maximum amounts smoked. 

1 J-~ cigarettes per day. ver ~ cigarettes per day. 

1.46 

!.tiS 

1.82 

1.76 

'I. 11 

'1. 50 

1.56 

1.84 

1.84 

2. 18 

'1.03 

3 1. 71 

2. 05 

I. 97 

2. 01 

2. 50 

!. 49 

!.tiS 

1.83 

2.W 

1.08 

I. 52 

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 

srnoked. Ipsen and Pfaelzer ( 14) have shown that the logarithms of the 16 

death rates at age 61 (approximately the average age) can be adequately rep· 

91 
resented as an additive function of the amount of smoking and the degree of 

inhalation (although other types of mathematical relationship would also fit 

the data). In their analysis, the average change in logarithm of death rate 

from "no inhalation" to "deep inhalation" is as great as the difference he. 

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 percent 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 subclassified 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 l.O 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 

ll 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 exsmokers 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. Finally, ex-smokers may have previously smoked 

smaller amounts than current smokers. This factor is not the explanation 

of the drops in mortality ratios in Table 11. In a further breakdown by 

amount of smoking, made for the three largest studies, the mortality ratio 

for ex-smokers is consistently below that for current smokers for each amount 

smoked. 

92 
TABLE !I.-Mortality ratios for ex-smokers and current smokers of cigarettes 

British 

I 

Men in 9 U.S. Canadian Men in 25 

doctors States veterans veterans States 

----

Ex-cigarettes. ____ ------------------- ______ 1.04 ' I. 40 I. 41 I. 42 1.50 Current cigarettes. ________ --------- _______ 1.44 i I. 70 1. 79 I. 65 1.83 

Ex-cigarette.s and other ________________ -___ 1. 21 

I 

1. 29 1. 21 I 1.18 1. 51 Current cigarettes and other _______________ 1.05 1. 45 I. 46 I 1.23 I !.54 I 

TABLE 12.-Mortality ratios for ex-smokers of cigarettes only by number of 

years since smoking was stopped and by amount smoked 

Number of years stopped 

Study Ci~arettes l---...,----.,------------

per day I 

Current 

smokers 

<1 1--4 1-9 ~9 I 10+ 

-M·--.-_

9

_s_t_t __ ' ---l-{--<-19-l---2-.04-~~~,~I 1. 61 

_e_n_m __ a_e_s _--_--_-_--_--_-1 ___ 20_+ -~ ---~ :..:.:.=.:=;~j ___ 2_. 0_2 

Men in 25 States ___________ { ~~ I ~: ~ ~:Zi ,::::::::::1 u~ I n~ I 

1 These data are from Hammond and Horn, 1958. 

l.i3 

2. 01 

TABLE 13.-Mortality ratios for ex-cigarette smokers by number of years of 

smoking, U.S. veterans study 

Cigarettes per day 

1-20 20+ :::::::::::::::::::::::::::::::::::::::::::::::::::: 

1-20 20+::::::::::: ::::::::::::::::::::::::::::::::::::::::: 

Number of years of smoking 

<15 

1.05 

1. 12 

1~24 

1.08 

1.18 

25-34 

1.25 

I. 41 

Age at which smoking was stopped 

<45 

1.09 

I. 12 

45-54 

1.24 

1. 59 

I. 51 1.86 

1.58 

2.00 

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 cor. 

responding ratios for current smokers being included for comparison. 

For ex-cigar smokers the mortality ratios are higher than those for non. 

smokers and higher than those for current smokers in all four studies presented. 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 ( lO) and Dorn ( 6), the explanation may be that a suh-

~tantial number of cigar and pipe smokers give up because they become ill: 

some data from cigarette smokers that support this explanation have recently been analyzed by Hammond (12). Further analysis of the U.S. 

veterans data indicates that mortality ratios run highest in ex-smokers who 

smoked heavily and for a long time. 

TABLE 14.-Mortality ratios for ex-smokers of cigars only and pipes only 

and for current cigar and pipe smokers 

Type of smoker British 

doctors 

Ex-cigar ................................... --···-·---·-

Current cigar. ···-·········-····-·······-· ........... . 

Ex-pipe .. ·················-······-·-·····- I 1. 12 

Current pipe.··························-·- I 0. 95 

1 Pipe and cigar combined. 

Men in 

9 States 

1.65 

1. 10 

1.29 

1.05 

u.s. Canadian veterans veterans 

1.30 1.17 1.07 1.11 

1.38 1. 01 1.06 1.10 

EVALUATION OF SOURCES OF DATA 

THE STUDY PoPULATIONs 

Men in 25 States 

1.24 

0. 97 

1.23 

0. 86 

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 hand 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 ( 10), 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. They point out that their death rates are substantially 

above those for males who had held ordinary life insurance policies for from 

TABLE 15.-Age-adjusted death rates per 1,000 man-years for current 

smokers of cigarettes only (aged 35 and over) , by amount smoked, in seven 

studies and for U.S. white males 

Study 

~~lt~~~···:·········:··················· 

Nonsmokers 

15.8 

1 14.4 

12.0 

1 10.5 

11.3 

14.1 

'12.8 

Current smokers of 

cigarettes only 

--------I U.S. white 

males, 1960 Less than 1 pack 1 pack or more 

19. 2 1 22.4 

18.1 

1 14.2 

16.4 

22. 1 

'18. 5 

23.2 

1 27.1 

23.9 

1 18.0 

16.3 

24.2 

2 19.2 

22.9 

1 22.6 

22.9 

122.6 

22.9 

22.9 

22.9 

1 Ages 50-69 . 

. '?hese figures may be too low by about 1. 7 percent, since the person-years used in the computation tnc Uded some contribution by men who had not been fully traced. 

714-422 0-64-8 95 
5 to 15 years. The U.S. veterans' study population also came mainly from the 

middle and upper socio-economic classes ( 6). 

Another reason might be a failure to trace all 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 fwm 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 proportions 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 u.s. California California Canadian 

doctors veterans occupa· Legion veterans tiona! 

68 68,85 85 56 57 

In the U.S. veterans study, 68 percent replies were obtained from the 

1954 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 

96 
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: 

Current cigarettes only ____________ _ 

Current cigarettes and other_ ______ _ 

1954 

respondents 

( 68 percent) 

1.87 

1.56 

1957 

respondents 

(]7 percent) 

1.71 

1.33 

Nonrespondents 

(15 percent) 

? 

? 

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 (l) produced a set of assumptions under which, with a mortality 

ratio of l in the whole population and a response rate of 7l 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 l 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 substantially 

higher than unity after adjustments for these amounts of over-estimation. 

MEASUREMENT OF SMOKING HISTORY 

Measurement of the type and amount of smoking, being based on a single 

mail questionnaire, was admittedly crude. Consider men recorded as 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" smokers, 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 measurement 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 youn!!er 

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 25-State 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 three 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 25-State 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 

Study 

Men in 9 States ....................................... . 

~~r. ~~t~&a·te.::::::::::::::::::::::::::::::::::::::: 

1 Includes towns of less than 10,000. 

Over 50,000 

1. 48 !.54 

1.89 

Population-size 

10,()()()- 50,000 Small 

towns 

1. 62 I. 50 1. 51 1. 42 

l 2. 02 ~------------

Rural 

I. 52 

I. 59 I. 74 

99 
grandparents were short-lived. Included among these variables were reli. 

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 7l 

computed ratios being 1.57 (for men with a history of previous serious 

disease). 

These data provide information on the association of the other variables 

with mortality as well as on the association of smoking with mortality. For 

six of the most relevant variables, Table 18 gives age-adjusted death rates, 

using the combined populations of non-smokers and cigarette smokers as 

the standard population. The death rates apply to a period of roughly 

22-months follow-up. As already mentioned, the cigarette smokers (of 

more than a pack per 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 somewhat 

TABLE 18.-Age-adjusted death rates per 1,000 men (over approximately 

22 months) for variables that may be related to mortality 

Long-lived Snort-lived No previous Previous 

Type of smoking parents and parents and serious serious grandparents grandparents disease disease 

None ______________________________________ 14.8 21.1 11.5 42. s Cigarettes 1 ________________________________ 27.1 44.8 22.3 M.O 

Single Married Use tran- Do not use quilizers tranquilizers 

None _________________________ 

Cigarettes I _____ ---------------

~one _____________ _ Cigarettes I __________ _ 

~one _____________________________________ _ Cigarettes '- ______________________________ _ 

26.0 18.9 29.1 50.1 33.0 52.4 

Educational level 

I No high · Some high High school Some 

school \ school graduate college 

35.2 22.71 

None 

23.8 

34.1 

20.0 

34.5 16.9 35.5 

18.3 

34.2 

Degree of exercise 2 

Slight 

14.7 

25.5 

Moderate 

11.0 

20.8 

18.2 

31.8 

College 

graduate 

Heavy 

15.8 

29.! 

9. 5 19.; 

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 {29.1 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 illness. The group of 

users is small, comprising only about 10 percent of those who answered this 

question. Death rates tend to decrease slightly as the educational level 

increases; this 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 (ll) carried out a "matched pair" analysis, 

in which pairs of cigarette smokers and non-smokers were matched on height, 

education, religion, drinking habits, urban-rural residence and occupational 

exposure. The percentage who had died in the 22 months was 1.64 for 

smokers and 0.88 for non-smokers. 

These informative analyses are available, unfortunately, fDr 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 was 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, 1.vas 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 FOR 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 cigarettes only, but in the two California studies 

and the 25-State study the cause-of-death breakdown was available only for all 

cigarette smokers including "cigarette and other" smokers and current and 

ex-smokers. 

For each listed cause, Table 19 shows the total numbers of expected and 

observed deaths of cigarette smokers summed over all seven studies, and 

TABLE 19.-Total numbers of expected and observed deaths and mortality 

ratios for smokers of cigarettes only 1 in seven prospective studies 

Mortality Median Non-smoker 

Underlying cause of death Expected Observed ratio mortality deaths 

ratio 

-·----

Cancer of lung (162-31- ____________________ 170.3 1,R33 10.8 11.7 1ZI Bronchitis and emphysema (502. 527.1) ' ___ 89.5 546 6.1 7. 5 59 Cancer of larynx (161) .. _ ------------------ 14.0 75 5. 4 5. 8 8 Cancer of oral ca\·ity (140--8) -------------- 37.0 152 4. 1 3. 9 27 Cancer of esopha~us (150) ________________ 33.7 113 3. 4 3.3 19 

Stomach and duodenal ulcers (54Q--1) ______ 105.1 294 2. 8 5.0 67 Other circulatory diseas~s (451--468) ________ 254.0 649 2. 6 2.3 170 Cirrhosis of liwr (581) _____________________ 169.2 379 2. 2 2.1 96 Cancer of bladder (181) ___________________ • 111.6 216 1.9 2. 2 92 Coronary artery disease (420) ______________ 6, 430.7 11,177 1.7 1.7 4, 731 Other heart diseases (421-2, 430--4) _________ 526.0 868 1.7 1.5 398 Hypertensive heart disease ( 440--3) 409.2 631 1.5 1.5 334 General arteriosclerosis (450) _______ :::::::: 210.7 310 1.5 1.7 201 

Canf't'r of kidney (180) ____ --------------- 79.0 120 1.5 1.4 59 All other cancer ___________________________ 1,061.4 I, 524 1.4 1.4 742 Cancer of stomach (151)_ __________________ 285.2 413 1.4 1.3 203 

Influenza, pneumonia (480--493) ___________ 303.2 415 1.4 1.6 169 All other causes ___________________________ 1, 508.7 1,946 1.3 1.3 1, 036 Cerebral ,-ascular lesions (330-4). __________ 1,461. 8 1,844 1.3 1.3 1, 069 Cancer of prostate (177) ____________________ 253.0 318 1.3 1.0 198 Accidents, suicides, violence (800--999) _____ 1,063.2 I, 310 1.2 1.3 627 Nephritis (592-4) __________________________ 156.4 173 1.1 1.5 98 Rheumatic heart disease ( 400-416) _________ 290.6 309 1.1 1.1 185 Cancer of rectum (154) _____________________ I 207.8 213 1.0 0. 9 !50 

~i'j";;~~~~~~t_i~e_s_ ~~ ~~~~::::::::: :::::::: 422.6 395 0.9 0.9 307 

15,653. 9 26,223 1.68 1.65 11,168 

1 Current cigarettes only for four studies: all cigarettes (current and ex-) for the two California studies 

and the study of men in 25 States. 2 .. Bronchitis and emphysema" includes "other bronchopulmonary diseases" for men in nine States and Canadian veterans. 

*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 causes--cancer of the larynx, 

oral cancer and cancer of the esophagus--the numbers of non-smoker 

deaths are small, so that the over-all mortality ratio cannot be regarded as 

accurately determined. 

The U.S. veterans' study and the 25-State study provide an additional 

breakdown for two of the causes listed in Table 19. For the rubric 527.1 

(emphysema without mention of bronchitis), these studies give mortality 

Iatios 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 l.l. 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. This group includes the leading cause of death, coronary artery 

disease, with a ratio of 1.7, cerebral vascular lesions with a ratio of 1.3, 

and the "all other causes" group with a ratio of 1.3. For each of these 14 

causes the mortality ratio differs from unity, by the approximate statistical 

lest of significance. 

Finally, there are four causes-nephritis, rheumatic heart disease, cancer 

of the rectum and cancer of the intestines--whose mortality ratios are close 

to unity. 

For smokers of cigarettes and other, the data from four studies agree in 

general with the ordering of causes in Table 19, although the mortality 

ratios for most causes are slightly lower than with smokers of cigarettes 

103 
only. These and the corresponding data for ex-cigarette smokers are shown 

in Table 20. 

Data on ex-cigarette smokers can be obtained from four studies. The causes of death with mortality ratios of 2.0 or higher are, in decreasing 

order, bronchitis and emphysema (7.6), cancer of the larynx (5.4), cancer 

of the lung (4.8), stomach and duodenal ulcers (3.1), oral cancer (2.0) 

and other circulatory diseases ( 2.0). ' 

The group of 17 causes with mortality ratios below 2 in Table 19 requires 

discussion. If cancer of the bladder (mortality ratio 1.9) and coronary 

artery disease (mortality ratio 1.7) are omitted, since they receive detailed 

consideration elsewhere in this report, the numbers of expected and observed 

deaths for this group as a whole are as follows: 

Expected 

8,241.3 

Observed 

10,789 

Mortality Ratio 

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 

7,164.0 

Observed 

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 he put forward. 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 high 

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 constitutional and genetic factors. 

Studies reported in Chapters 14 and 15 indicate that some average differences can be detected between smokers and non-smokers on behavioral, 

psychological and morphological characteristics. Nevertheless, the same comparisons show considerable overlap between the individual men in a group of 

smokers and a group of non-smokers. For what they are worth, these com104 
TABLE 20.-Expected and observed deaths and mortality ratios for current 

smokers of cigarettes and other (three studies) 1 and for ex-cigarette 

smokers (jour studies) 2 

Cigarettes and other 

I 

Ex-cigantte 

Underlying cause of death Number of deaths :>/urn ber of deaths Mortality Mortality 

ratio ratio 

Expected Observed Expectijd Observed 

Cancer otlung (162-3) _________ 60.9 510 8. 4 30.4 145 4. 8 Bronchitis and emphysema 

(502, 527.1) , ___ ------------- 53.2 191 3. 6 17. 4 133 7. 6 Cancer otlarynx (161) _______ 1.6 20 12. 5 1.3 7 5. 4 Cancer of oral ra vity (14(}-8) __ 11. 1 42 3. 8 5. 9 12 2.0 Cancer of esophagus (150) ____ 13. 1 57 4. 4 5. 4 6 1.1 Stomach and duodenal ulcers 

(54(}-1) --------------------- 23.0 99 4. 3 13.0 40 3. I Other cirrulatory diseases 

(451-468) ------------------- 99.0 227 2. 3 45.8 93 2. 0 Cirrhosis of liver (581)__ _______ 57.3 85 1.5 22.4 27 1.2 Cancer of bladder 1181). _______ 58.2 73 1.3 29.8 31 1.0 Coronary artery disease (420) _ 2, 335.0 3, 262 1.4 1, 245.0 1, 731 1.4 Other heart diseases (421-2, 

43(}-4)_---------------------- Hypertensive heart disease 225.9 321 1.4 124. 1 178 1.4 

(440-3) --------------------- 144.4 174 1.2 93.0 133 1.4 General arteriosclerosis ( 450) __ 106.8 146 1.4 63.7 75 1.2 Cancer of kidney (180) ________ 25.0 37 1.5 13.9 25 1.8 

All other cancer . ------------ 272.9 339 1.2 199.3 239 1.2 Cancer of stomach (151) _____ 101.0 139 1.4 51.4 66 1.3 Influenza. pn· urr.onia (480-493)_ 199.2 153 0.8 55. 1 55 1.0 

All other causes ------------- 769.3 700 1.0 308.1 357 1.2 Cerebral vascular lesions (33(}- f) ___________________________ 634.0 605 1.0 300.1 321 1.1 Cancer of prostate 077) ______ 97.1 118 1.2 52.0 57 1.1 Accidents, suicides, violence 

(800-999) ------------------- 'JS7.1 316 1.1 169.6 159 0.9 

Nephritis (592-4) ------------ 30.7 44 1.4 21.7 23 1.1 Rheumatic heart disease ( 40(}- 416) _________________________ 96.0 86 0.9 47.9 59 1.2 

Cancer of rectum (154) ------- 89.7 64 0. 7 43.3 38 0.9 Cancer of intestines (152-53). __ 149.6 164 1.1 85.8 97 1. 1 

AU causes _____________________ 5, 941.1 8,062 1.4 3, 045. 5 4, 107 1.35 

1 British doctors, U .8. veterans and Canadian veterans. ' British doctors, men in nine States, U .8. veterans, and Canadian veterans. 1 ''Bronchitis and emphysema" includes "other bronchopulmonary diseases" for men in nine States and Canadian veterans. 

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 
MoRTALITY RATIOS FOR CIGARETTE SMoKERS BY AMOUNT SMOKED 

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 studies, in which the data are for all cigarette 

smokers (current and ex-smoke~rs combined) show a less marked trend. 

TABLE 21.-Mortality ratios for coronary artery disease for smokers of 

cigarettes only by amount smoked 

Number of packs per day British Men in 9 

I u.s. Canadian I Men in 2.1 doctors States veterans veterans States 

1.0 1.2 1.3 1.7 - 1.3 1.5 1.9 1. 8 1.7 2.0 11.7 2.1 1.7 12.0 2.1 ·----------- 2. 4 1.9 2.5 

<>2 .... -----------· ----------- >2-L ... ---------------------------------- 1-2.--------------------------- ----------- Over 2 _____________ -----------------------

1 More than one pack. 

TABLE 22.-Lung cancer mortality ratios for current smokers of cigarettes 

only by amount smoked 

Number of packs per day British 

doctors 

<»----------------------------------------- 4.4 H-L. ... ____ ... ____________ ---------------- 10.8 

1-2------------------------ .............. I~. 7 Over 2_. ____________ .. ___________ ------------ _ -----------

1 Over one pack. 

Men in 9 States 

5.8 

7. 3 15.9 

21.7 

u.s. Canadian veterans veterans 

5. 2 8.4 9. 4 13.5 18. 1 1 15.1 23.3 ------------

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 observed deaths and mortality ratios for current 

cigarette smokers, for selected causes of death, by amount smoked, in six 

studies 

One pack or less More than one pack 

' 

Causes of death ! X umber of deaths Number of deaths 

Mortality Mortality ratio ratio I Expected Observed Expected Observed 

I 

Bronchitis and emphysema._ 44.6 225 5. o I 17.2 147 8. 5 Cancer of larynx .. _ ------- 3.6 19 5. 3 ; 4.1 31 7.6 Cancer of oral cavity __________ 16.8 53 3. 2 ! 14.1i 60 u Cancer of esophagus __________ 13.2 40 

3. 0 I 9. 7 4S 4. 9 Stomach and duodenal ulcers_ 32.5 110 3. 4 31.2 91 2. 9 Other circulatory _______ --I 98.5 253 2. 6 00.4 175 2. 9 Cancer of the bladder ___ ----- 57.3 80 1.4 23.7 73 3.1 

106 
men in the 25-State study. Cancer of the bladder is included m Table 23 

as background data for Chapter 9. 

All causes except stomach and duodenal ulcers show some increase m 

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 ( l. 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 1-----,-------1 M~i~!ity 

Expected Observed 

~~~H~ ~i~~~~}hl~~~~~~~~~~l~l~~~~~~~~~~~~~~~~~~:~~~~~~~~~ ~U ~ H 

Stomach and duodenal ulcers (54o-1)________________________________ 35.2 56 1. 6 

8:~~~ ~~~~~~rn~~ &si..:a)~:::::::::::::::::::::::::::::::::::::::: 1~n 2~~ U Other circulatory diseases (451-468) _ _ ______ _____ _ _ _ ___ ___ _____ __ __ __ 89.1 105 1. 2 

~fu~n!r~~~()lm~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~=~=~~~~~~~ i~:i ~~ n 

Hypertensive heart dil'ease («o-3)__________________________________ 194.5 218 1.1 Other heart diseases (421-2, 43o-4)___________________________ ________ 272.6 303 1.1 

~ronchitls and emkhysema (502, 527.1)------------------------------ 33. 7 ~b 1.1 

xrr1rEl?"~~~:~~~~~:::::::::::::::::::::::::::::::::::: 2' m: ~ 2

' ~~~ t g Influenza and pneumonia (48o-493)_________________________________ 93.8 88 o. 9 

Accidents, suicides, violence (80o-999)_______________________________ 347.1 318 0. 9 Cancer of bladder (181). _ _ __ ___ _____ _______ _ ______ ______ _ _______ _ ___ 63.1 56 o. 9 

General arteriosclerosis (450)---------------------------------------- 124.1 109 0. 9 Nephritis (592-4) _________________ ------- _______ _ __ _____ _ _ ______ _____ 63. 6 55 0. 9 

Rheumatic heart disease (4Qo-416)___________________________________ 100.5 69 o. 7 

1-----1-----1----- All causes___________________________________________________________ 6, 500.9 6, 919 1. 06 

1 Includes British doctors, men in 9 States, U.S. veterans, Canadian veterans, and men in 25 States; 

Includes ex-smokers for men in 9 States; excludes pipe smokers for Canadian veterans. 

Separate breakdowns by cause of death for cigar-only smokers and for 

pipe-only smokers are available in only three studies. The numbers of 

deaths are too few to throw any light on the question whether there are 

differences between cigar and pipe smokers in the causes of death for which 

mortality ratios are elevated. 

107 
THE CoNTRIBUTION OF DIFFERENT CAusEs To ExcEss MoRTALITY 

Several of the reports previously published on these studies have included 

a table showing how the excess number of deaths of cigarette smokers over 

non-smokers is distributed among the principal causes 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 

due to different causes 1 

I British Men in u.s. Calirornia I California Canadian Men in 

Cnderlying cause I doctors 9 States veterans occupa~ Le~ion veterans 25 States 

I 

tiona! 

:------------------- Coronary artery disease ____ 32.9 51. 9 38.6 43.5 43.5 I 44.2 51.7 Other heart disease _______ 9. 8 3.1 6. 8 1.4 4. 5 5. 9 5. 5 Cerebral vascular lesions _______ 6.1 4. 5 4. 9 5. 3 6. 5 -1.8 3.3 Other circulatory diseases. ___ 1.9 2. 7 7.1 1.7 0. 2 5. 6 4.4 Cancer oflung _________________ 24.0 13.5 14.9 20.2 16.8 18. 3 13.6 Cancer of oral cavity, esopha- gu.,, larynx_ __________________ 3. 3 2. 9 2. 7 0.2 3. 0 2. 2 2. 2 

Other cancer_------------------ -0.2 9. 8 8. 9 6. 3 -2.2 7. 2 7. 6 Bronchitis and emphysema 9. 6 1.1 4. 0 1.3 5. 6 8. 2 3. 8 Influenza and pneumonia ______ -2.4 1.6 0.4 2. 4 1. 5 1.5 1.5 Stomach and duodenal ulcers __ 2. 7 3.1 1.4 -1.7 2. 2 2.9 1. 3 Cirrhosis of liver _______________ 2. 9 1.6 2. 5 6.9 2. 2 0.8 0. 9 Accidents, suicides, violence ___ 0.2 1.2 2. 0 8. 3 3. 7 4. 6 0.8 All other causes ________________ 9. 2 3.0 5. 8 4. 21 12. 5 0. 4 3. 4 All causes --------------------- 100.0 100.0 100.0 100.0 100.0 100.0 100.0 

1 All cigarette smokers (current and ex-) for the two California and men in 25 States studies; current 

cigarette smokers only for the remainder. 

As previous writers have noted, all studies agree 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. 

TorAL 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 
1-' 

0 

\0 

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 States U.S. veterans California occupational 

Cause of death Deaths Deaths Deaths Deaths 

Mortality Mortality Mortality Mortality ratio ratio ratio ratio 

Expected Observed Expected Observed Expected Observed Expected Observed 

--------------------------------------------

Cancer of lung ... ----------------------- (162-3) 6. 4 129 20.2 23.4 233 10.0 43.3 519 12.0 8. 7 138 15.9 Bronchitis, emphysema _____________ (502, 527.1) 4. 2 53 12. 5 12.8 30 2. 3 !4. 4 141 9. 8 2.6 11 4.3 Cancer of iaryux. .. ____ ------------------- (161) .0 7 1.3 17 13.1 2. 4 14 5. 8 .0 3 Cancer of oral cavity ____________________ (I4Q-8) .0 6 7. 8 22 2. 8 8.1 54 6.6 7. 2 7 1.0 Cancer of esophagus _______________________ (150) 3.3 7 2.1 2. 7 18 6.6 5. 2 33 6. 4 5. 5 4 .7 Stomach and duodenal ulcers ......... (540, 541) .0 14 12.2 61 5. 0 21.5 67 3.1 23.1 12 .5 Other circulatory diseases .............. (451-68) 17.2 27 1.6 19.7 53 2. 7 66.4 228 3. 4 11.5 18 1.6 

Cirrhosis of liver .. ------------------------ (581) .0 15 23.5 49 2.1 31.2 Ill 3. 6 14.7 59 4.0 Cancer of bladder. _____ ------------------- (181) 13.9 12 .9 17.2 41 2. 4 31.4 55 1.8 2. 2 13 6.0 Coronary artery disease ................... (420) 366.9 535 1.5 927.7 I, 734 1.9 I, 803.3 3, 037 1.7 273.9 551 2. 0 Other heart diseases .. __ ---------- (421-2, 430-4) 78.8 115 1.5 72.5 108 1.5 122.2 244 2.0 23.8 24 1.0 Hypertensive heart disease .............. (44Q-3) 21.0 32 1.5 89.7 107 1.2 138.7 223 1.6 27. 2 28 1.0 General arteriosclerosis._------------------ (450) 21.2 21 1.0 9.1 18 2.0 97.0 163 1.7 .0 5 

Cancer of kidney .. ------------------------ (180) .0 8 14.0 21 I. 5 23.1 34 1.5 .0 10 

All other cancer .. -----_------------------------- 81.7 73 . 9 132.9 230 1.7 315.8 407 1.4 72. I 105 1.5 

Cancer of stomach. __ ._------------------- (151) 28.3 31 1.1 33.7 76 2. 3 61.5 90 1.5 31. 4 24 . 8 Influcma, pneumonia .. --------------.. (48o-93) 47.0 35 . 7 15.6 41 2. 6 22.6 36 1.6 10.3 25 2. 4 

All other causes ..................... ------------ 144.0 182 1.3 209.5 263 1.3 354.8 530 1.5 68.9 101 1.5 

Cerebral vascular lesions.--------------- (33Q-4) 161. I 192 1.2 208.8 279 1.3 309.1 467 1.5 42.2 76 1.8 Cancer of prostate _________________________ (177) 29.0 15 . 5 32.4 51 1.6 53.7 106 2. 0 8. 6 4 .5 Accid•nts, suicides, violence ___________ (BOo-999) 89.2 90 1.0 174.1 192 1.1 241.5 306 1.3 108.4 161 1.5 Nephritis. ______________ ---------------- (592-4) 8.1 17 2.1 43.3 34 .8 18. 6 30 1.6 16.0 10 . 6 

Rheumatic heart disease.-------------- (400-16) 10.2 13 1.3 48.4 43 .9 67.4 77 1.1 22.9 31 1.4 

Cancer of rectum. -----------------------054) 4. 2 15 3. 6 29.8 25 .8 68.7 62 .9 13. 6 14 1.0 

Cancer of intestines .. ___ .--------------- (152-3) 26.1 28 I. I 65.6 35 .5 121.2 152 1.3 23.7 22 . 9 ------------------------------------------------ All causes _________________________ ------------ 1,161. 8 I, 672 I. 44 2, 227. 7 3, 781 I. 70 4, 043. I 7, 236 I. 79 818.5 I, 456 I. 78 
...... 

...... 

0 TABLE 26.-Numbers of expected and observed deaths for smokers of cigarettes only, and mortality ratios, each prospective 

study and aU studies-Continued 

Cause of death 

------

Cancer of lung ___ ............. (162--3) 

Bronchitis, emphysema .. (502, 527.1) 

Cancer of larynx ......•......... (161) 

Cancer of oral cavity ......... (140·8) 

Cancer of esophagus ............ (!50) 

Stomach and duodenal ulcers 

(540, 541) 

Other rirculatory diseases ... (451-68) Cirrhosis of liver ___ ............. (581) 

Cancer of bladder .............. (181) 

Coronary artery disease ........ (420) 

Other heart diseases .. (421-2, 430--4) 

H ypertensive heart disease ... (44(}--3) 

c 

A 

c 

ln 

A 

c 

c 

A 

General arteriosclerosis ......... (450) ancer of kidney ............... (180) 

II other cancer ...................... sneer of stomach_ ............ (151) 

fluenza, pneumonia ....... ( 480-93) 

II other causes ...................... erebral vascular lesions ..... (330--4) 

ancer of prostate ........••••.. (177) 

ccidents, suicides, violence 

(800-999) 

N 

R 

c 

c 

epbritis ...............•.... (592--4) 

beuroatlc heart disease ..... (40Q-16l ancer of rectum •.............. (154 ancer of intestlnes ......•.... (152-3) 

A II causes .••..•••••..•............... 

California Legion 

Deaths 

Mortality 

ratio 

Expected Observed 

--------

19.9 98 4. 9 3. 6 30 8. 4 4.0 6 1. 5 5. 2 10 1.9 1.8 9 5.1 

1.8 12 6. 8 

16.7 37 2. 2 13. I 23 1.8 1.8 7 4.0 

312.8 515 1.7 13. 1 26 2.0 24.9 29 1. 2 

39.1 20 . 5 8. 3 6 . 7 75.4 84 1.1 

20.5 25 1.2 14.7 22 1.5 39.1 94 2. 4 

57. 1 87 1.5 22.1 19 . 9 

45.0 62 1.4 .0 3 ---------- 14.2 18 1.3 12.0 9 .8 33.2 13 .4 ------------ 799.4 1,264 1.58 

Canadian veterans 

Deaths 

Mortality 

ratio 

Expected Observed 

------------

27. 1 317 11.7 36.5 166 4. 6 

.0 5 ---------- 5. 1 20 3. 9 6.8 22 3.3 

7.9 54 6. 9 41.5 96 2.3 

37.6 50 1.3 22.3 38 1.7 882.5 I, 582 1.8 

75.3 156 2.1 36.2 58 1.6 14.7 48 3.3 9.5 13 1.4 104.1 149 1.4 41.2 76 1. 9 135.0 159 1.2 361.5 360 1.0 294.1 266 -9 32.3 48 1.5 

101.3 174 1.7 11.6 17 1.5 48.1 39 .8 41.3 24 .6 46.6 64 1.4 

------------ 2, 420.1 4,001 1.65 

Men in 25 States Total, all studies 

Median 

Deaths Deaths mortality Mortality Mortality ratio 

ratio ratio 

Expected Observed Expected Observed 

----------------------------

41.5 399 9. 6 170.3 1,833 10.8 11. 7 15.4 115 7. 5 89.5 546 6.1 7. 5 6.3 23 3. 7 14.0 75 5. 4 5. 8 3.6 33 9. 2 37.0 152 4.1 3. 9 8. 4 20 2. 4 33.7 113 3. 4 3.3 

38.6 74 1.9 105.1 294 2. 8 5.0 81.0 100 2. 5 254.0 649 2. 6 2.3 49.1 72 1.5 169.2 379 2. 2 2. 1 22.8 50 2.2 111.6 216 1.9 2. 2 1, 863.6 3,223 1.7 6, 430.7 11, 177 1.7 1.7 140.3 195 1.4 526.0 868 1.7 1.5 71.5 154 2. 2 409.2 631 1.5 1..5 29.6 35 1.2 210.7 310 1.5 1.7 24.1 28 1.2 79.0 120 1.5 1.4 279.4 426 1.5 1,061.4 1, 524 1.4 1.4 68.6 91 1.3 285.2 413 1.4 1.3 58.0 97 1.7 303.2 415 1.4 1. 6 330.9 416 1.3 1, 508.7 1,946 1.3 1.3 389.4 477 1.2 1, 461.8 1, 844 1. 3 1.3 74.9 75 1.0 253.0 318 1.3 1.0 

303.7 325 1.1 1, 063. 2 1, 310 1.2 1.3 58.8 62 1.1 156.4 173 1.1 1.5 79.4 88 1.1 200.6 309 1.1 1.1 38.2 64 1.7 207.8 213 1.0 . 9 106.2 81 .8 422.6 395 .9 . 9 ---------------------------- 4,183.3 6, 813 1.63 15,653.9 26,223 1.68 1.65 
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 in· 

crease 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 I. 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 I 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 0-64-9 Ill 
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 ratioa. 

Although similar information from other studies would have been wei. 

come, it is our judgment that the mortality ratios are unlikely to be explained 

by such environmental, social class, or ethnic differences between cigarette 

smokers and non-smokers. 

Except for the analyses reported above by longevity of parents and grand. 

parents and by previous serious disease, no direct information is available on 

whether there are basic constitutional differences between cigarette smokers 

and non-smokers that would affect their longevity. As described 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 nonsmokers 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 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 lO or more pipefuls per day and with 

men who had smoked pipes for more than 30 years. 

Ex-pipe smokers, on the other hand, showed higher death rates than both 

non-smokers and current smokers in four out of five studies. The epi· 

demiological studies on ex-cigar and ex-pipe smokers are inadequate to 

explain this puzzling phenomenon. According to Hammond and Horn (10) 

and Dorn ( 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 1954-1956: 32 percent for the British doctors' 

study; and about 44 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 purpose 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-adjnsted death rates (per 1,000 person-years) for 1954 

respondents, 1957 respondents, and non-respondents in U.S. veterllliJ 

study 

- Proportion Death rates Groups in population - 1958 1959 

0. 17 13.29 - 12. s. . 51 19.26 19.00 

.04 17.96 --16.37 .13 22.67 21.61 

- 1957 respo d ts {Non-smokers _________ _ n en ···-------- -------------- Allsmokers __________ _ 

-------1------1----1 Non-respondents.__ ____________ __ _________ AlL _________________ _ . 15 21.99 19. s. 

1958 and 1.27 in 1959. For smokers the corresponding figures are 1.18 in 

1958 and 1.14 in 1959. 

If the adjusted death rates in Table 27 are weighted by the proportions of 

men in the population, it is found that the over-all 1958 death rate for 1954 

respondents was 17.77 as compared with 19.05 for the complete study population. 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 l957 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. 

l. The proportions of the relevant groups in the complete population are 

as follows: 

Groups Non· 

smokers Cigarette 

smokers Total 

Non-respondents____________________ 0.14 0.18 0.32 Respondents .. ______________________ .34 .34 .68 

1-----1-----1------

Completepopulatlon ........ _ .48 .52 1.00 

This assumes that in the 68 percent of respondents, non-smokers constitute 50 percent of non-smokers plus cigarette smokers, but in the non-respondents this figure has dropped to 44 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.-/llustration of calculation of non-response bias 

Assumption ( 3a) Assumption ( 3b) 

Mortality ratios Mortality ratios 

Non· Cigarette smokers smokers Non· Cigarette smokers smokers 

------ --- ~on-respondents ..... _ • (1.865) 1.700 I (1. 772) esponaents ____ ______ 1.000 1. 700 l (1.350) 

Non-respondents ... __ • (1,646) 1.870 • (1. 772) 

Respondents ......... 1.000 1. 700 l (1.350) --------- ------ Complete population. '(1.252) • (1. 700) '(1.485) M.R •.•.. _____________ , (1.36) 

I 

Complete population. I (1.188) • (1. 759) '(1.485) M.R ................. , (1. 48) 

I 

TThe figures without parentheses in the mortality ratio tables represent the start of the computations. he Indexes (' 'etc.) show the order in which other figures are computed. For assumption (3a): 

(1.350) l =[ (0.34) (1.000)+ (0.34) (1.700) )/ (0.68) 

(1.485) '= (1.1) (1.350) 

(1. 772) •=[ (1.485)-(0.68)(1.350) II (0.32) 

(1.865) ·= l (0.32) (1.772)-(0.18) (1.700)!/(0.14) 

(1.252) •= [ (0.14) (1.865)+ (0.34) (1.000) I (0.48) 

(1.700) '=[(0.18)(1.700)+(0.34)(1.700) /(0.52) 

(1.36) , = 1. 700/1.252 

Thus, the mortality ratio drops from l. 7 to 1.36 in the complete population 

under assumption ( 3a) and to 1.48 under assumption ( 3b) . One conse· 

quence of assumption ( 3a) is that the mortality ratio of cigarette smokers 

among the non-respondents is less than l. 

Table 29 shows the results obtained for a range of mortality ratios in the 

respondent population. 

For the high mortality ratios the assumptions may appear unduly extreme. 

For instance, under assumption (3a) with mortality ratio 10.0 in the respondents, the non-smoker death rate in the non-respondents has to be 3.6 times 

us 
that in the respondents, although the smoker death rates are assumed the 

same in respondents and non-respondents. 

It may be of interest to quote Berkson's ( 1) example in the same form 

(Table 30). 

TABLE 29.-Mortality ratios in respondents and computed values for the 

complete population 

In respondents (68 percent) 

1.2 ___________________________ --------------------

1.4_- ------------------------- -------------------- 1.6 ___________________________ --------------------

1.8.-------------------------- -------------------- 2.0 __________________________ -------------------- 5.0 ___________________________ -------------------- 10.0 __________________________ --------------------

In complete population 

Assump- Assump- tion (3a) tion (3b) 

1.00 

1.14 

1.28 

1.43 

I. 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 

Group Non- Smokers Total Non- Smokers smokers smokers 

Non-respondents ______________ 0. 00494 0. 28360 o. 288M 60. 121 4. 217 Respondents ___ --------- ______ .19506 . 51640 . 71146 1.553 2.332 

TotaL------------------ -~ .80000 1.00000 3.000 3.000 

Total 

5.174 

2.118 

3.000 

In their general direction, Berkson's assumptions are similar to those made 

in this Appendix, but the differences in death rates between respondents and 

non-respondents were more extreme in his example. The 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 nonrespondents 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 interpret 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 1 denote the number of smoker deaths and Xt 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) _, 

(p f k . I . ) x, -/\tXt erson-years or non-smo ers m c ass 1 

(say) 

The estimated mortality ratio R is defined as 

(l) 

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. 

l. The numbers of deaths Yt and Xt are distributed as Poisson variables. 

As Chiang (3) has shown, a more accurate assumption is to regard Yt and Xt 

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 assump· 

tion, which is slightly conservative, is reasonable. 

2. The quantities ,\1 can be regarded as known constants. This is not 

quite correct. Initially, the At 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 y 1 and y J are uncorrelated. An error in the age assigned 

to a death, putting it in the wrong age-class, induces a negative correlation 

between Yt and YJ· The existence of such errors should have no effect on 

117 
the variance ascribed to ly i on the assumption of independence. The same 

remarks apply to the assumption that x1 and XJ are uncorrelated. 

4. The variates x1 and y1 are uncorrelated. An error in assigning a death 

to the correct smoking category would induce a negative correlation between 

x1 and y;. Such errors should of course not be allowed to happen, since 

they vitiate the comparison of the death rates that is the main point of the 

study, but occasional errors oi' this type may have 5_)Ccurred. 

With these assumptions the numerator ly1 of R follows a Poisson distrj. 

bution. The denominator lA;X; 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 given. Confidence limits are presented rather than the 

standard error of R because the distribution of R is skew when the numbers 

of deaths are moderate or small, so that the standard error is harder to 

interpret. 

The Binomial Approximation 

If the A1 can be regarded a:s approximately constant (=A, say) then R 

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 follows that x/(y+x), the ratio of non-smoker 

deaths to smoker plus non-smoker deaths, is distributed as a binomial 

proportion with 

n=number of trials=y+x 

p =probability of success= I/ (I + 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: 

Non- Smokers 

smokers 

Observed Observed Expected 

Number of deaths_.--------·-------- 16(x) 15(y) 9.7l(AX) 

Hence, A=9.7l/I6=0.607 and the binomial ratio is I6/3I=0.5I6. 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)/.\p 

This yields 0. 7 and 3.3 as the 95 percent limits for R. Since the lower limit, 

0.7, is less than unity, the estimated R, l.S, is not significantly above unity. 

118 
Unfortunately the assumption that A1 is constant is not true in these studies. 

For instance, in the study of men in 25 States At 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 

Auctuation in Yt with age is less drastic but is still noticeable. 

The Normal Approximation 

This approach avoids the assumption that the At 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= ~A tXt is the expected number of smoker deaths. will follow a 

distribution that has mean zero. If 1-'-t· lit denote the true means of y; and 

Xt. respectively, the variance of (y- Re) is 

~(p.t+R A~m ) 

The basis of this approximation is to regard the quantity 

y-Re 

V~(p.t + A~m ) 12) 

as normally distributed with zero mean, since Yt and Xt 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.1 and the m1 are unknown, a further approximation is to 

substitute y as an estimate of ~1'-t and ~A ~x 1 as an estimate of ~Aim 1• 

Example. For the example previously discussed the data are as follows: 

y= 15: e=9.7l: ~A.1x =6.059 

On squaring (2), the quadratic equation becomes 

(l5-9.7lR) 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. 

Number of deaths I 9.) percent limits 

I 

Mortality I Cause of death Non· Ci~arette smokers ratio smokers Binomial I .'o!ormal 

observed 

Observed I Expected 

---

~anhr of lung ________________ 16 3991 41.20 9. (5.0,14.5) (5. 0, 21. 4) cmp ysema _________ : _______ 7 115 15.31 7. (3. 5. 18 I) (4. 0, 40. 0) 1n'\lcer of rectum ____________ , 16 64 38.42 l. (1. 0. 3. 3) (l. 0, 3. 6) 

_ uenza and pneumonia _____ ~ 29 97 58.01 I. (1.1, 2. 6) (1. I, 2. 9) 

119 
The lower confidence limits agree well, but the upper limit runs higher 

for the normal approximation. For cigarette smokers the normal method 

is perhaps more accurate. The binomial method has some advantage ia 

simplicity. 

REFERENCES 

L Berkson, J. The statistical study of association between smoking and 

lung cancer. Proc Staff Meeting, Mayo Clin 30: 319-48, 1955. 

2. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mortality 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, 1961. 

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 Soc 

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. Smoking 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, 1962. 

14. Ipsen, J., Pfaelzer, A. Special report to the Surgeon General's Advisory 

Committee on Smoking and Health. 

15. Korteweg, R. The significance of selection in prospective investigations 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, Lon· 

don, (Section 9.4), 1960. 

120 
Chapter 9 

Cancer 
Contents 

CANCER MORBIDITY AND MORTALITY 

Page 

127 

Sources of Information . . 127 

Sex Ratio . . . . . . 133 

Geographic Variation 133 

Urban-Rural Gradients. 133 

Income Class . 133 

Occupation . . 134 

Ethnic Group . 134 

Trends . . . . 135 

Age-Specific Mortality From Lung Cancer 136 

Effects of Changes in Lung Cancer Diagnosis on Time 

Trends . . . . 139 

CARCINOGENESIS . 141 

Fundamental Problems in Carcinogenesis in Relation to 

Induction of Neoplastic Changes in Man by Tobacco 

Smoke . . . . . . . . . . . . . . . • . . . • 141 

Threshold . . . . . . . . . . . . . . . . . . . . 143 

Carcinogenicity of Tobacco and Tobacco Smoke in Animals. 143 

Skin . . . . . . . . . . . . . . . . . . . . . . . 143 

Subcutaneous Tissue . . . . . . . . . . . . . . . . 144 

Mechanism of the Carcinogenicity of Tobacco Smoke 

Condensate . . . . . . . . . . . . . . . . . . . 144 

Other Materials of Possible Importance in Carcinogenicity . . . . . 145 

Pesticides. . . . . . . . 145 

Lactones . . . . . . . . 145 

Radioactive Components 145 

Summary. . . . . . . . . 146 

Carcinogenesis in Man . . . . 146 

Polycyclic Aromatic Hydrocarbons 146 

Industrial Products . 147 

Soot . . . . . . . 147 

Coal Tar and Pitch. 147 

Mineral Oils 147 

Summary. . 148 

CANCER BY SITE 148 

Lung Cancer . . 149 

Historical . 149 

Retrospective Studies 150 

Methodologic Variables . 151 

Form of Tobacco Use. . 155 

122 
CANCER BY SITE-continued 

Lung Cancer-Continued 

Retrospective Studies-Continued Page 

Amount Smoked 155 

Duration of Smoking. 158 

Age Started Smoking 158 

Inhalation. . . . . . 159 

Histologic Type . . . 159 

Relative Risk Ratios from Retrospective Studies. 160 

Prospective Studies . . . . . . . . . . . . . . 161 

Experimental Pulmonary Carcinogenesis . . . . . 165 

Attempts to Induce Lung Cancer with Tobacco and 

Tobacco Smoke . . . . . . . . . . . . . . 165 

Summary . . . . . . . . . . . . . . . . . . 165 

Susceptibility of Lung of Laboratory Animals to Carcinogens . . . . . . . . . . . . 166 

Polycyclic Aromatic Hydrocarbons 166 

Viruses . . . . . . . . . . . 166 

Possible Industrial Carcinogens . . 166 

Summary . . . . . . . . . . . . 167 

Role of Genetic Factors in Cancer of the Lung. 167 

Summary . . . . . . . . . . . . . . . . 167 

Pathology-Morphology . . . . . . . . . . . . 167 

Relationship of Smoking to Histopathological Changes in 

the Tracheobronchial Tree 167 

Summary. . . . . . 172 

Conclusion . . . . . 17 3 

Typing of Lung Tumors 173 

Conclusions . . . . . 17 4 

Evaluation of the Association between Smoking and Lung 

Cancer . . . . . . . . . . . . . 175 

Indirect Measure of the Association . 175 

Direct Measure of the Association . 179 

Establishment of Association . . . 179 

Causal Significance of the Association 182 

The Consistency of the Association. 182 

The Strength of the Association . . . 183 

The Specificity of the Association . . 183 

Temporal Relationship of Associated Variables 185 

Coherence of Association . . . . . . 185 

(I.) Rise in Lung Cancer Mortality . . . . 185 

(2.) Sex Differential in Mortality . . . . . 185 

(3.) Urban-Rural Differences in Lung Cancer Mortality. . . . . . . . . . . . . . . . . . 186 

(4.) Socio-Economic Differentials in Lung Cancer 

Mortality . . . . . . . . . . . . . . . 186 

(5.) The Dose-Response Relationship. . . . . . . 187 

(6.) Localization of Cancer in Relation to Type of 

Smoking . . . 188 

Histopathologic Evidence. . . . . . . . . . . . . . 189 

123 
CANCER BY SITE-Continued 

Lung Cancer-Continued Pa~e 

Constitutional Hypothesis 190 

Genetic Considerations . 190 

Epidemiological Considerations 192 

(I.) L1mg Cancer Mortality 192 

(2.) Tobacco Tars . . . . . 192 

(3.) Pipe and Cigar Smoking 192 

(4.) Ex-Cigarette Smokers . 192 

Other Etiologic Factor!'. and Confounding Variables 193 

(I.) Occupational Hazards . . . . . . . . . 193 

(2.) Urbanization, lndustralization,and Air Pollution . 194 

(3.) Previous Respiratory Infections . 195 

(4.) Other Factors. 196 

Conclusions . . . . . . . 196 

Oral Cancer . . . . . . . . 196 

Epidemiological Evidence. 196 

Carcinogenesis 202 

Pathology 203 

Evaluation . . 203 

Conclusions . . 204 

Laryngeal Cancer 205 

Epidemiological Evidence. 205 

Retrospective Studies 205 

Prospective Studies 209 

Carcinogenesis . . . . 210 

Pathology . . . . . . 210 

Evaluation of the Evidence . 210 

Time Trends . . . • . . 210 

Sex Differential in Mortality 211 

Localization of Lesions . 211 

Conclusion . . . . . . . 212 

Esophageal Cancer . . . . 212 

Epidemiological Evidence. 212 

Retrospective Studies 212 

Prospective Studies . 217 

Carcinogenesis . . . . 217 

Evaluation of Evidence 217 

Conclusion . . . . . . 218 

Urinary Bladder Cancer. .. 218 

Epidemiological Evidenee. 218 

Retrospective Studies . 218 

Prospective Studies .. . 222 

Carcinogenesis . . . .. . 223 

Evaluation of the Evidence . 223 

Conclusion . . . . . .. . 225 

Stomach Cancer . . . . . . 225 

Epidemiological Evidenee. 225 

Retrospective Studies 225 

Prospective Studies . . 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 

Page 

228 

228 

229 

229 

229 

233 

233 

234 

234 

235 

235 

Area of 1900, 19Q0-1960 . . . . . . . . . . . . 128 

2. Age-adjusted mortality rates for cancer-all sites, in 17 

countries, 1958-1959 . . . . . . . . . . . . . . . . 129 

3A. Age-adjusted mortality rates for cancer of six sites in six 

selected countries-males . . . . . . . . . . . . . . 130 

3B. Age-adjusted mortality rates for cancer of six sites in six 

selected countries-females . . . . . . . . . . . . . 131 

4. Comparison of age-adjusted mortality rates by sex, United 

States, 1959-1961, with incidence rates from State registries of New York and Connecticut . . . . . . . . . . 132 

5. Trends in age-adjusted mortality rates for cancer by sexall sites and respiratory system in the United States, 

193Q-1960 . . . . . . . . . . . . . . . . . . . . . 136 

6. Trends in age-adjusted mortality rates for selected cancer 

sites by sex in the United States, 193Q-1960 . . . . . . 137 

7. Age-adjusted mortality rates for cancer of the lung and 

bronchus by birth cohort and age at death for males, 

United States, 1914, 193Q-1932, 1939-1941, 1949-1950, 

1959-1961 . . . . . . . . . . . . . . . . . . . . . 138 

8. Age-adjusted mortality rates for cancer of the lung and 

bronchus by birth cohort and age at death for females, 

United States, 1914, 193Q-1932, 1939-1941, 1949-1950, 

1959-1961 . . . . . . . . . . . . . . . . . . . . . 139 

9. Crude male death rate for lung cancer in 1950 and per capita 

consumption of cigarettes in 1930 in various countries . . 176 

10. Percentage of persons who have never smoked, by sex and 

age, United States, 1955 . . . . . . . . . . . . . . . 178 

125 
Illustration 

I. Examples of normal and abnormal bronchial epithelium 

List of Tables 

l. 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 studi~s 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. \i:ortality 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 . . . . . . . . . . . . . . . . . . 

lOA. Summary of results of retrospective studies of smoking and 

detailed sites of the oral cavity by type of smoking . . . 

11. Oi'Itline 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 . . . . . . . . . . . . . . 

IS. Summary of results of retrospective studies of smoking and 

cancer of the bladder . . . . . . . . . . . . . . . . 

15A. Summary of results of retrospective studies of cigarette 

Page 

168-9 

149 

152 

156 

161 

164 

168 

171 

174 

175 

198 

201 

206 

214 

216 

220 

221 

smoking and cancer of the bladder in males . . . . . . 222 

16. Summary of methods used in retrospective studies of 

smoking and cancer of the stomach . . . . . . . . . . 226 

17. Summary of results of retrospective studies of smoking 

and cancer of the stomach . . . . . . . . . . . . . . 227 

126 
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 lO states---the so-called Death Registration Area of 1900) it can 

be seen that the number of cancer deaths per year has increased markedly 

I Figure l). 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 

lery 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 1947--48 (91) and in 

Iowa in 1950 ( 148). Each body of material has its virtues and weaknesses. 

Mortality statistics report on the national experience and cover longer time 

spans than the specialized sources, but the diagnostic information in the 

death certifications is less reliable and complete. Recent studies of medical 

certifications have demonstrated that the quality of information for most 

714-422 0--64-10 127 
MORTALITY FROM CANCER (All sites), U.S. DEATH 

REGISTRATION AREA Pl OF 1900, 1900-1960 

70 

RESIDUAL 

INCREASE 

60 

0 "' 

z so :;. 

:::> 

0 

:I: 

t. 

:I: "'

1-

... 40 w 

0 

"" INCREASE w 

u DUE TO z 

... AGING u 

LL 30 0 

c:i 

z 

20 INCREASE 

DUE TO 

GROWTH OF 

POPULATION 

CANCER 

DEATHS IN 

1900 

FIGURE l. 

Includes Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, Connecticut, 

New York, New ] ersey, 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 
AUSTRIA 

FINLAND 

ENGLAND & WALES 

SWITZERLAND 

FRANCE 

GERMANY FR 

DENMARK 

NETHERLANDS 

UNITED STATES 

.t.USTRALIA 

CANADA 

J.t.PAN 

IT .t.L Y 

IRELAND 

NORWAY 

SWEDEN 

ISR.t.EL 

DENMARK 

.t.USTRIA 

GERMANY FR 

NETHERLANDS 

SWITZERLAND 

ISRAEL 

C4NADA 

FINLAND 

IREL.t.ND 

SWEDEN 

UNITED STATES 

FRANCE 

NORWAY 

AUSTRALIA 

ITALY 

U.PAN 

AGE-ADJUSTED MORTALITY RATES FOR 

CANCER- ALL SITES, IN 17 COUNTRIES 

1958-1959. (1) 

RATE PER 100,000 

0 50 100 150 200 .. 250 

MALE 

I 

FEMALE 

I FIGURE 2. 

U.S. data age-adjusted to total population of the continental United States, 1950. 

Source: Calculated from Segi, M., and Kurihara, M. (317}. 

and New York have been in operation long enough to provide reliable data 

on incidence trends over the past two decades. The morbidity surveys for 

1947--48 produced a comprehensive report on cancer incidence in large 

cities with very good medical care 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 1

1

1 

ENGLAND 

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 

LUNG, BR NCHUS & I TRAfHEA I 

STOMACH 

I 

UCCAL CAVITY & 

PHAiYNX 

====~~~ ••••••••••• ESOPrGUS 

I 

·····•····•····1 I I ~~~~f!!!f::"::: BLADDER & URINARY ~ TRACT\ (excludit 9 Kidn•rl 

I 

LARYNX 

I 

FIGURE 3A. 

U.S. data age-adjusted to the total population o/ 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 paUerns of risk for 

130 
AGE-ADJUSTED MORTALITY RATES FOR CANCER 

OF 6 SITES IN 6 SELECTED COUNTRIES - FEMALES 11 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 

EHGLAMD 

JAPAN 

FIMLAHD 

CANADA 

UNITED STATES 

NORWAY 

RATE PER 100,000 POPULATION 

I 

LUNG, BRONCHUS & TRACHEA 

I I I 

! I 

I 

I 

STOMACH 

I 

BUCCAL CAVITY & PHARYNX 

I , I 

~=~~~~r=--1·--1~- ESOPHAGUS 

g- I 

BLADDER & 

I ••••I I URINARY TRACT 

(excluding Kidney) I 

I t I 

r FIGURE 3B. 

I 

I 

LARYNX 

I 

I 

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 differences 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 REGISTRIESUPPER NEW YORK STATE 1958-1960 AND 

CONNECTICUT 1959. 

Lung and bronchu1 

bophagu1 

Stomach 

Buccal cavity 

and pharynx 

Bladder and other 

urinary organ1, 

excluding kidney 

Larynx 

MALES FEMALES 

- MORTALITY, UNITED STATES WHITE POPULATION, 1959-1961 

Em INCIDENCE, UPPER NEW YORK STATE, 1958-1960 

rzzz::l 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 
cia! 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., 1959-61) (252) 

from cancer for the six sites common to both sexes are given below: 

Male/Female Ratio 

Whites Larynx ________________________ _ 

Lung and bronchus ______________ _ 

Oral cavity _____________________ _ ESophagus ______________________ _ 

Stomach------------------------

Urinary bladder_ ________________ _ 

10.8 

6. 7 

3.8 

4.1 

2.0 

1.3 

Male/Female Ratio 

Nonwhites 

7.6 

6.2 

3.3 

4.2 

2.3 

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 l. 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 Cuss 

Information on income class gradients in cancer risks by site was secured 

in the morbidity surveys of ten U.S. metropolitan areas in 1947-48 (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 

i"emales 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 re· 

corded for native.born white males and females. Lung cancer mortality is 

about one.third higher among the foreign·born, again for both sexes. No 

important differential between native- and foreign-born has been observed 

for 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 (144). 

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 

born 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-horn, 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-born 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. This form 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 shUt in 

risk. The rates for stomach cancer, however, have been declining steadily. 

This has led some observers to conjecture that the rise in lung cancer and the 

decline in stomach cancer may represent two aspects of the same phenomenon, 

a progressive transfer of deaths to lung cancer which might formerly have 

been certified as stomach cancer. Detailed examination of the data on 

possible compensatory effects by country, sex, age and other variables conclusively rules out diagnostic artifacts of this type as a possible 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 1958-60, and 

the Connecticut experience revealed a similar displacement. A possible 

reason for this increase in case reports of prostatic cancer to registers may 

he found in more careful examination by pathologists of prostates removed 

135 
:z: 

0 

>= 

< _J 

::::> 

ll. 

0 

ll. 

g 

0 

::'! 

"' UJ 

ll. 

w 

>--

< 

c:: 

TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR 

CANCER BY SEX- All SITES AND RESPIRATORY SYSTEM 

IN THE UNITED STATES, 1930-1960. tll 

100 

MA 

50 

CANCER, ALL SITES 

- CANCER, EXCLUDING RESPIRATORY SYSTEM 

-=-- CANCER, RESPIRATORY SYSTEM ONLY 

FIGURE 5. 

Age-adjusted ta 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 asympto· 

matic prostatic carcinomas. The mortality data relate to clinically active 

prostatic carcinomas and in this instance probably give a more accurate 

assessment of changes over time than the registry data. 

AGE-SPECIFIC MoRTALITY FROM LuNG CANCER 

The schedules of age-specific lung cancer mortality rates for males studied 

in five successive time periods from 1914 to 1960 are shown in Figure 7 

(dotted lines) . It can be seen that the rate rises to a maximum at age 70 

and then declines gradually thereafter. Incidence data from cancer registers 

provide a close parallel ( 112) . 

136 
0 

0 

0 

o' 

0 

TRENDS IN AGE-ADJUSTED MORTALITY RATES FOR 

SELECTED CANCER SITES BY SEX 

20 

10 

.5-

IN THE UNITED STATES, 1930-1960. 1

1

1 

--......... ............... 

. . 

. . 

... ·· .................. ..·· ............... .. · 

.·· ............... 

--. :...:· t-_:1, 

. 

. . 

'-- .· 0~7 ~,......,-f-~ ......... -·~•i•c;;;,.;.;,;·• • .CJ:'":.:C':...:J•"> 

. 

MALES 

/ 

/ 

---

)-

-t-

................. 

..· 

..: -..... -· 

.. ····· 

~-- -- ~----

' ' 

--- - ',, 

..... ····· -

1-

1930 1940 1950 19601930 1940 1950 1960 

LUNG AND BRONCHUS 

STOMACH 

o.o-o-o-o BLADDER AND OTHER URINARY ORGANS 

(EXCLUDING KIDNEY) 

PROSTATE 

FIGURE 6. 

ESOPHAGUS 

- BUCCAL CAVITY AND PHARYNX 

LARYNX 

KIDNEY 

Data are for the white population, 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 

0 

0 

0 

o· 

0 

a:: 

w 

Q_ 

w 

t-

< 

a:: 

1914, 1930-32 , 1939-41, 1949-50, 1959-61. Ill 

AGE 

FIGURE 7. 

Data are for the white population. 

Sources: Dorn, H. F., and Cutler, S. ]. (91). 

Unpublished calculations of the Biometry Branch, National Cancer Institute, U.S. Public 

Health Service. 

to the admixture of cohorts with differing mortality experiences. When the 

points representing mortality rates among members of the same cohort group 

are connected, from each dotted-line curve to the next, the new curve (each 

of the bold lines) represents the mortality rates over time for the members 

of a cohort. Thus, to cite the cohort born around 1880 as an example, the 

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. Ill 

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. The pattern would suggest that the effects 

noted may he 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 clin· 

ical 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 prepared 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 mir:roscopic confirma· 

tion. Sufficient time has now elapsed to permit the tumor registries in 

Connecticut ( 136) and New York ( 112) to supply convincing evidence for 

a true increase in lung cancer. Diagnostic comparability is a far less im· 

portant consideration in the review of data collected by cancer registries. 

Between 194 7 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 fwm 17.8 in 194 7 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 con· 

tribute valuable information.· The records of large general hospitals where 

diagnostic accuracy of lung cancer has been uniform and excellent for many 

years also support the thesis of a 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. 

(56), 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 principles of carcinogenesis. 

FuNDAMENTAL 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) ( 40, 351). More often, however, it appears 

to be characterized by a slow multi-stage process, preceded by non-specific 

tissue changes, as exemplified by cancers arising in burns. Evidence is 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 polycyclic 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. The 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), 

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 be susceptible to the carcinogenic action of many different 

chemicals as well as of complex materials. Another test, which has been used 

in some studies and can be read within five days after painting the skin of 

mice with a carcinogen, consists of determining 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. 

Skin 

Many investigators have shown that the application of tobacco tar to the 

skin of mice and rabbits induces papillomas and carcinomas (31, 42, 92, 93, 

714--422 0-64-11 143 
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 papillomas (372, 373). Since the 

carcinogenic potency of a smoke condensate can be altered by varying conditions of pyrolysis, the manner of preparation of the tar is of importance 

(392). This may be one reason for the negative reports (154, 262, 267, 

268) encountered in the literature. Extracts of tobacco usually have weaker 

carcinogenic activity than do the condensates of cigarette smoke (93, 390). 

Gellhorn (126) and Roe et al. ( 290, 293) have reported that condensates 

of cigarette smoke have cocarcinogenic or promoting properties. It was 

found that the application of a mixture of benzo (a) pyrene plus condensate 

of cigarette smoke to the skin of mice resulted in the production of many 

neoplasms, whereas the same concentration of benzo (a) pyrene alone failed 

to elicit tumors. Gellhorn ( 126) found that the tobacco smoke condensate appeared 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 con· 

densates 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 hydro· 

carbons (Table 2, Chapter 6). Benzo (a) pyrene is present in much larger 

concentrations than is any other carcinogenic polycyclic hydrocarbon. The 

inability to account for the carcinogenicity of the tobacco products, except 

to a very minor degree, by the amount of benzo (a) pyrene present was 

unanticipated. Both Druckrey (92) and Wynder (372) emphasized that 

144 
the benzo(a)pyrene concentration of various tobacco and smoke prepara· 

tions is only sufficient to account for a very small part of the carcinogenicity 

of these materials. One hypothesis suggests that promoting agents present 

in tobacco and tobacco smoke, such as various phenols, enhance the potency 

of the carcinogenic hydrocarbons so as to account for 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 dis· 

covery (74, 74A, 291, 292, 362) that ,8-propiolactone, used as a sterilant and 

preservative, is carcinogenic for mice. Coumarin, a 8-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 

y·lactone, ,8-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-lactones (patulin, penicillic acid, methyl 

protoanemonin) and 8-lactones (parasorbic acid lactone and aflatoxins). 

RADIOACTIVE COMPONENTS 

Potassium 40, a ,B·emitter, has been reported to be a source of radioactivity 

in cigarette smoke. The amounts of this activity taken into the lung, even by 

the heavy smoker, are minute when compared with the daily uptake of K 40 

from the diet. Furthermore this material is highly soluble and it is rapidly 

eliminated from the lung tissue thereby 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 

unpublished 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 application 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 carcinogenic 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 tQbacco 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. 

(108)-

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 LO 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 now working in industries 

involving exposure to "carbon black" is being debated ( 108). The chemical and physical properties of "carbon black" vary widely (109, llO). 

As early as 1922, Passey (266) found that cancer of the skin could be 

produced experimentally by extracts of soots. More recently, Falk et a!. 

lll1) 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, llO) found furnacetype black rich in pyrene, ftuoranthene, benzo (a) pyrene, benzo (e) pyrene, 

anthanthrene, benzo ( g, h, i) perylene, and coronene in particles having an 

average diameter of 80 IDft 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 grn. 

(307). 

COAL TAR AND PITCH 

Butlin (50) in 1892 described cancer of the skin as an occupational 

hazard in the coal tar industry. The distillation of coal tar yields many 

different organic compounds 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, t~e 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 

132) reported an interesting case of pulmonary cancer in a workman exposed 

to hot tar containing three percent benzo (a) pyrene. He estimated that 320 

~- 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 hut by exposure to 

impurities in oils used in the process of purification ( 165, 203) . Recent 

Work (321) has confirmed the view that refined paraffin wax does not 

contain polycyclic aromatic hydrocarbons and that it is not carcinogenic. 

The danger incidental to exposure to mineral oils has been decreased by 

extraction of carcinogenic hydrocarbons with sulfuric acid ( 164). Bioassay 

of mineral oils indicates that their content of carcinogens varies with their 

147 
geographic ongm (348). Animal tests show that the carcinogenicity of 

mineral oil increases as the temperature of distillation increases or when 

cracking is instituted for the formation of new compounds. A variety of 

carcinogenic compounds has been isolated from different fractions. Some 

fractions presumably free from benzo{a)pyrene have nevertheless been 

found to be carcinogenic. Coal tar contains 0.3 to 0.8 percent benzo(a). 

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 he induced in man 

by industrial exposure to soots, coal tar and pitch, and mineral oils. AU 

of these contain various polycyclic aromatic hydrocarbons proven to be 

carcinogenic in many species of animals. Some of these hydrocarbons 

are also present in tobacco smoke. It is reasonable to assume that these 

can be carcinogenic for man also. 

CANCER BY SITE 

The 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 he discussed further at this time. This decision does not imply a conclusion that 

the findings must he 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 pros· 

pective 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, and all 

causes of death; each prospective study and all studies 

I 

United Cali- Cali- i CanaSite of cancer British I Men in States fornia !ornia I dian doctors 9 States veterans occupa- Legion 1 vrterans tiona!' 

--~ --~ --~ ---

Lung 

hronchus, 

and 

Expected 

Observed 12\l 6.4 233 

23.4 519 43.3 138 8,7 - ~ 91~g_l- 1ft2-3' Ratio 20.2 10.0 12.0 15.9 4. 9 II. 7 ---·--~ 

Larynx, 161 Observed 7 17 14 3 fi 5 Expected 0.0 1.3 2. 4 0.0 4. 0 0.0 Ratio --------- I3.I 5.8 --------- 1.5 --------- ------------ --~ --- Oral Cavity, Observed 6 22 54 7 10 20 )4(}-8. Expected 0.0 7. 8 R.I 7. 2 5. 2 5. I 

Ratio --------- 2.8 6.6 1.0 1.9 3. 9 - --- --~ --~ --~ --~ --~ 

F.>'Opbagus, I50 Observed 7 I8 33 4 9 22 Expected 3. 3 2. 7 5. 2 5. 5 I. 8 6. 8 Ratlo 2.I 6. 6 6. 4 0. 7 5. I 3. 3 --------~ --------- lllactder, 18I Observed 12 41 55 13 7 38 Expected I3. 9 17.2 31.4 2. 2 1.8 22.3 Ratio 0. 9 2.4 1.8 6.0 4. 0 1.7 --------- --~ --~ --- Kidney, 180 Observed 8 21 34 10 6 13 Expected 0.0 14.0 23.1 0.0 8.3 9. 5 

Ratio --------- 1.5 1.5 --------- 0. 7 1.4 

--------------- Stomach, 151 Observed 3I 76 90 24 25 76 Expected 28.3 33.7 fii. 5 31.4 20.5 41.2 Ratio 1.1 2. 3 1.5 0.8 1.2 1.9 --~ ------------ Prostate, 177 Observed 15 51 106 4 19 48 Expected 29.0 32.4 53. 7 8.6 22.1 32.3 Ratio 0. 5 1.6 2.0 0. 5 0. 9 1.5 

-----~ --~ ------ .~II Other Sites Observed l16 290 671 141 I06 237 Expected 112.0 228.3 505.7 109.4 120.6 192. 1 Ratlo 1.0 1.3 1.3 1.3 0.9 1. 2 

--- ---~----- --- -~ll Causes of Observed 1,o72 3, 781 7, 236 1, 456 11, 2&1 ~.001 

Death. Expected 1, 1oi. s 2, 227.7 4,043.I 818. 5 799. 4 2, 420.1 Ratio 1.~ 1. 70 1. 79 I. 78 I. 58 1. 65 

1 Inc!Ldes all cigarette smokers (current and ex-smokers). 1 International Statistical Classification number. 

Mpnin I TotRI 25 

Stat.s 1 

___ , ___ 

399 II, 833 41.5 170.3 9. fi 10.8 

23 75 6. 3 14.0 3. 7 5. 4 ---

33 152 

3. 6 37.0 9. 2 4. I --~ 

20 l13 8. 4 33.7 2. 4 3. 4 

---

50 216 22.8 111.6 2. 2 1.9 --~ 

28 120 24. I 79.0 1.2 1.5 --~ 

91 413 68.6 285.2 1.3 1.4 ---

75 318 74.9 253.0 1.0 1.3 ---

571 2,132 423.8 1,692.0 

1.3 1.3 --~ 

6, 813 26,223 

4,!83.3 15,653.9 1.63 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 the United States were those of Ochsner 

and DeBakey (258) who were impressed by the probable relationship be. 

tween cigarette smoking and lung cancer. The initial observations prior to 

Muller's work were not, however, corroborated by surveys including controls 

without lung cancer. 

As early as 1928, Lombard and Doering (221) in a 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 individuals 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. The 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 Muller 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 25 additional retrospective (38, 82, 138, 147, 150, 152, 

192, 199, 207, 2ll, 222, 236, 238, 277, 283, 301, 3ll, 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 Selection1. Males and/or females 

2. Occupational groups 

3. Hospitalized cases 

4. Autopsy series 

5. Total lung cancer deaths in an area 

6. Samplings of nationwide lung cancer 

deaths 

Control Selection--

1. Age matching vs. age groups 

2. Healthy 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 Interviewing-

}. Mailed questionnaires 

2. Personal interviewing of subjects (or 

relatives) and controls 

a) By professional personnel 

b) By non-professional personnel 

Tobacco.use Histories-

!. 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 

1 L 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 non-smokers 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.-0utline of methods used in retrospective studies of smoking zn relation to lung cancer 

Number of persons and method of selection 

Investigator, year, and Country Sex of Collection of data 

reference cases Cases Controls 

Muller 193Q (250) Germany M 86 Lung cancer decedents, Biirger 86 Healthy men of the same age Cases: Questionnaire sent to relatives of 

Hospital, Cologne. deceased. Controls: Not stated. 

Schairer and Sehoeniger Germany M n Cancer decedents autop•ied at Jena 270 Men of the cit~· of Jena al!'ed 1>3 and Cases: Questionnaire sent to next of kin 1943 (309). Pathological Institute, 1930-1941. M (average ageoflung cancer victims- (195 for lung canr<>r). Controls: Ques· 53.9). tlonnaire sent to 700. 

Potter and Tully 1945 (280) U.S.A. M 43 Male patients aged over 40 in Mas· 1,847 Patients of same group with Cases and controls interviewed in clinics 

sacbusetts cancer clin!cs with cancer diagnoses other than cancer. of respiratory tract. 

Wassink 1948 (363) Nether lands M 134 Male clinic patients with lung can- 100 Normal men of same age llJ'OUps as Case.s: Inten·iewed in clinic. Controls: cer. cases. Not stated. 

Schrek ct al., 1950 (311) U.S.A. M 82 Male lung cancer cases among 5,003 522 Miscellaneous tumors other than Smoking habits recorded during routine 

patients recorded, 1941-48. lung, larynx and pharynx. hosp!tal interview. 

Mills and Porter 1950 (237) U.S.A. M 444 Respiratory cancer decedents In 430 Sample of residents matched by age Cases: Relatives queried by mall ques- Cincinnati, 1941}-45 and in Detroit, in Columbus, Ohio, from census tra~ts tfonnalre or personal visit. Controls: 

1942-46. strat !fled by degree of air pollution. House-to-bouse interviews. 

Levin ct al., 1950 (207) U.S.A. M 236 Cancer hospital patients diagnosed 481 Patients in same hospital with non- Cases and controls: Routine clinical lung cancer. cancer diagnoses. history taken before diagnosis. 

Wynder & Graham 1950 U.S.A. M-F 605 Hospital and private lung cancer 780 Patients of several hospitals with Nearly all data by personal interview; a (381). patients In many cities. diagnoses other than lung cancer. few cases by questionnaire; a few from 

Intimate acquaintances. Rome interviews with knowledge or presumption of diagnosis, some with none. 

McConnell et al., 1952 (236) England M-F 100 Lung cancer patients, unselected, 200 Inpatients of same hospitals, Personal Interviews by the authors of in 3 hospitals In Liverpool ares, matched by a~e and sex, without can· both cases and controls, with lew ex- 1946-49. cer, 194'1-50. ceptions. · 

Doll and Hill 1952 (82) Great M-F 1,465 Patients with lun!! cancer In hos· 1,465 Patients in same hospitals, Personal interviews of cases and controls 

Britain. pitals of several cities. matched by sex and age group; some by almoners. 

with cancer of other sites, some with· out cancer. 

Sadowsky eta\., 11153 (301) U.S.A. M 477 Patients with lung cancer In bos- 615 Patients In same hospitals with Ill· Personal questioning by trained Inter· pitals ln 4 states. · nesses other than cancer. viewers. 
l\'ynder and ComtleJd U.B.A. M 63 PhysJctans reported tn A.M.A. 133 Phy!'!lctans of sarne group dying of Mall Questionnaire to estates of decedents 19.53 (3711). Journal as dying of cancer of the canrer of ce.rtafn other sites. lung. 

Koulumles 1953 (192) Finland M-F 812 Lung cancer patients diagnosed at 300 Outpatients of same hospital aged Cases and controls questioned about one hospital In 16 years. over 40, living In similar circum- smoking habits when taking case stance•. and without cancer, February historiP.s. 

and March 1952. 

Lickint 1953 (211) Germany M-F 246 Lung canrer patients In a number 

of hospitals and clinics. 2.002 Sample of persons without cancer Personal interviews by stall members of 

living in the same area and of same sex cooperatin~ hospitals and clinics, 

and age range as cases. corresponding In time to Interviews of CSS!'S. 

Breslow Pt al., 1954 (38) U.S.A. M-F 518 Lung canrer patients in 11 Callfor- 51R Patients admitted to same hospitals Cases and controls questioned by trained 

nia hospitals, 19411-52 about the same time, for conditions interviewers, each matched pair by the 

other than cancer or chest disease, ~~ame person. matched for race, sex, and age group. 

Watson and Coote 1954 U.S.A. M-F 301 All patients of Thoracic Clinic at 468 All patients of same clinic during The 769 consecutive patients of case and 

(365). Memorial Hospital who were diag- same period with diagnoses other than rontrol groups were questioned by the 

nosed lung cancer, 1 115()-52. lung cancer. same trained interviewer. 

Gsell 191\4 (138) Switzerland M 135 Men with diagnosis of bronchial 135 Similar hospital patients with dlag- Personal interviews, all by the same carcinoma. noses other than lung cancer, anrl of person. the same age. 

Randig 1954 (283) Germany M-F 448 Lung cancer patients In a number 512 Patients with other diagno~es, Controls were interviewed at about the 

of West Berlin hospitals, 1952-1954. matched for a~e. same time .... the cases, each case- control pair by the same physicianStocks and Campbell 11155 (337). (Preliminary; see 19m report below.) 

Wynder et al., 1900 (375) U.S.A. F 105 Patients with lung cancer In sev- 1,304 Patients at Memorial Center with Cases: Personal interview or (jUestlonera! New York City hospitals, 1953- tumors of sites other than respiratory naire mailed to close relatives or friends 55. or upper alimentary, 1953-11155. Controls: Personal interview. 

Segi et al., 1957 (316) Japan M-F 207 Patients with lung cancer in 33 5,636 Patients free of cancer in 420 local Cases and controls by personallnter>iew 

hospitals In all parts of the country, health centers, selected to approxi- using lon~ questionnaire on ocrupa- 195.3-55. mate the sex and a~e distributions of tiona] and mc<iicai history and living ca5PS. hahits. 

Mills and Porter 1957 (238) U.S.A. M-F 578 Residents of defined areas dying of 3,~10 Population sample approximately Cases: From death certificates, hospital 

respiratory cancer, 1947-55. proportional to rases as regards areas records, and close relatives or friends. 

of reslrlence, and 10 years or more in Controls: Personal home visits or telethe area. phone cn.lls, usually interviewing housewife. 

Stocks 1957 (335) England M-F 2,356 Patients sutlerlng from or dying 9,362 Unse!ectcd patients of the same Cases: Histories taken at the hospital or with lung cancer within certain area admitted lor conditions other from relatives by health visitors. areas. than cancer. Controls: Personal interview in hospital. 
TABLE 2.--0utline of methods used in retrospective stu dies of smoking in relation to lung cancer-Continued 

Number of persons and method of selection 

Investigator, year, and Country Sex of Collection of data reference cases 

I 

Cases Controls 

Schwartz and Denoix 1957 France M 002 Patients with bronchopulmonary 1,204; 3 groups: patients in same hospi- Personal interviews in the hospital; cases (313). cancer in hospitals In Paris and a tals with other cancer, with non- and controls at about the same time by few other cities. cancer illness, and accident cases, the same interviewer. 

matched by age ~oup. 

- Haenszel et al., 1958 (150) U.S.A. F 158 Lung cancer patients available for 339 Patients in same hospital and service Personal Interviews by resident, medical 

interview In 29 hospitals, 1956-57. at same time, next older and next social worker, or clinic secretary. 

younger than each case. 

Lombard and Snegireff U.S.A. M 500 Men dying of lung cancer, micro- 4,23~ Controls in 7 groups including Personal interviews by trained workers. 

1959 (222). sooplcally confirmed, 1952-53. volunteers, hospital and clinic pa- tlents, random population sample, and house-to-house survey samples. 

Pernu 1900 (277) Finland M-F 1,006 Respiratory cancer patients in 4 1,773 Cancer-free persons recruited by Cases: From case histories or mailed 

hospitals and from cancer registry Parish Sisters of 2 Institutes in all questionnaires. between 1944 and 1958. parts of the country. Controls: Questionnaires distributed by Parish Sisters. 

Haenszel et al., 1962 (147) U.S.A. M 2,191 Sample of 10 percent of white 31,516 Random sample from Current Cases: By mail from certifying physl- male lung cancer deaths in the U.S. Population Survey used to estimate clans and family informants. 

in 1958. population base. Po8.ulation: Personal interview by ensus enumerators. 

Lancaster 1962 (199) Australia M 238 Hospital patients with lung cancer 476 Two groups, one with other eanced Personal interviews of both cases and one with some other disease, matche controls In hospitals. by sex and age. 

Haenszel and Taeuber U.S.A. F 749 Sample of 10 percent of white 34 339 Random sample from Current Cases: By mall from certifying physi- 1963 I (152). female lung cancer deaths in the Population Survey used to estimate clans and family informants. 

U.S. in 1958 and 1959. population base. P~ulatlon: 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 consump· 

tion, found a significant association between smoking of any type and lung 

rancer (138, 199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381); 16 

~tudies yielded an even stronger association with cigarettes alone as compared to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236, 237. 

238, 277, 283, 301, 311, 314, 335, 379) when these forms "f smoking were 

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. 

AMOUNT SMOKED 

Twenty-six of the studies quantitated the amount of smoking per day 

either by combining weights of tobacco consumed in any form, or, more 

often, by quantities of the specific forms of tobacco. In each of the studies 

inrestigating 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). 

On!"- 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 

a~ 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 ll 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 

rlass; 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, 

2ll, 314); in one of these ( 314), where relative risks were derived indirectly 

by the Cornfield 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 clu&racteristics in retrospective studies on lung cancer and tobacco use 

"~~-

Males Females 

Ref&· Cases Controls Cases Controls 

Authors ence Year Remarks 

Num· Percent Percent Num· Percent Percent Num- Percent Percent Num- Percent Percent 

ber non· heavy ber non- heavy ber non· heavy ber non- heavy 

smokers smokers • smokers smokers • smokers smokers 1 smokers smokers I 

------- ~-- ---------------------

Miiller .....•... --------- (250) 1939 86 3. 5 66.1 86 16.3 36.0 (') (') (') (') (') (') 

Schairer & Schoenlger •.. (309) 1943 93 3. 2 31.2 270 15.9 9. 3 ~·) r (') ~·) (') (') 16 female cases not analyted. 

Potter & Tully ••.•...... (280) 1915 43 7.0. 30.2 1, 847 26.0 230 ') ') (') ') (') (') Wassink ________________ (363) 1918 134 4. 8 54.8 100 19. 2 19. 2 (') ') (') (') (') (') Percentages estimated from 

chart. 

Schrek et aL ... --------- '311) 1!150 82 14.6 18.3 622 23.9 9.'2 (f) (') (') (') (') (') Mills & Porter __________ (237) 1950 444 7. 2 (") 430 30.5 (") (') (') (') (') (') (') Levin et aL _____________ (207) 1950 236 15.3 ('') 481 21.7 (") (') (') (') (') (') (') Quantity smoked not con-

. 2s.o sidered . Wynder & Graham •.•.• (381) 1!150 605 1.3 51.2 780 14.6 19.1 40 57.6 552 79.6 1.2 

McConnell et aL •...... (236) 1!152 93 5. 4 38.5 186 6. 5 23.2 7 57. 1 (") 14 78.6 (") Doll&Hill _____________ (82) 19.52 1. 357 0. 5 25.1 1.357 4. 5 13. 4 108 37.0 11.1 108 54.6 0.!1 Percentage "heavy" smokers 

understated. 

Sadowsky et aL ........ (301) 19tl3 477 3" 8 (") 615 13. 2 (") (') (') (') (') (') (') Gradient with amount smoked. 

Wynder & Cornfield ••.. (379) 19tl3 63 4.1 67.6 133 20.6 2!1. 3 (') (') (') r) (') (') 

Koulumi~"---··-------- . (192) 19tl3 812 0.6 58.9 300 18.0 25.0 (") ('') (") ') (') (') Lickint. ________________ (211) 1!1tl3 224 1.8 35.8 1.000 16.0 4. 8 22 64.0 4. 5 1, 002 00.4 0.1 Breslow et aJ.. __________ (38) 1954 518 3. 7 74. 1 518 10.8 42.7 (") (") (") (") (") ('') Data Include 493 males, 25 

females. 

Watson & Conte ........ (365) 1!154 265 1.9 71.7 287 9. 7 51.6 36 58.3 2. 8 181 82.0 1. 1 GselL ___________________ (138) 1954 135 o. 7 68.1 135 16.0 14.0 (') (') (') (') (') (') Randlg __________________ f283) 1954 415 I. 2 34.2 381 5. q 17.9 33 51.5 3.0 131 70.3 0 

Stocks & Campbell ••... 337) 1955 (See reference (335) below) Wynder eta! ............ (375) 1956 (') (') (') (') (') (') 105 56.2 16.2 1, 304 66.0 3. 4 Beg! et aL ______________ (316) 1957 166 ('') (") 2, 124 (") (") (") ('') (") (") (") (") Quantities smoked stated as averages only. DIIIerences are statistically significant. 

Mills & Porter .......... (238) 1957 484 8.4 26.0 1,588 27.6 5.3 94 83.0 4.3 1, 722 73.3 0. 5 Percent uheavy" smokers 

understated. Ouly 50% survey response among 

2M 

female cases. Stocks __________________ (335) 1957 2, 101 1. g 28.2 5,960 8. 7 22.3 57.6 17.2 3, 402 68.6 10.7 

Schwartz & Denoi< •.•.. (313) 11157 602 1 58.2 1, 'f.t 9. 5 36.2 (') (') (') (') (') (') 

Haenszel et aL .......... (150) 1958 (') (') (') (') (') 158 51. g 14.6 339 69.6 8.2 
,_. 

VI 

-I 

p 

H 

H 

>mbard & Sneg!retf ____ (222) 1959 llOO l.fl (•') 4, 2as I 11.0 ('') 

>mU------------------- (277) 1960 I, 477 6.6 34.6 713 37.2 20.8 

1.ensrel et aL ---------- (147) 1962 2,191 3. 4 41. g (') 16.2 12.0 

Lncaster _ ---- __ ........ 1199) 1962 238 2. 5 86.1 476 20.1 71.2 ~~enszel & Taeuber .... (152) '1963 (') (') ('•) (') (') (') 

------- ----------

' For this table heavy smokers are defined as those smoking 20 or more cigarettes per day. 'To be published. 'Doo• not apply . .. Data not given. 

(') (') (') (') (') 

129 85.3 26.4 1,060 91.6 

(') (') (') (') (') 

(') (') (') (') (') 

749 60.9 11 .• s (2) 67.3 

(') 

0. 7 

(') 

(') 

2. 5 

Authors• calculations r, 

heavy smokln~ based u 

ll[etlme num her of pacl of cigarettes. 

Quantities given grams per day. only ~ 

Population sample of 31,5 used as base. Not a cas control study. 

Population sample of 34,3: used as base. Not a cas control study. 

n 

• 

n 

6 

;g 
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-s~oker 

risk but approximately equal to that for the non-smoker. 

DURATION OF SMOKING 

Duration of smoking was considered m 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 cases and wntrols, 

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 difierences 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 smaking 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 difierence 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 ( 82 I, 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. 

Although in Breslow's study (38) of age-, sex· and race-matched case and 

control patients, the variable "quantity-smoked" was not held constant in 

the comparison when type of smoking though not quantity was controlled, 

an association was found between inhalation and lung cancer. In the 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) demonstrated similar relative risk ratios. 

HISTOLOGIC TYPE 

The earliest retrospective study which considered histologic type of lung 

cancer was by Wynder and Graham (381) in 1950. These authors presented 

data on smoking habits of male and female adenocarcinomatous patients and 

for female patients with epidermoid cancers which were but 25 in number. 

With this partial analysis only a hint of a higher proportion of smokers 

among female epidermoid cases could be derived. Of the 1,465 lung cancers 

in the Doll and Hill retrospective study (&2), 995 were histologically con· 

firmed (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 anapla8tic types as Group I and the adenocar· 

cinoma and bronchiolar or alveolar cell types as Group II, and the suggestion 

of a relationship between Group I and smoking ( 196), several ensuing 

retrospective studies dealt with this question. 

Breslow's study revealed a higher percentage of non-smokers among the 

patients with adenocarcinoma than among those with epidermoid types ( 38). 

In rapid succession six additional retrospective studies analyzed the relationship between histologic type of lung cancer and smoking. The 1956 

study of female lung cancers by Wynder eta!. {375) indicated that adeno· 

carcinomata apparently had little or no relationship to smoking but that a 

relationship did exist between smoking and the epidermoid and anaplastic 

types. Schwartz et al. (313), similarly, in 1957, found a highly significant 

714~422 0-64-12 159 
associatiOn between smoking of cigarettes, amount of smoking as well as 

inhaling, and the epidermoid and anaplastic types of tumors. No such 

association with "type cylindrique" was noted. In that same year Doll and 

Hill furnished Kreyberg with lung cancer slides from 933 British patients. 

Kreyberg, without knowledge of the patients' smoking history or clinical 

data, separated these into two groups. A strong correlation was found 

between smoking history and histologic type; smoking and amount were 

highly associated with the epidermoid and anaplastic types, and non-smokers 

were predominantly among the adenocarcinomatous types ( 86). 

In this study of lung cancer in women, Haenszel, et al. ( 150) found statis. 

tically significant relative risk gradients for amount of cigarette smoking 

among Group I cancer patients. No increased risk was established for 

Group II cancers. In his later study of a current mortality sample of white 

males for 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: I 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 17:1 and 25.5:1, respectively. 

Randig (283) also demonstrated a linear progression of risk with increasing 

amounts of daily tobacco consumption and an over-all ratio of 5.1:1 for all 

smokers to non-smokers among males and 2.2:1 for females. Schwartz 

and Denoix (313) reported similar findings in amount smoked daily and 

a risk ratio of smokers to non-smokers of approximately 8: 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 mortalitv 

as related to residence and smoking histories, calculated relative risk ratios 

of 4.1:1 for one pack or less daily and 16.6:1 for more than one p'ack 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 

Sadowsky et al. (301) 

Doll and Hill (82) 

Wynder and Graham (381) 

Breslow et al. (38) 

Randig (283) 

Schwartz and Denoix (313) 

Lombard and Snegireff (222) 

Baenszel (147) 

Baenszel (152) 

Yesr 

1953 

1952 

1950 I 

1954 

1954 

1957 

1959 

1962 

Sex Relative risk-Smokers: 

non-smokers 

M 4.6 

M 13.8 

M 13.6 

7. 7 8j!;C 50-59 

M 4. 6 " 6<HI9 

~~: ~ :: ~~}very heavy smokers 

M-F 5.1 M 2. 2 F 

M 8.0 

M 2. 4 li~ht smokers 34. I heavy smokers 

M 4. 1<1 pack/day 16. 6> 1 pack/day 

Unpublished F 2. 5<1 pack/day 10. S> I pack/llay 

' Calculated by Sadowsky et a!. (301) from other authors' data. 

Prospective Studies 

It 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 assumptions referred to above. The validity of such assumptions may at times he 

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 are 

included in a study, the estimates of risk bear high validity. 

Despite the criticisms leveled at the retrospective method in general and 

its obvious defects as practiced by some investigators, a number of the retro-

~:;pective 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 this 

point that certain shortcomings of the retrospective survey approach, some 

real and some exaggerated, led several courageous investigators to undertake 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, 84) . There then followed in rather rapid succession, five additional independent studies in the United States and Canada 

(25, 87, 88, 96, 97, 157, 162, 163), all but one of which continue to be active. 

The earlier study, by Hammond and Horn, among 187,783 white males aged 

50-69 years, initiated between January and May 1952, was terminated after 

44 months of follow-up ( 162, 163). This has been succeeded by the current 

Hammond study which broadened its age-base (35-89 years) and contains 

l,085,000persons (in25states) ofwhom447,831aremales (157). 

These studies have been described in detail, analyzed, and evaluated in 

Chapter 8 of this Report where a discussion of difierences 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 (84, 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 smoking classes, including combinations of 

cigarettes with pipes and/or cigars (25, 84, 88, 157, 1631. 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 (83), the ex-smoker ratio was less than the current smoker ratio 

even when cessation had occurred less than 10 years before entry into the 

study. This, however, was not true for the first Hammond and 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 ( 87, 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 cross· 

classification by these variables, and amount smoked as well, leads to cells 

with small numbers of deaths. Most prospective studies have thus far con· 

fined themselves to analyzing the effect of these additional variables on 

deaths from all causes, or in one case ( 157) from cardiovascular diseases. 

The current Hammond study is concerned with inhalation practices, but 

here also the total number of lung cancer deaths analyzed to date does not 

permit extensive classification by age, type of smoking, amount smoked 

daily, present smoking status, and age when smoking was begun. In the 

studies of total mortality ratios, duration of smoking, obviously immediately 

dependent upon the age of the individual, was in turn dependent upon age 

when smoking (cigarettes) was begun. Age when smoking began was also 

a determinant, not only of the number of cigarettes smoked daily, but of the 

degree of inhalation, with smokers starting at earlier ages very distinctly 

tending to smoke more 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 
TABLE 5.-Mortality ratios for lung cancer by srrwking status, type of smoking, and amount smoked, from seven prospective 

studies 

Study Doll and rrm 

Lung cancer deaths In StudY~-------------~------ ~---------------------- 129 Lung cancer deaths Non-smokers________________________________________ t3 

(Reference number) (83) 

MORTALITY RATIOS: All Smokers________________________ ------------------------- 12.8 1-14 gm. tobacco__________________________________________________ 6. 7 

1~24 gm. tobacco.------------------------------------------------ 12.3 25 gm. tobacco ____ ------------------------------------------------ 23.7 Current: •• 

Cigarettes only __________ -----....... ___ -------------------------- t:MJ. 2 <IO .. _. ____ _ _____ _ __ _ __ __ ____ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ___ ___ _ __ ___ _ _____ 4. 4 

11}-20_------------------------------------------------------ 10.8 

Ut~: :::::::::::::::::::::::::::::::::::::::::::::::::::::: } 43.1 

;:il pack t _- -----.---------------------------------------------------- >1 pack t -------------------------------------------------------------

~}Es~~j~~;::::::::::::::::::::::::::::::::::::::::::::::::::::::} Cigarettes, pipes and cigars ____ ------------ ______ --------------------- OccasionaL __________________________________________________________ _ 

Ex-Smokers: >to yrs. since stopped ..... _______________________ ----------------

<20 cigarettes. __________ ---------------------------------- __ _ 

>20 cigarettes. __ --------------------------------------------- <10 yrs. since stopped ... ----------------------------------------- <:MJ cigarettes .. _ .. _._ .... _. _________ . ___ •.. ___ .............. . >20 cigarettes .. _ .. ____ ._._._._ ........ _. ___ .......... _ ...... . 

<20 cigarettes (Irrespective or when stopped).-------------------- >20 cigarettes (Irrespective of when stopped).--------------------

•Current and ex-smokers combined. tMost recent Information. 

8.1 

43.8 

5. 4} 

9. 7 

5.0 

8.4 

t4- 6 

Ua.nunond 

and Hom 

448 

t25 

(163) 

10. 7 

tlO.O 

t5. 8 t7. 3 tl5. 9 t21. 7 

Dom 

635 

t56 

(88) 

6.0 

tl2.0 

t6.2 9.4 

us. 1 t23.3 

Dunn, Linden and BreslowOccupatlonal 

139 

t3 

(00) 

tl5. 9 ( 5)- 8. 3 (10)- 9. 0 (20)-19. 4 (30)-25.1 

(4())-28. 7 

13.6 

24.1 

Dunn, 

Buell and BreslowLegton 

98 

tl2 

(97) 

Best, Josle and Walker 

221 

ts 

(25) 

Hammond 

414 

tl6 

(157) 

----1-----1------

t4. 9 

4.2 

7. 4 

*25. 2 

tl1.7 

tS. 4 ua. 5 

} tl5. 1 

11.8 

15.1 

} tl.l 

t24. 4 

tS. I 

t9- 6 

} tl- 5 

-Data not available or not available for designated cia....,., ••Two Ca.!Uomia studies and current Hammond study Include all cigarette smokers (cigarettes and other and current and ex-cigarette smokers). 
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 

ATIEMPTS 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 I 6 ~. 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 ( 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 eta!. (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 

~moke. 

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. Hypefplastic 

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, hut 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 TO 

CARCINOGENS 

PoLYCYCLIC AROMATIC HYDROCARBONS.-Epidermoid carcinoma has 

been induced in mice by Andervont by the transfixion of the lungs or bronchi 

with a thread coated with a carcinogen (5) and by Kolin and Wiseley (191) 

by treatment with an aerosol of ozonized gasoline plus mouse-adapted 

influenza viruses. 

Kuschner et al. (197, l97a) 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. The changes 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 insuffiation of benzo (a) 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. 

VIRUSES.-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 CARCINOGENS.-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 bronchogenic 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 insufHation 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), Sunderman and Sunderman ( 342) induced bronchogenic carcinoma in rats by exposure to this compound. This 

166 
. group also found 1.59 to 3.07 p.g. of nickel per cigarette in the ash and in 

the smake 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 ar-

~enical 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 

been investigated only superficial1y. 

SUMMARY.-Genetic susceptibility plays a significant role in the development 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. (II, 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) 1 oss of cilia, (b) basal cell hyperplasia (more 

than two layers of basal cells), and (c) presence of atypical cells. The 

atypical cells had hyperchromatic nuclei which varied in size and shape. 

The arrangement of such cells was frequently disorderly (see illustration1 

below). Hyperplastic chan!!es were also seen in the bronchial glands. 

TABLE 6.-Percent of slides with selected lesions,' by smoking status and 

presence of lung cancer 

Group 

Percent of slides with cilia absent and 

averaging 4 or more cell rows in depth 

N~r Ns~~r !-------,------,-----,------

No cells Some cells All cells Total 

atypical atypical atypical • 

---------------------------1------ ---------------------------

CSS<'s without lung cancer Never smoked regularly ____________ _ 

Ex-cilmrette smokers_ ---------------- Cigarettes-~2 pk. a day_------------- Cigarettes->~-1 pk. a day ___________ _ Cigarettes-1-2 pks. a day ___________ _ Cigarettes-2+ pks. a day ___________ _ Lung cancer cases a __ _ 

65 

72 

36 

59 

143 

36 

63 

3,324 

3,436 

1,824 

3,016 

7,062 

I, 787 

2, 784 

LO 

3. 5 

0. 2 

0.03 

0.4 

4. 2 

7.1 

12.6 

26.2 

12.5 

0. 2 

0. 3 0.8 

4.3 

11.4 

14.3 

Ll 

4.1 

4. 7 

7. g 16. g 37.5 

26.8 

1 In some sections, two or more lesions were found. In such instances, all of the lesions were count.- 1 and are included in both individual columns and in the total column of the table. Lesions found at the edge or an ulcer were excluded. • These lesions may be called carcinoma-in-situ. 

'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 occa- 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 

I. Normal 

168 
2. Basal-cell hyperplasia-replacement of ciliary epithelium with a thick layer of cells 

resembling stratified squamous epithelium. 

3. Extensive basal-cell hyperplasia with numerous atypical cells. 

Source: Auerbach, Oscar. Special 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. The most severe lesion, aside from invasive 

carcinoma, consisted of loss of cilia, and hyperplasia up to five or more cell 

rows composed entirely of atypical cells. This lesion was never found 

among men who did not smoke regularly and was found only rarely among 

light smokers. However, it was found in 4.3 percent of sections from men 

169 
who smoked one to two packs a day, in 11.4 percent of sections from those 

who smoked two or more packs a day, and in 14.3 percent of sections from 

smokers who died of lung cancer (15). 

While epithelial changes were found in all portions of the tracheobronchial 

tree, quantitative differences were found between the changes in the trachea 

and those in the bronchi; hyperplastic lesions consisting entirely of atypical 

cells without cilia were found in all regions of the bronchial mucosa but only 

rarely in the trachea. It is notable that cancer rarely occurs in the trachea. 

In 35 children less than 15 years of age, Auerbach et al. (16) found the 

same percent of epithelial changes in the tracheobronchial tree as in the same 

number of adults who had never smoked regularly (16.6 percent of children 

and 16.8 percent of adults). No hyperplasia with atypical cells was seen 

in any section. 

Later, Auerbach et al. (l5a.) studied the morphology of the tracheobronchial tree from 302 women and 456 men with respect to additional variables.---

sex, age, pneumonia, and amount smoked. One or more epithelial lesions 

were found in 68.2 percent of sections from men smokers and 68.6 percent 

from women smokers when matched groups were examined. However, on 

further study, hyperplastic lesions composed entirely of atypical cells were 

found in 6.9 percent of the sections from the male group and in 2.5 percent 

of those from females. 

Matched groups of male cigarette smokers of two age groups (averages 

of 37 and 67 years) were compared. Many more lesions, characterized by 

a large number of cells with atypical nuclei, were observed in the older than 

in the younger group. In a parallel study of women who did not smoke 

(average ages of 46 and 76 years), no difference in the number or type of 

lesions was noted. Few changes in the bronchial epithelium were found in 

sections from 27 women non-smokers over 85 years of age. 

Occasional atypical changes were found in women non-smokers (a) who 

died of pneumonia, (b) who died of various other causes hut 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 

bronchial epithelium to he 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 tobacco. 1 

Number Group of SUb· 

ject• 

7th set (none vs. pipe vs. cigarette)' 

Non-smokers . ---------------------- 20 

Pipe smokers.----------------------- 20 

Cirarette smoker .. s .. ··-------------- 20 8th set (none vs. pipe vs. cigarette) 

Non-smokers ____ ._------------------ 25 

Pipe smokers_----------------------- 25 Cigarette smokers _________ ---------._ 

9th set (none vs. cigar vs. cigarette) 25 

Non-smokers 35 

Pipe smokers._=========::=========== 35 

Cigarette smokers .. ------------------ 35 

'Modified table from Auerbach et al. (158). ' Carcinoma in situ. 

Total Sections with 1 sections or more epithelial with epi- lesions thelium 

Number Percent 

------

985 2H 21.7 924 60.1 65.5 914 885 96.8 

I, 246 285 22.9 1,164 800 68.7 1,126 1.064 96.3 

1, 706 467 27. 1 I, 733 I, 573 90.8 I, 526 I, 511 99.0 

3+1'(>11 rows with cilia present Cilia ab•ent 

Number Percent Number Percent 

------------

110 11.2 101 10.3 352 38.1 117 12.7 810 88.6 116 12.7 

167 13.4 132 10.6 451 38. 7 172 14.8 999 88.7 238 21. I 

216 12. 7 281 16.5 694 40.0 247 14.3 I, 414 92.7 428 28.0 

• Triads were matched for age, occupation, residency and (for smoker.) by amount or tobacco used. 

Atypical cells Atypical cells present with cilia Entirely atypical cells with cilia present absent absent' 

Number Percent Number Percent Number Percent 

---~-- ------------

26 2.6 3 0.3 0 342 37.0 29 3. I 0 870 95.2 111 12. I 35 3.8 

9 0. 7 I 0.1 0 445 38.2 38 3. 3 0 1,008 89.5 205 IS. 2 70 6.2 

14 0.8 3 0. 2 0 I, 275 73.6 173 10.0 5 0. 3 I, 493 97.8 417 27.3 196 12.8 
bronchial epithelium of 43 out of 72 ex-smokers. These cells were llot 

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 observeu 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 observations 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 other sites, such as the 

cervix, skin, and larynx. 

Lung cancer was induced in animals by radioactive substances ( 198, 217), 

chemical carcinogens ( 198, 340) , and air pollutants plus influenza virus 

( 191). These studies have demonstrated the occurrence of extensive atypical 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. 

SUMMARY.-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, 1961 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 

types. 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 Krey· 

!:>erg's conclusions. These investigators, analyzing the autopsy data on lung 

cancer from 1927 to 1957 at LACGH, observed a marked increase in the 

number of lung cancer cases as had been noted by many other investigators. 

However, the ratio of Kreyberg's Group I to Group II had not changed per· 

ceptibly over this period and was notably lower than in other series studied. 

The Committee on Smoking and Health sponsored a workshop in which 

slides from coded cases of lung cancer from four different institutions in 

three areas of the United States were typed "blind" by Dr. Kreyberg and 

pathologists from the cooperating institutions.' There was good agreement 

as to typing. The low ratio of Group I to Group II cancers at L\CGH was 

confirmed. When typing of the reviewed cases was compared with smoking 

1 Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963. 

173 
TABLE B.-Relation between WHO and Kreyberg classifications of lung tumors 

WHO classification 1 

----------------

A. Rpilhelial Tumors 1. Epidermoid carcinomas ________ _ 

a. highly differentiated 

b. moderately differentiated c. slightly differentiated 2. Small-<"'ll anaplastic carcinomas. ______ . ______________________________________ _ 

a. with oval--cel1 structure (Hoat-cell" carcinoma) ~- Adenocarcinomas .. ____ ... ________________________ _ 

a. acinar (with or without formation of mucus) h. papillary (with or without formation of mucus) r. tumors with a pr{>.dominance of "large cells" some of which show formation of glands and/or production of mucus. 4. Large-('('11 undifferentiated carcinomas. ______ . _________________ ·-----------------

~: ~~~~~~~~:a1~~~~:;; ~11 ~ci~~~O:~~~~~~~ ~ ~ ~ ~ ~~~ = =:::::::::::: :::::::::::::::: 7. Carcinoid tumors (solid, trabecular, alveolar) ___________________________________ _ 

8. Tumors of mucous glands ....... ___________________ ----------------------------- a. cylindroma b. muco-epidermoid tumors 

9. Papillomas of the surface epithelium_ ·-------------·- ------------------------- a. epidermoid b. epidermoid with goblet cells 

n. lr;;arcomas_------------- -:---------------------------------- -;----- ------------------------- C. Combined Tumors of Epithelial and Mesenchymal Cell•-------------------- -·----------- D. Mesotheliomas of the Pleura .. ----------------------------------------------------------- 1. Localized 2. Diffuse 

E. Tumors Unclassified 

1 Committee on Cancer of the Lung, World Health Organization. 

Kreyberg 

classification • 

Group I 

Group I 

Group II 

Other' 

Other 

Group II 

Group II Group II 

Other 

Other 

Other 

Other 

' Kreyb<>rg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor- wegian Universities Press, 1962. ' 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 1/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 Dorn, Herrold and Haenszel (Table 9) ( 89) showed high mortality ratios for both Group I and 

Group II cancers in current heavy smokers (over 20 cigarettes/day), although Group I had 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 

University (260), indicated that adenocarcinoma is also contributing to the 

increment of lung cancer in women. 

CoNCLUSIONs-( 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 magnitude of increase in lung cancer is of limited value. 

174 
TABLE 9.-Mortality ratios for cancer of the lung by smokinf!, class and 

by type of tumor, U.S. veterans study 

All Deaths Group I I Group II 

~~F.~~~~~rJii~s~~i~fr:s:~~::::::=::::::::::::::::::::::::::::::::: -tT- ~U ~-!~ cur~~a~i;a.r;t:t:.:irday::::::::::::::::::::::::::::::::::::::: :_ ~: ~ ~~: g ! ~: ~ >20 ciqarettes/day___________________________________ lli. 0 31.2 ' 7. 2 Discontinued (By Maximum Amt. Ever Smoked) Total ______________________________________________________ _ ~20 cigarettes/day _________ . _____________________________ _ >20 cigarettes/day _________ .. ___________________________ . __ _ 

1 Includes occasional smokers. 'Jncludes men who were usin~ pipe and/or ci~ars in addition to ciearcttes. 

4. 'j' 

3. !i 

7. 4 

Souret': Darn, H. F., Haenszel, W. and Herrold, K. (89) (see Chapter 8 also I. 

8.4 I 

fi " I 12. I I 

3. 7 

2. 7 !i. f) 

(b) Squamous and oval-cell carcinomas (Group I) compri~e thf:' predominant types associated with the increase .of lung cancer in both males 

and females. In several studies, adenocarcinomas (Group II\ have 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 be 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 

in II 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 ±: 0.30) between the death rates and cigarette consumption. Since 

virtually all the tobacco consumption in 1930 was among men in the countries 

714-422 0-64-13 175 
500 

400 

z 300 

2 

--' --' 

::IE 

"' UJ 

[]._ 

"' I 

f-

< 

UJ 

Cl 200 

100 

CRUDE MALE DEATH RATE FOR LUNG CANCER 

IN 1950 AND PER CAPITA CONSUMPTION OF 

CIGARETTES IN 1930 IN VARIOUS COUNTRIES. 

GREAT BJITAIN 

• 

~ 

FINLAND / :/ 

SWITZERLAND /0.73±0.30 

•• ~ 

HOLLAND ~ 

... 4' • U.S.A. 

DENMARK~· AUSTRALIA 

~ ·• CANADA 

/ *swEDEN 

/ .NORWAY 

ICELAND • 

'250 500 750 1000 1'250 1500 

CIGARETTE CONSUMPTION 

fiGURE 9. 

Source: Doll, R (76) 

represented (Great Britain, Finland, Switzerland, Holland, the United States, 

Australia, Denmark, Canada, Sweden, Norway, and Iceland), it seemed 

reasonable to compare the annual per capita consumption of each country 

with the crude, male lung cancer death rates. 

It will be noted in Figure 9 that the data from the United States show a 

relatively low death rate in relation to cigarette consumption. Doll sug· 

gested two explanations: the influence of a higher proportion of young 

176 
people in the U.S. population and the method of smoking, with the U.S. 

smokers consuming less of each cigarette than the British smokers. Since 

Doll's explanations of the discrepancy. additional information has become 

available. Studies on length of cigarette butts discarded have shown Amer· 

ican discards to be significantly longer than British discards; 30.9 mm 

(156) and 18.7 mm ( 85) respectively. Also, there is a significantly greater 

percentage of smokers in Great Britain than in the Cnited 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 

1156) the length of the cigarette butts was almost the same as in Great Britain 

119.7 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 he 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) found the following disparities 

between male and female smoking patterns: 

l. Whereas only 22.9 percent of males had never smoked, 67.5 percent 

of females had not. 

2. Males showed relatively little variation among the component age 

groups in percentage not smoking, whereas females after age 

25-34 showed a consistently increasing percentage of non-smokers 

in successively higher age groups (Figure 10) . 

3. Sixty-five percent of males smoked cigarettes as compared with 32 

percent of females. 

4. Cohort analyses revealed the adoption of cigarette smoking late in 

life for both males and females among cohorts born before 1390; 

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 SMOKEI 

BY SEX AND AGE, UNITED STATES, 1955 

Age (in years 

18-24 

25-34 

35-44 

45-54 

55-64 

PERCENT NEVER SMOKED 

- MALES Eil{i,~U FEMALES 

FIGL:RE IO. 

Source: Haenszel, 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. 

British studies ( 344) also revealed that females, especially before World 

War II, consumed much less tobacco than did males. A correction for the 

marked disparity in smoking habits of males and females reduced the ob· 

served 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 1958-

59 among male and female non-smokers were 12.5 and 9.4 respectively for a 

ratio of 1.33 ( 145). This residual ratio implies that there may be other 

factors operating to produce a portion of the sex differential in mortality. 

DIRECT MEASURE OF THE ASSOCI A TIOI\ 

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, ll5, ll6, 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 

fl78). 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 

been 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 nonresponse, the validity of the results in the early phases of a prospective study. 

and the misclassification of both variables: smoking habits and lung cancer. 

It should be noted that the Current Population Survey of 1955 yielded 

results highly consistent with data on tobacco production and taxation 

( 151 I ; that classification errors in terms of amount of smoking were rela. 

tively minor in a reliability study by Finkner ( 113) ; and that, in at least 

three prospective studies, in which subjects were requestioned on smoking 

habits at intervals of at least two years, the replies were closely reproducible 

( 87, 88, 157, 159, 162, 163), particularly if no illness had intervened ( 159). 

With regard to the retrospective studies, it has also been suggested that 

knowledge of the illness might have introduced bias in relation to historie8 

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, ISO, 163, 313, 375). The 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 (24) 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 ( 379). 

Another criticism of patient selection in retrospt>ctive studies deals with 

the danger that, in studies highly cross-sectional in time, if smokers live longer 

than non·smokers. there would obviously he more ~mokers in the disease 

group, and thus a, spurious association or" disease 11 ith smoking would result 

1254). There is no evidence for this basic a~sumption. Furthermore. it 

is inapplicable because almost all the retrospective studies were actually 

based on newly diagnosed cases collected serially over an interval of time 

long enough to remove this bias. 

Control groups pose a problem in retrospt>ctive studies. ln 27 of the 29 

retrospective studies (exceptions are references 14/ 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 a;o:sociated with smoking. Furthermore, 

several studies have. in addition to controls with other diseases, selected a 

second set of random controls from the general population ( 32, 150, 222), 

only to find that the association utilizing sick controls, significant though it 

proved to be, was intermediate to the association utilizing random population 

controls. 

The problem of selection bias in prospective studies is much more subtle, 

since there may be self-selection on the basis of illness existing at the time 

the study begins. This is essentially a problem of non-response which has 

been handled in detail in Chapter 3. 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 (83). 

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 Dorn study the mortality ratio was 9.9 after three years experience 

and 12.0 after six years experience; the Hammond study gave 9.0 after 10.5 

nionths (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 US(' 

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 SIG'IIFICA:\CE oF THE AssociATION.-As already stated, statistical 

methods cannot establish proof of a causal relationship in an association. 

The causal significance of an association is a matter 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: 

(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 tht! association. 

THE CoNSISTENCY OF THE AssociATION.-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 heen 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 

~ignificant 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 

t'n the basis of an unknown source of bias. It is difficult to conceive of a 

universally &cting 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 he 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 AssociATIO:"'.-The most direct measure of the 

~trength 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 si::e of the effect 

of a factor on a disease and which, even 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-causal agent. Cornfield et al. ( 62 1 havt> 

not only provided us with a detailed analysis of the applications of both 

absolute and relative measures of risk, but han· abo demonstrated thf' usdulness of the relative risk measure in judging causal and non-causal efft>cts 

with mathematical proof of their statements. 

An absolute measure of difference in prevalt>nce of a disease bet\veen 

populations with or without the agent 1 e.g., cigarette smoke '1. where the 

agent may be causal in its effect on several diseases. can provide us with the 

means of appraising the public health significance of the disease. i.e. the 

size of the problem, in relation to other diseases. It is less effective for 

appraising the non-causal nature of agents having apparent effects, the 

importance of one a)!ent with respect to other agents, or the effects of refinement of disease classification. This, Cornfield and his co-authors 162 I have 

demonstrated. 

In essence, then, a relative risk ratio measuring the strength of an association provides for an evaluation of whether this factor is important in the 

production of a disease. In the data of the nine retrospective studies for 

which relative risks of lung cancer among smokers and non-smoker~ were 

calculated, the ratios were not only high in all of the studies but showed a 

remarkable similarity in magnitude. More important, in the sc\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. Furthermore, 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 5). Even the retrospective studies for 

which relative risks were calculated by amount smoked (38, 147, 152, 222) 

showed similar increases in risks with amount smoked !Table 4), 

It may be estimated from the data in the prospective studies that, in comparison with non-smokers, average smokers of cigarettes have a 9- to 10-fold 

risk of developing lung cancer, and heavy smokers, at least a 20-folrl risk. 

Thus it would appear that the strength of the association between ci~wrette 

smoking and lung cancer must be judged to be high. 

THE SPECIFICITY OF THE AssocJ..\.TJON.-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 '1 will predict, in the same individual, the presence of another (e.g., cigarette smoki11g). 

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 recIS.i 
ognized that rarely. if ever, in our biologic universe, does the presence of 

an agent invariably predict the occurrence of a disease. Second, but not 

less important, is our growing recognition that a given disease may have 

multiple causes. The ideal state in which smoking or smoking of cigarettes 

and every case of lun;r canct~r was correlated one-to-one would pose much 

less difficulty in a judgment of causality, but the existence of lung cancer in 

non-smokt:>rs 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 lun![ at autopsy and finds tubercle formation and caseation 

necrosis would almost invariably be able to predict the coexistence of tuhercle bacilli. Experience has shown that the lesions are highly specific for 

Mycobacterium tuberculosis. On the other hand, a clinician may encounter 

a combination of signs and svmptoms 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. This may well be the condition which prevails in 

coronary heart disease where the mortality ratio is between 1.6 and 1.8 or a 

60 to 80 percent excess among smokers of cigarettes. If this ratio is applicable to the entire population from which the sample data are derived, another 

way of expressing this relationship is that, of the total load of coronary heart 

disease mortality among maleo. 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 I 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 ha1.e yet been demonstrated. 

Another aspect of specificity requires some insight. Several critics 

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 122, 7). In a sense, this viewpoint is an exaggeration, 

for not all the specific disease mortality ratios in excess of l.O are large 

184 
enough to warrant secure judgments of the strength of the association and 

of causal significance. A detailed discussion of this latter point has been 

presented in Chapter 8. The number of diseases in which the ratios remain 

significantly high, after consideration of the non-response bias, is not so 

great as to cast serious doubt on the causal hypothesis. Even if we were 

dealing with a single pure substance in the environment, the production of a 

number of disease entities does not contradict the hypothesis. It is well 

known that a single substance may have several modes of action on the 

several organ systems and that neither inhalation nor ingestion implies 

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 would not be surprising to find that the diverse substances in tobacco smoke 

could produce more than a single disease. 

Actually, the finding that an excess risk for smokers does 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 RELATJO:'<ISHIP oF AssociATED VARIABLEs.-In chronic diseases, 

insidious onset and ignorance of precise induction periods automatically 

present problems on which came first-the suspected agent or the 

disease. In any evaluation of the significance of an association, exposure 

to an agent presumed to be causal must precede, temporally, the onset of a dis· 

ease which it is purported to produce. The early exposure to tobacco smoke 

and late manifestation of lung cancer among smokers, seem, at least 

superficially, to fulfill this condition. This does not, however, preclude the 

possibility that such patients who, many years after the initiation of smoking 

are diagnosed as having lung cancer, may have had the primitive cellular 

changes or anlage (as postulated by Cohnheim) before the advent of their 

smoking. However, no evidence has thus 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. 

CoHERE:"'CE OF THE AssoCIATION.-A final criterion for the appraisal 

of causal significance of an association is its coherence with known facts in 

the natural history and biology of the disease. In the lung cancer-cigarette 

smoking relationship the following should be noted: 

(1.) Rise in Lung Cancer Mortality.-The increases in per capita consump· 

tion of cigarettes ( 76, 138, 211, 239, 255 l and the age-cohort patterns of 

smoking among males and females ( 151) 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 age-cohort patterns between 

males and females, particularly in the older age groups-over 55 ( 151) 

and over 50 (160) -and the more recent adoption of cigarette smoking by 

women (151, 344) are all compatible with the high male-to-female ratio 

of lung cancer mortality and also with the lower ratios of 30 years ago 

(130). Haenzel and Shimkin (149) developed a statistical model for 

determining whether the results of the retrospective and prospective studies 

185 
"were compatible with the information on distribution of lung cancer and 

thus valid for generalization to larger populations." Applying their model 

of scheduled relative risks to data on cigarette consumption by age and sex 

derived from the Current Population Survey of 1955, their predicted male/ 

female ratio came quite close to the observed ratio in the general population. 

(3. 1 Urban-Rural Difference·s in Lung Cancer Mortality.-A number of 

sources in this country (90, 136, 148, 175, 238, 252) and overseas (82, 199, 

33S) have firmly established the 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 with the smoking-lung cancer hypothesis ( 178, 229) or minimizing 

its significance 169,70, 71,101, 190). The data of the studies of a number 

of authors have clearly shown, however, that although adjustment f(}r 

smoking history does not equalize the urban-rural lung cancer mortality ratio 

( 149), control on the urban-rural residence factor nevertheless leaves a 

large mortality risk difference between smokers and non-smokers. Haenszel 

has demonstrated this fact in his two population sample studies on males 

and females ( 147, 152). Mills and Porter (238) demonstrated a much 

greater effect of smoking on lung cancer mortality 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 ( 162) 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 are doubled by the factor of country of origin; whereas, with country of origin controlled, the lung cancer risk increases 

from 3 to 20 times as the amount of cigarette smoking increases. After 

smoking patterns are controlled, the residuals in the urban over rural excess 

imply other factors, although tht~ 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 lowe-st income groups. In Denmark, Clemmesen 

and Nielsen, utilizing data derived from the Danish Cancer Registry, also 

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 studv (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) were found in the ~roup 

classified as "some high school education I but not hif!h school graduates I," 

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 level 

in women is more complicated, the group which had been to college al~o had 

the highest proportion of ex-smokers. Finally. college graduates had the 

next to the lowest proportion of heavy cigarette smokers. l\ one 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. l\o definitive study has 

been reported in which lung cancer has been correlated with occupation 

and smoking class; the current Hammond 115 7 I and Dorn 1 88 I 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 

1.151). 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 di::.continuance 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 (in their prospective study) on inhalation for the 

mortality experience since 1958. These data are not presently available ( 80) . 

However, until the current ongoing prospective studies will have yielded 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 noninhalers diminished. There is no immediate explanation for this apparent di::.crepancy. 

Hammond has studied the smoking habits of the men and women in his 

current prospective study quite intensively ( 160). He has observed that the 

majority of men (92.9 percent) who smoke cigarettes inhale, and of these 

the majority inhale "moderately" to "deeply." Pipe or cigar smokers inhale 

rarely. Combination smokers (i.e., cigarettes in combination 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 rish, 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 wa~ 

not until the systematic, controlled study of lung, lip, pharynx, esophagus. 

colon and rectum cancers in relation to types of smoking by Levin in 1950 

that significantly distinctive associations between localization of the cancer 

and type of smoking were elicited ( 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 oi 

smoking is the associated faetor, rather than the actual use of tobacco." 

Since then other studies have pointed up the relationship between type of 

smoking and localization of cancer. Sadowsky 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 I only a slight rise for whites 

between 19.30 and 1955 '! in the face of increased cigarette consumption. 

Although among cigarette smokers, the relative risk of mortality from lung 

cancer is presently greater than the relative risk for laryngeal cancer, the 

reverse seems to be true among cigar and pipe smokers I Chapter 8, Tables 

19 and 24). Furthermore, the per capita rise in cigarette consumption has 

been accompanied by a concomitant decline in consumption of pipe and 

cigar tobacco, the smoke of which was not deeply inhaled. It is thus con· 

ceivable that the increase in cigarette consumption (and decline in cigar and 

pipe smoking) could affect an increase in lung cancer more significantly 

than in laryngeal cancer. 

Finally. there is no reason to assume that the sus<eptibilitv of the larynx 

to cancer equals that of the bronchus. Thus. a reasonable explanation for 

the difference in localization and relative risk is apparent. especially when 

it is known that in certain industrial exposures in which the irritant is in· 

haled and lung cancer is associated with such inhalation I chromates) , 

laryngeal and tracheal cancer is rare. It is. on the other hand. easier to 

visualize a mode of action for pipe and cirrar tobacco in production of I ip and 

tongue and other oral cavity cancers. Thus, none of these considerations de· 

tract from the coherence of the association between cigarette smoking and 

lung cancer. 

HISTOPATHOLOGIC EVIDENCE 

In earlier sections of this Chapter it has been noted that the application 

of tobacco extracts, smoke or condensates to the 1 ung or tracheobronchial 

tree of experimental animals has failed to produce bronchogenic carcinoma, 

except possibly in dogs ( 289). In addition. no animal experiments have thus 

far been devised to duplicate precisely the act of smoking as it is practiced by 

man. However, that the lungs of experimental animals are susceptible to car· 

cinogens, particularly polycyclic aromatic hydrocarbons isolated from to· 

bacco smoke. has been demonstrated by a number of workers ( 5. 197, 302). 

Of immediate import to the smoking-lung cancer relationship is the observa· 

tion that the histopathologic characteristics of the cancers thus produced are 

similar to those observed in man and are predominantly squamous in type. 

Furthermore. certain bronchial epithelial changes, sequentially observed 

prior to the malignant changes in animals exposed to these carcinogens are 

similar to those in the bronchial epithelium of human smokers (9). In 

this latter extensive and well-controlled study, these changes were rarely 

seen among non-smokers, but increased in frequency and intensity with the 

number of cigarettes smoked daily by individuals without lung cancer and 

were most frequent and intense in patients dying of lung cancer I Table 6 

of this Chapter). Ex-cigarette smokers and pipe and cigar smoker~ vielded 

a higher frequency of such cellular changes than non·smokers but less than 

did current cigarette smokers. Thus. the histopathologic evidence derived 

from laboratory and clinical material support the cigarette smoking-lung 

cancer hypothesis. 

189 
CONSTITUTIONAL HYPOTHESIS 

GE:\ETIC CoXSIDERATIO:\S.-~ Thus far in the evaluation, the Committee has 

consiclerPcl whether the available data are consistent with the hypothesis 

that ~mokinp: causes cancer c•f the lung. The analysis must consider with 

equal attention the alternative hypothesis that both the smoking of cigarettes 

and cancer of the lung have a common cause which determines both that an 

individual shall become a smoker and also that he shall be predisposed to 

lung cancer. This has often been called the constitutional hypothesis. How· 

ever. one should distinguish between the morphologic and physiologic characteristics of any individual due to a given environment and those characteristic,, (phenotype 1 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 

phvsique or somatotype, height and weight and their ratios, masculinity, 

anthropometric variables, physiologic variables (heart rate, pulse pressure, 

blood pressure, cholesterol levels), and physical activity; others have been 

psychosocial (including perso'lality) 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 

heing more likelv to have at least one parent with hypertension or coronandisease (ISO. 214, 235). Many studies have been poorly designed and 

controlled. otlwrs have yielded contradictory findings, and still others, by 

admission of their authors. have included characteristics that could either 

haw been acquired or have been produced by smoking. None of these 

constitutional attributes have been included in a prospective study of mortalitY from lung cancer fulfilling satisfactory epidemiological criteria. except 

for a breakd01m b, longo>vitr of parents and grandparents in one study 

I].')() I. The go>no>tics of tho> characteristics themselves has not been determined. and adequate analysi~ of common genetic determinants in relation 

to tlw habit of ~rnoking has not been atto>mpted. :\ o environmental determinant~ that would unin·rsallv induce smokin~ and also produce the characteri~tic~ are evident ( (>2 I or have been proposed. 

Fisher I 11 [;I ha~ been foremost in calling attention to the possibility that 

cancer of the lun!! and the habit of smoking may be due to a common genotype. Selection of ~mokers then would automatically provide a population 

in "hich pulmonarY cancer would appear on the basis of genetic susceptibilit\. Sturlies on the concord.mce of smoking in twins (122, 127,281, 356) 

were usPd to support the hypothesis, since more monozygotic pairs have 

similar smokin~ habits than do dizvgotic pairs. Although the data on the 

smoking habits of identical and fraternal twins raised apart are compatible 

with this hvpothesis. the history of cancer in twins whose smoking habits are 

kno\' n has nen~r been documented sufficiently to be useful in helping to 

resolw. 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 parent:'. 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 flung cancer) in an heterogeneous population would require numerous coincidences with small probabilities. Also, in order to adhere to a consistent argument in explaining 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 

with 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 fadors 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 may add an extrinsic determinant which can increase the 

incidence of cancer of the lung beyond that which would otherwise prevail 

in the same population. 

It ;;hould 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 genic pool, or to the introduction of an agent into 

the environment, or a quantitative increase of an agent or agents capable of 

inducing this type of cancer. The genetic factors in man were evidently not 

strong enough to cause the development of many cases of lung cancer under 

environmental conditions which existed half a century ago. In terms of 

what is known about rates, pressures, and equilibria of human mutations the 

assumption that the genome of man could have changed gradually, simultaneously and identically in many countries during this century is almost 

inconceivable. 

714-422 0-64-14 191 
Smoking may be placed more properly in the role of an environmental 

determinant than as part of the phenotype of the pluripotential gene or 

genes, interacting with the environment and resulting in cancer of the lung. 

Current evidence is compatible with the opinion that genetic factors play 

a minor role compared to the contribution of the smoking habit in the 

etiology of lung cancer today. 

EPIDEMIOLOGICAL CoNSIDERATIONS.-Although evidences for the constitutional hypothesis are, at present, either tenuous or actually lacking, the 

basic philosophical and logical prerequisites for this hypothesis are contra· 

dicted by a number of well-established observations ( 62): 

( 1.) Lung Cancer Mortality.-Lung cancer mortality has been increasing 

in the Ia!?!: .50 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 in· 

crease, we must postulate either that there are genetic differences which make 

some individuals sensitive to a new environmental factor (not tobacco), or 

that differences in constitutional makeup ~re not genetic but the result of 

differential exposure to some nPw factor that predisposes to lung cancer and 

creates the desire to smoke, or that the mu:tation has produced an increased 

susceptibility and a desire to smoke. For the first two postulates a new en· 

vironmental factor, other than tobacco, is required. Such a factor, it must. 

be remembered, must be correlated with lung cancer as highly as are 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. Although carcinogenicity of tobacco tars has not 

been demonstrated in man, the constitutional hypothesis would require that 

they are not, and that the association with lung cancer in man of substances 

found to be carcinogenic for experimental animals is a coincidence. 

(3.) Pipe and Cigar Smoking.-Pipe and cigar smoking appears to have a 

higher correlation with laryngeal and oral cancer than with lung cancer. 

The constitutional hypothesis would require that there shall be two constitutional makeups, one predispo5ing 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 constitutional 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 1 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 IS). The role of the 

genetic factor in carcinogenesis has been discussed earlier in this Chapter. 

OTHER ETIOLOGIC FACTORS Al\'D CONFOUNDING VARIABLES 

Throughout this evaluation, it has been recognized that a causal hvpothesis 

for the cigarette smoking-lung 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) has provided 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, Selt~er 

1318) 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 

I the risk for nasal cancer was 150 times higher). Among uranium miners 

an excess risk is apparent ( 360), and is greater than in certain other miners 

of similar ores without the high radioactivity component (361). Although 

the induction of lung cancer by radio nuclides is probable 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 181) and asbestos workers (77l. 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 Buechley ( 45) has 

193 
recently suggested that it merits epidemiological investigation. The chief 

points of evidence cited include l) the universality of arsenic in many ores 

and in the atmospheres in and near smelters; 2) the widespread use of 

arsenic as an insecticide and the consequent exposure of workers in insecticide manufacture, agricultural workers, and those handling or consuming 

crops with arsenic residues; and 3) reports of a relatively high incidence of 

lung cancers in people living around smelters processing arsenic-containing 

ores, and also in vineyard workers exposed to large amounts of arsenical 

pesticides and consuming larg·e 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 the 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 etiologic 

factors in an urban environment. This has been the explanation offered in 

the studies by Stocks and Campbell ( 337) and Stocks ( 335 l who noted a 

gradient among non-smokers, light cigarette smokers and pipe smokers by 

density of population but who found no gradient among heavy smokers. 

Less direct evidence was derived by Eastcott ( 101) and Dean ( 69, 71) who 

found higher lung cancer rates among migrants from Great Britain to New 

Zealand, South Africa and Australia, respectively. Their inferences were 

that these immigrants had had significant exposure to air pollution in Eng· 

land prior to coming to the Commonwealth countries. l'nfortunately, 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 urbanizatior.. 

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 nega· 

live 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 Tobacr:o Smoking, Air Pollution. Residential and Occupa· 

tiona! Histories and Mortalitv from Cancer of the Lung in Two Cities. Inter-regional 

Symposium on Criteria for A.ir Qu~lity and Methods of ;\1easurement, 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 applications 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 1147, 1521 have also indicated that migration of rural pt>ople 

into urban areas subjects them to lung 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 lnfections.-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 a~d 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 Beebe study to affirm the Case and Lea findings in regard to 

chronic bronchitis may lie in the problem of differences in British and 

American diagnoses of chronic bronchitis. 

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 lung 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 10-fold risk in average cigarette smokers and the 20 + fold risk in heavy 

~mokers. 

Conclusions 

l. Cigarette smoking is camally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. 

The data for women, though l~.s 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 m-

~ufficient to warrant a conclusion for each group individually. 

ORAL CANCER 

Epidemiological 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 tobacco. 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 

196 
various fonns 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 Ahlborn (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 increase 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 canct>r must take into account 

not only the specific sites (lip, cheek, gingiva, tongue, oropharynx, etc.) 

hut also the precise form of tobacco use (pipes, cigars, cigarettes, chewing 

tobacco, snuff, etc.). 

Of additional interest is the specialized use of tobacco as a component of 

betel nut quids in certain areas of the world: several observations suggest an 

association with oral cancer (66, 67. 269, 319). In contrast. observations 

of populations using betel nut quids without tobacco (104, 234, 367) in 

certain other areas of the world show no association of betel nut with oral 

cavity cancer. 

More formalized case-control or retrospective studies varying in spe· 

cific approach, in suitability of controls and in sample size have appeared 

between 1920 and the present (26, 41, 103, 202, 207, 221, 237, 245, 272, 301, 

306, 314, 326, 355, 369, 385, 387, 388, 398). These studies are described 

in Table 10 which includes general smoking data, for the most part, on combinations of specific sites of oral cancer. A number of these investigations 

either did not separate the several sites of the oral cavity because of the small 

number of cases for each site or, upon separation into such sites, found the 

~moking 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 fonns 

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 smoking is associated with lip cancer in all six 

studies in which this site and form of tobacco use was analyzed ( 41, 103, 207, 

301, 378, 385). 

In one additional study (237) an association with pipe and cigars com197 
TABLE 10.-0utline of retrospective studies of tobacco use and cancer of the oral cavity 

Investigator and year Ref- Country Sex l'f('fl('(' 

Nun1l>e rl 

-------1-- ~-- --- -~-

Broders !!flO (41) U.S.A. M 

F 

----1----------

Lombard and Doer- ing 1928. 

(nl) U.S.A, M-F 

526 

II 

217 

--------1-- --~· ---- Bigelow and 

Lombard, 1933. 

Ebenius 1943 

(26) U.S.A. M-F 

(103) Sweden M 

F 

---- -~ ------ Levin et al. 1950 (207) U.S.A. M 

(') 

Cases 

Mf'thod or selection 

Series ot rlinie patients with epi~ 

thclioma or the lip. 80.5% tobacco users 75.1 CJ;~ smokers 0.9% <'igarettes 

24.0'7, chew 59.0% pipes 38.5% cigars --

Clinic patients with cancer of 

various sites. Site breakdown and smoking d:.1.t~ not clf'ar. -· 

Clinic and hospital patients, ap- parently several hundred. 

14.20; non-users 3fi.4% excessive users (Table 111). 

Clinic patients with cancer of the 

lip. 

79.7o/,) tobacco users, M 57.6% tobacco user<, F (all pipes) 61.8% pipes, M 47 .4o/,l chew or use snuff, M 12.9% cigars and cigarettes, M 

Canrer institute patients with cant-er of the lip. 84.5% smokers 45.3% cigarettes 48.1% pipes 26.5% cigars -------1--------------

M1lls and Porter 1950 (217) U.S.A. M 124 Deaths frow cancer oi oral cavity in Cincinnati and Detroit, 1940- 45 and W42-46, respectively. 35.5% cigarettes only 54.R% pipes, dgars. or com bina- tions. ---- - ------· ----

Controls 

Collection of data 

Number Method of selection 

---

500 Series or clinic patients without Apparently by interview in the 

epithelioma of the lip. clinic. 78. 6o/r1 to Ua.cco users 

7S.2% smokers 44.4% cigarettes 

13.4!);1 chew 

28.6% pipes 44.0% cigars ----· 

217 Clinic patients without cancer, Personal interview by investigators matched hy sex and age. Smok- in clinics. inf: data not clear. 

(?) Patients without cancer, in coni- Personal interview in hospitals and 

parable numbers. cllnics. 

26.5o/,l non-users 24.0% excessive users (Table Ill). 

---- Not defined. 68.7% tobacco nsers, M 1 to 2 %' tobacco users, F 22.9% pipes, M 60.7% chew or use snuff, M 32.5% cigars and cigarettes, M 

.51 Canrer institute patients with Routine clinic Interview. non-cancer diseases of same site. 74.0% smokers 4.1.0% dgarettes 30.7% pipes 34.9% cigars 

1!!5 Sam pie of population of Colum- From next of kin of deceased by 

bus, Ohio, and in same proportion mail questionnaire or by personal of rolor, sex, and age as in eaS£"S. interview. Controls by house- 3?.4% cigarettes only to-house interview. 

29.7% pipes, rlgars, or combina- tions. -----1 
Moore et a!. 1963 (245) U.S.A. M 112 

-------1---------

Sadowsky et al., 1953 (301) U.S.A. M 

----------------

Sanghvl et al., 1955 (306) India M 

F 

--------1-------

Ledermann 1955 (202) France M 

------1-------

Wynder et al., 1957 (378) U.S.A. M 

F 

--------1-------

Wilkins and Vogler 

1957. 

(369) U.S.A. M 

F 

--------1-------

Schwartz et a!. (314) France M 

--------1-------

1,136 

657 

81 

240 

543 

116 

37 

44 

332 

Patients over liO yrs. old since 1951 with cancer of oral cavity. 

58.0% chew 

42.0% pipes 38.4% cigars and cigarettes 

Hospital patients with oral and 

pharyngeal cancer, 1938-43. 

42.3% cigarettes only 

4.0% cigars only 

17.8% pipes only 

28.2% mixed 

Hospital patients with cancer of 

oral cavity and pharynx. 

38.8% smoke and chew, M; 3. 7% F 46.7% smoke only, M; 6.2% F 11.7% chew only, M; 64.2% F 2.7% neither, M; 25.9% F (Smoking is of bidis among both cases and controls.) 

Patients with cancer of oral cavity & pharynx. 4.6% non-smokers 23.4%>20 cigarettes per day 

Patients with cancer of oral cavity 

3% non-users, M; 47% F 20% cigars, M 

ll% pipes, M 

8%mixed, M 

17% chew, M 

57% cigarettes, M; 53% F 

29%>35 cigarettes per day, M 

34%> 16 cigarettes per day, ~' 

Clinic and hospital patients with cancer of gingiva. 

32% chew or chew and smoke, M 

20% smokers, M 52% use snuff, li' 9% smokers, F 

Hospital patients with cancer of oral cavity awl pharynx. 

16.4% non-smokers 

62.7% cigarettes only 

3.3% pipes only 

38 Patients or same age groups with benign oral lesions or benign surgical conditions. 31.6% chew 

47.4% pipes 

Personal interview of controls; for cases, next-of-kin were visited or contacted by letter. 

_5_2_.6_7~_c_ig_ar_s_an_d_c~ig~a._re_t_t_es ____ 1 _____________________ _ 

615 Patients with illness other than By trained lay Interviewers. cancer. S3.3% cigarettes only 3.4% cigars only 7.0% pipes only 23.1% mixed 

M 288 Hospital patients with diseases F 112 other than cancer. 24.0% smoke and chew, M; 0% F SO.O% smoke only, M; 6.3% F 8.7% chew only, M; 23.2% F 17.3% neither, M; 70.5% F 

Personal history Interview in hospital. 

--------------------1-------------------

62 Patients with cancer of skin, bone, muscle. 17.2% non-smokers 18.6%>20 cigarettes per day 

M 207 Patients with cancer of other sites Personal interviews In hospital or F 232 and benign diseases. clinic. 10% non-users, M; 70% F 

13% cigars, M 

uo/opipes, M 

BC:Io mixed, M 8% chew, M 63% cigarettes, l\1; 30% F 17%>3.1 cigarl'ttes per day, M 11%>16 cigarettes per day,~· 

None. 

608 Hospital putirnts with non-cancer illnl'ss and accident cases, matched by agP. 

23.4% non-smokers 58.:J.<,'{) cigarettes only 

Clinic and hospital histories. 

Questioned about the same time 

by the same interviewer. 

_3_.o_7._c_~_P_es __ o_n_lY ________________ 1 ___________________________ __ 
TABLE 10.---0utline of retrospective studies of tobacco use and cancer of the oral cavity-Continued 

Cases Controls 

Investigator an<l year Ref- Country Sex Collection of data ere nee Number Method of selection Number Method of selection 

-------

Wynder et al. 1957 (388) Cuba M 178 Hospital clinic patients with M 220 Patients in same clinics with Personal questioning in clinic, all F ::w cancer of oral cavity and F 214 non-malignant conditions, by 2 interviewers. 

pharynx. matched by sex and age. 4% non-smokers, M; 24% F 16% non-smokers, M; 66% F 45% cigarettes predom., M; 62% F 45% cigarettes predo'M' M; 27% F 33% cigars predom., M; 12% F 22% mgars predom., ; 6% F ------------ Wynder et al. 1967 (386) Sweden M 115 Hospital patients with cancer of M 116 Patients in same hospital with Personal interview in hospital; and F 140 oral cavity and pharynx. F166 cancer or sites other than oral, medical histories. 

pharynx, larynx, lung, esopha- gus and breast. 

36.5% cigarettes, M 36% cigarettes, M i3.0% dg11.r:=:., 1v1 9% dgans, !vi 12.2% pipes, M 16%pipes, M 15.7% mixed, M 13%mixed, M ------------ Peacock et al. 1000 (272) U.S.A. M u IIospital patients with oral cancer M 74 Patients in same hospital without Personal interviews. F 20 F 72 oral cancer and 117 male and 

100 female randomly selected 

outpatients. 

65.6% chewed or used snuff over 32.6% of first group, 20 years. 43.3% of second group chewed or used snuff over 20 years. -------

Staszewski 1000 (327) Poland M 383 Male patients with oral cancer 912 Male patients with other cancer Personal interviews. 

and non-cancerous conditions. 

5. 7% non-smokers 17.3% non-smokers 

72.8% "heavy" smoking index 49.0% "heavy" smoking index 

72.3% cigarettes only 60.5% cigarettes only 12.8% pipes and/or cigars 11.1% pipes and/or cigars ---------- Vogler et al. 1962 (365) U·.S.A. M 188 Clinic patients with cancer of Up M 521 Patients or same clinic with other Personal interviews in clinic. F 92 and oral cavity. F 1,064 cancer or non-malignant conditions. 

32.9% chewers, M ' 6.1% snuff dippers, F' 22.9% excessive chewers, M 56% to hacco users, M + F 72.0% snuff dippers, F 41.3% excessive snuff dippers, F 90% tobacco users, M + F 

' Estimate of prevalence o use. ' Due to varying tabular treatment of the data, tbe percentages of tobacco users are not all based on the same numbers of cases. 
TABLE lOA.-Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites 1 

Investigator and reference Cigarettes Pipes Cigars Chewing Miscellaneous 

----~-----------1-----------------~l----------------l-----------------l--------------l 

Broders (41) __ --~- _________ (Lip)---~------------_ 

Lorn bard and Doering 

(221). 

(Lipl+------------------

(Oral)+ (Lipl--------------------

Bigelow and Lombard (26)_ ---------· ---~---~------------ -----------------------~------ -------------------------- Ebenlus (103)~------------ (Lip)-'-_ ----------~------ (Llpl+---~------------------ -----~------------ Levin eta!. (207)_~--------- (Lip)------------- _______ (Lip)+--------------------- (Lip)±. Mills and Porter (237) ____ (Oral)±-- ___________ ----------------------- ---------------------

Moore eta!. (245) (Lip, mouth)-'-_ _ ____ (Lip, mouth)- ____________ _ 

Sadowsky et al. (301) __ _ (Lip, tongue, other oral, (Lip, tongue, other orall+--- (Tongue, other oral)+. 

pharynx)-. 

Sanghvi et al. (306) ________ (Oropharynx)+'-------------------------------------

Ledermann (202) _______ _ (Oral)+. Wyndcr et al. (378) _______ _ ±M, +~'(Floor of mouth) __ 

(Pharynx)+ •--------------- M-, F+ (Oral and phar-

(Each site except tongue>+-- (Each site)+-- ____ --·_ Schwartz et al. (314) __ . Wynder et al. (388) _______ _ 

Wynder et al. (385) 

Peacock et al. (272) _______ _ Staszewski (326) _______ _ 

Vogler ct al. (355) _________ _ 

ynx). 

(P_harynx)+, (Other 

sites)-

(Oral)-. 

(Lip)+---------------------

-- -------- ----------------------------------------

M+, F+ (oral and phar-r ynx). 

(Tongue, gingiva, phar- _ ynx)+. 

(Lip, oral cavity)+--______ _ __________________ ----------- ----------------- _ 

----------------------,-----------------------

--------~--------------

!+=Significant association. 

-=Association absent or not significant. 

±=Association of doubtful <lgntficance. ' Cigarettes and cigars. 

'Hidis. 

• Includes cigarettes and other. ' Only In individuals M low economic status and over 60 year• old. 

(Lip)+. 

(Lip)-. (All forms combined-oral)+ 

(Pipes and cigars combinedoral)+. 

(Lip, mouth)+---------- (Snuff-lip, mouth)+. 

(Oral)+----------------- (If smoke and chew-base of 

tongue, hypopharynx)+. 

(Oinglva, lip)±. 

(Oral)+'---------------

(Pipes, and cigars com- bined -tongue)+. 

(Snuff -oral)+.' 

(Pipes and cigars combinedlip, oral cavity)±. 

(All forms combined)+, F+ (snuff ··-lip and buccal 

cavity In both cases). 
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 (:~01, 

:306, :378, 385\. An association with cigarette smoking was noted in two out 

of three ( 306, 385) ; with cigars in two ( 378, 385) ; and with pipe in one 

(378). 

Among the better studies in which the sample sizes were large and con· 

trois adequate, one deserves special mention ( 301). In this investigation 

by Sadowsky and others, it was possible to establish gradients for lip cancer 

by number of pipefuls smoked a day, for tongue cancer by amount of to· 

bacco in pipes and cigars combined, and for other oral cavity cancers by 

number of pipefuls. No 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 as· 

sociated with cigarette smoking. The mortality ratios ranged from 1.0 in the 

Dunn, Linden, Breslow occupational study ( 96) , in which only seven cases 

have thus far been observed, to 9.2 in the current Hammond study (157). 

(See Table 1 of this chapter.) 

For cigar and pipe smokers, oral cancer has the highest mortality ratio, 

3.3, of all causes of death, exceeding cancer of the esophagus, larynx and 

lung. Recently calculated data from six of the prospective studies (excluding 

the current Hammond study\ show a slight gradient in the mean mortality 

ratios for cigarette smokers of more than a pack a day as compared to 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\ and rabbits 

( 312) or to the palate of hamsters (194, 303). Exposure of the hamster 

cheek pouch to cigarette tar, snuff, or tobacco also failed to induce cancer 

202 
(95, 194, 243, 244, 245, 246, 271, 272, 303, 303a). Leukoplakia was re· 

ported to have been induced by the injection of tobacco smoke condensates 

into the gingiva of rabbits ( 296) . 

The oral mucosa appears to be resistant in general to cancer induction 

even when highly active carcinogens such as benzo (a) pyrene ( 95, 194, 209, 

243,244, 245.246,271,272, 296, 303) are applied. Mechanical factors, such 

as secretion of saliva, interfere with the retention of carcinol!enic agents. 

Saliva mav 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 benzo (a) pyrene, 20-methylcholanthrene, and 9,10-dimethvl-1.2-benzanthracene applied to the cheek · 

pouch of the hamster 1244, 303, 343). The cheek pouch, however, lacks 

salivary glands, and its structure and function differ from those of the 

oral mucosa. 

Pathology 

There is a strong clinical impression linking the occurrence of leukoplakia 

of the mouth with the use of tobacco in its various forms ( 201). However, in 

almost all the studies, the diagnosis of leukoplakia was made without his: 

topathologic examination. It is difficult to distinguish clinically between 

hyperplasia of the surface epithelium with keratinization (termed pachyderma 

oralis) and "true" leukoplakia, which resembles microscopically senile kera· 

tosis, a preneoplastic lesion of the skin, showing atypical changes and mitotic 

figures, in addition to hyperplasia. 

In a study of the tissue changes in the palate of women in a part of India 

where the burning end of a cigar is held inside the mouth, Reddy and Rao 

(284) found ulceration, increased pigmentation of the epithelium of the 

palate and leukoplakia. Many of these women develop cancer at the same 

site. The carcinomas found are epidermoid and are frequently surrounded 

by an area of leukoplakia which sometimes shows changes characteristic of 

carcinoma-in-situ. Leukoplakia is a common finding in patients with multiple 

oral carcinomas, the majority of whom use tobacco ( 241). A 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). 

Although 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 consistency of the association except for cancer of the lip and 

pipe smoking. 

Inasmuch as only one retrospective study ( 301) had large enough numbers 

of cases to derive the relative risks for specific site associations, reliance 

for strength of the association must be placed on the prospective studies. 

Since, in turn, the numbers of deaths from cancer of these sites so far have 

been small, only a combination of such sites could be analyzed for relative 

risk determinations. Five of the seven studies show reasonably high rela· 

tive risk ratios for cigarette smokers and for cigar and pipe smokers. 

Specificity of the association cannot be said to be as high as that noted 

for lung cancer. The prospective studies provide no information as to 

specific localizations within the oral cavity. Sadowsky et al. (301) showed 

an association of pipe smoking with cancer of the lip and of pipe and cigar 

smoking with cancer of the tongue. 

Data are presently inadequate for a reliable assessment of the coherence 

of the association. However, it should be noted that the prospective studies 

provide a definite suggestion that a gradient of risk by amount smoked 

does exist for oral cancer and that in one large retrospective study (301) 

prevalence rates for every specific age group of smokers was consistently in 

excess over non·smokers. 

It has been noted that during the past 30 years cancer of the oral cavity 

and pharynx has declined, primarily because of a decrease in lip cancer 

among males (130). Cancer of the lip has never been an important localiza· 

tion for females and the rates in females have remained fairly constant. 

In males pipe smoking has decreased markedly in the United States during 

the past 30 years, so that the decline in lip cancer among males is not neces· 

sarily incompatible with a strong association between cancer of the lip and 

pipe smoking. 

Furthermore, other probable factors in the production of oral 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 benzo (a) pyrene and other hydrocarbons to the 

cheek pouch of the hamster. 

The relationship of leukoplakia to tobacco use has been described earlier. 

Conclusions 

1. The causal relationship of the smoking of pipes to the development o• 

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 Evidence 

RETROSPECTIVE STUDIES 

The possible association between tobacco smoking and laryn~eal cancer 

received some attention in studies as early as 1931 11, 1851. Ahlborn noted 

a marked association between cigar and c.igarette smoking and cancers of the 

pharynx, larynx and esophagus, but because of the small sample size, the 

three sites as defined were grouped together ( l). The Kennaways calculated 

standardized mortality ratios for various occupational ~roups I against the 

age-specific mortality rates for the general population of England and Wales 

for 1921-32'1 and found barmen, cellarmen. and tobacconists to have sig· 

nificantly higher ratios (185). This latter study was repeated in 1947 and 

again the tobacconists and their assistants were noted to have an excess 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 

i~ 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 (314), Sweden (385), Cuba (388), India (100), and Poland (327) 

~Table 111. These were stimulated in part by the retrospective studies of 

lung cancer and the general prospective studies. 

Most of the studies (30, 100, 301, 311, 314, 327, 376, 385, 388\ show a 

stronger association between cigarette smoking and laryngeal cancer than for 

other forms of tobacco use but one of the studies shows a borderline relationship with cigar smoking (385). Wynder et a!. ( 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, :114, 

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 ll.~Outline of retrospective studies of tobacco usf' and cancer of the larynx 

J{ef. I 

Investigator and year cr- Country 8ex ence Number 

Cases 

Method of selection Number 

-----1---------------------1---

Schrek et al. 1950 (311) U.S.A. M 

Valko 1952 (353) C1.echo· M-F 

slovakia. 

Sadowsky eta!. (1953) (301) U.S.A. M 

Bliimlein 1955 (30) Germany M 

Wynder et al. 1956 (376) U.S.A. M 

73 Referrals from V.A. hospitals In 

"entire midwest" to V .A .. Can .. cer Center, Hines, Illinois, durIng 1942--44: patients with larynx· pharynx tumors clinically or histologically diagnose\~. 

13.7% non-smokers 

79.5% cigarettes 

3.7% cigars 

6.8% pipes 

226 Clinic patients with cancer of the 

larynx. 

83.2% cigarettes 

4.4% cigars 

10.6% pipes 

7.5% non-smokers 

273 Admissions to hospitals InN. Y.C. 

Missouri, New Orleans, Chicago: patients with diagnosed laryngeal tumors, 1938--1943. 4.0% non-smokers 

60.1% cigarettes only 

2.2% cigars only 

4.8% pipe only 

28.9% some combination 

241 Clinic patients with cancer of the 

larynx. 

0.8% non-smokers 

79.3% hP.avy smokers 

95.0% inhalers 

209 Inpatients Memorial Cancer Re· 

search Center during 1952 to 1954, with henlgn or malignant 

epidermoid tumors of larynx. 

0.5% non-smokers 

86.0% cigarettes 

I 7. 5% cigars 5.0% pipes 1 f)O"" ,.;n..,,.colnh·v'<' 

522 

108 

615 

200 

209 

-

Controls. 

Collection of <lata 

M<•thod of selection 

From same set of referrals, patients Random sample of 5003 admissions; 

with tumors other than lip, lung, questionnaires !rom Hines re- larynx-pharynx. ferrals for 1942-44; records In· 

eluded smoking history. 

23.9% non-smokers 

59.2% cigarettes 

10.0% cigars 

11.5% pipes 

Clinic patients of same age group 

with other diagnoses. 

Medical history and questionnaire 

In clinic. 

22.2% non-smokers 

From same set of admissions: Sample of 2005 out of 2847 Inter· 

patients with Illnesses other views (Including smoking histhan cancer. tory) by trained lay Interviewers. 

13.2% non-smokers 

53.3% cigarettes only 3.4% cigars only 

7.0% pipe only 

23.1% some combination 

Patients with no laryngeal disease. Personal history taken In clime. 

18.0% non-smokers 

4.3% heavy smokers 

17.0% Inhalers 

Patients with other than ";Ptlder· Trained lay Interviewers. 

mold cancer, indlvi uall;;-

matched controls In same instJ· 

tutioos. 

10.5% non-smokers 

73.7% cigarettes 10.1% cigars 

3.8% pipe 1 fl(- --~~.~ .. ~'~.:~ 
India M 132 Laryngeal cancer patients at Tata Memorial Hospital, 1952-1954. 

13.6% non-smokers 

78.8% bidls 

5.3% cigarettes 

1.5% hookah 

0.8%chilum 

132 [ Controls Individually matchl'd as Interviews for smoking and medlfor U.S.A. data abov<'. cal histories. 

30.3% non-smokers 

62.1% bidis 

4.5% cigarettes 

0.8% hookah 

2.3% chilum 

----1-----.. ·----------1------------

Schwartz eta!. 1957. (314) France 

Wynder eta!. 1957 ____ (385) Sweden 

Wynder eta!. 1958. (388) Cuba 

M 

M-F 

M 

F 

121 Patients hospitalized from 1954 

through 1956 with laryngeal can- cer, in Paris and other large 

cities. 

96% smokers 

58% inhalers 

44% roll their own cigarettes 

63 Patients at Radlumhernwet with 

squamous-cell cancer or larynx, 

from 1952 through 195.5. 

Males: 

5% non-smokers 

47% cigarettes 

17% cigars 

15% pipes 

17% mixed 

!42 Clinic patients in Havana during 

32 1956, 57, with histologically diagnosed epidermoid cancer of 

larynx. 

!%non-smokers, M; 13% F 62% cigarettes, M; 72% F 20% cigars, M; 6% F !%pipes, M 16% H.ixed, M; 9% F -------1-----------

Dutta-Choudhurl et (100) India 

a!. 1959. M-F 582 Patients in Calcutta cancer hospital during 195G-54, with laryn- geal tumor diagnosed and con- firn.cd by biopsy or smear. 14.1% non-users 77.8% cigarettes or bidi 

3.1%chew 

5.0% both ----------------__ , _______ _ 

242 San•e time and sources; patients 

hospitalized for non-canrflrous 

eonditions or trauma. 

84% smokers 47% inhalers 

31% roll their own cigarettes 

Cases and controls Individually matched within Institutions; 

each member of a set questioned 

by the same trained lay interviewer. 

271 Patients from same source and By trained lay interviewers In time, with cancer other than hospital. squamous-cell of larynx. Mal<•s: 

24% non-smokers 

36% cigarettes 

9% cigars 

16% pipes 

13%mixed 

----------------1 

M 220 Same source and time; apparently IntNview of patients in clinic. F 214 patients with cancers other than 

larynx, lung, or oral cavity, 

matched for age. 

16% non-smokers, M; 66% I' 

45% cigarettes, M; 27% F 22% cigars, M; 6% F 1o/opipes, M 16% mixed, M; O% F 

288 Not specified. 

41.7% non-nS<.'rs 

52.1% ci~arettes or bl<li 

3.8% chew 

2.4% both 

Tobacco histories obtained during 

1951-54, apparently by interview. 
TABLE H.-Outline of retrospective studies of tobacco we and caru:er of the larynx-Continued 

Cases Controls 

RetIn veatlgator and year er- Country Sex Collection of data ence Num- Method of selection Num- Method of selection 

her her 

Stu~ewskl 1960. (327) Poland M 'JJYl Patients admitted to chronic dis- M9!2 Patients admitted during 1957 & Author Interviewed patients sus- F 13 ease hospital during 1957 & F 1813 1958 to chronic disease center pected oflung cancer for smoking 1958 with histologically con- for cancerous and non-cancerous history and background. firmed squamous-cell carcinoma conditions presumably not re- of the larynx. lated to tobacco consumption. 0.5% non-smokers 17.3% non-smokers 

87.9% cigarettes on! y 60.5% cigarettes only 

1.9% pipes and/or cigars 

88.4% 11 heavy smokers" 

11.1% pipes andjor cigars 49.0%" heavy smokers" 

96.1% Inhalers 66.8% Inhalers 

30.8% smoke, F 8.4% smoke, F 
A combination group of lung and laryngeal cancer cases was also included 

by Wynder et al. ( 376) and relative risks for lung cancer as well as 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) found an association with inhalation 

among light cigarette smokers and among pipe and cigar smokers. 

For both whites and non-whites the male-to-female age-adjusted sex ratios 

in laryngeal cancer are higher than for any other site common to both sexes 

( 130). Despite the fact that the female case material is exceedingly sparse, 

at least two studies concerned themselves with laryngeal cancer in the female 

(377, 388). The material in one study was adequate to establish an associa· 

tion with cigarette smoking ( 388) whereas in the other only a suggestion 

was elicited in view of the paucity of the material ( 377). 

Wynder and co-workers ( 387) in their study of Seventh Day Adventists 

noted that cancer of the larynx was an extremely uncommon reason for 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) ], 5.8 [Dorn (88) ], and 13.1 [Hammond and Horn 

( 163) ] . A summation of all seven studies yields a mean mortality ratio of 

5.4 (Table 1) for cigarette smokers. For five studies in which laryngeal 

cancer cases were associated with cigar and pipe smoking, the mean 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 tobacco 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 lO 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 smoker~ 

over the number expected from the incidence among non-smokers adds to 

the level of consistency noted. The calculations for cigarette smoking alone. 

as well as for the combination of cigarettes, pipes, and cigars, were almost 

identical to those in the prospective studies. 

The relative strength of the association as measured by the specific mortality ratio (as an average of combined experiences) is admittedly not a~ 

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 de· 

tailed study ( 376) the laryngeal cancer risk for cigarette smokers, irrespective 

of amount smoked, seems to be equal to that for pipe and cigar smokers (as a 

combined group). Furthermore, while the per capita consumption of 

cigarettes has risen, the consumption of pipe and cigar tobacco has declined. 

In addition, there is no evidence or reason to assume that the su~ceptibility 

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). 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 among betel nut chewers in India 

indicates that even among smokers of cigarettes. cigars, pipes or bidis * 

the addition of tobacco to the material chewed is associated with an even 

greater risk of laryngeal cancer 1100, 376). The evidence from the retro· 

'pective and prospective studies is compatible with the small rise in laryngeal 

cancer incidence observed. 

SEX DIFFERENTIAL IN MORTALITY 

As has been noted in the discussion of I ung cancer, the much later advent 

of cigarette smoking among females would be compatible with their lower 

laryngeal cancer mortality rates. Furthermore, the negligible degree of pipe 

11nd cigar smoking and tobacco chewing among females would not only be 

compatible with a significantly lower risk of cancer of the larynx among 

them today as compared to males (WM: WF=' 10.8) but also with a lower 

sex ratio 30 years ago (WM: WF=6.3) fl30). Assuming a reasonable 

induction period, the mortality rates 30 years ago could have been a reflec· 

tion of the much lower consumption of tobacco even among males between 

]900-1910 (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 

( 327, 376). · (Most laryngeal cancers designated as extrinsic arise in the 

larynx proper; about 30 percent designated as extrinsic arise in adjacent 

*Bidi (variant of biri) -a locally made cigarette of tobacco flakes rolled in the dried 

leaf of a 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, whereaa 

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 

~rooking and chewing patterns of males vs. females are compatible with 

the data on localization differences between the sexes. Extrinsic laryn~eal 

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 STUDIES 

As with cancers of other sites, clinical impressions of an association he· 

tween smoking and esophageal cancer led to more or less controlled studies 

of the two variables as early as in 1937. Ahlborn ( 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 associa· 

212 
tions with cigarette and with cigar smoking but only the cigarette smoking 

relationship was noted to be statistically significant. 

Since then there have been six other retrospective studies ( 306, 315, 325, 

329, 374, 385) (Tables 12 and 13). It should be noted, however, that one 

of these ( 329) 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 por· 

tion of this same study was devoted to analyses of data collected in India. 

The Indian data should not be given the same weight as the others, since 

only 10 percent of the male cases and 4 percent of the female cases were 

histologically confirmed. It is of interest, however, that an association he· 

tween tobacco smoking and esophageal cancer was observed. 

The retraining study in this group is that of Sanghvi et a!. ( 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 demon-

~trated 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 

significantly more smokers among cases than among controls. However, 

the difference in daily amount of cigarettes smoked was not significant. 

A refinement of the data in two studies (301, 374) by classes of number of 

cigarettes smok-ed 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 (325, 374). The Polish data 

revealed a relative risk ratio of 16:1 for heavy smokers as compared with 

non-smokers, whereas the latest Wynder study revealed ratios paradoxically 

lower for heavy smokers than for the category "all smokers." 

In view of previous studies which had revealed an association between 

esophageal cancer and alcohol consumption, Wynder and Bross ( 374) tested 

213 
TABLE 12.-Summary of methods used in retrospective studies of wbacco use and cancer of the esophagus 

Cases I Controls 

Investigator, year, and reference Coun try Sex Num- Num- Collection of data 

her Method of selection ber Method of selection 

---

Sadowsky eta!. 1953 (301) U.S. A. M 104 White patients admitted during 615 White patients with 1llnesses other (I) Obtained by 4 especially trained 

1938-43 to selected hospitals In than cancer admitted to same lay interviewers. 

N.Y. Cityc Missouri, New Or- Kroup of hospitals during same (2) 242 records out of a total of 2,847 

Jeans, and hicago. period. excluded becaw.e of incomplete or questionable smoking histories. --- Sanghvi et al. 1955 (306) India M 73 Consecutive clinic admissions to (1) 288 Consecutive clinic admissions of By means of 'detailed questionary'. 

Tate. Memorial Hospital, Born- patients without cancer. No other details given. bay. (2) 107 Con.secutive admissions of patients 

with cancers other than intraoral or esophagus. ----- Steiner 1956 (329) U .B. A. M+ 116 Consecutive cases studied at au- 464 Autopsy cases comprising: Not clear how smoking histories were F topsy in University of Chicago 116 stomach cancer obtained-from hospital records, 

Dept. of Pathology during 1901- 116 lung cancer probably, which indicates they 1954. 116 malignant lymphatic dis. may be inadequate. 116 cases without any malignant neoplasm. Matched by age, sex, race and year of autopsy. --- Wynder eta!. 19.17 (385) Swed en M 39 Patients admitted to Radiumhem- 115 Patients admitted to same hospital 

met, Stockholm during 1952·1955. with cancer of skin, and head and 

neck region other than squamous 

cell cancer, leukemia, colon, other 

sites. No matching. --- 8taszewski1960 (326, 327) Polan d M 24 Patients admitted to Oncological 912 Other patients sent to Institute with No details given on method of data 

Institute during 1957-59. symptoms probably not etiologi- collection. No age adjustment or cally connected either with smok- matching. A vcrage age of rancer ing or with diseases of esophagus, patients= 60.5 and of controls= 53. 

stomach or duodenum. ----- Schwartz et a!. 1961 (315) Fran "" M 362 Admis.,ions to hospitals in Paris and 362 Healthy individuals admitted to Interviewed hy team of special inter- a few large provincial cities since same hospital because of work or viewers who interviewed the 

I 

1954. traffic accidents-matched by 5 largest proportion possihle of a!: 

I yr. age group and tirnt.• of admis- cancer patients. Ca...~s and 

I Rion. matchNi rnntrols intcrvil.>\\-'ed hy 

I same per . .;on. - - -----· - ------------------, ----·----------------- ----------

I 

I 
Wynder and Bross, 1961 U.S.A. M 150 C'anrer patients seen in Memorial (374). llospit.al, N.Y.r. and Kings- brld~e and Brooklyn VA lfospl- tals durin~ 1950-.0P (86% white). 

F 37 Same hospitals and same time )eriod as male patients (86% white . 

--- Wynder and Bross 1961 India M 67 Admitted to Tata Memorial IIospi- (374). F 27 tal, Bombay. 

1.';() 

37 

134 

Patients seen in same hospitals Our- Data collected hy trained inter- ine: Rame time period with o ther viewers. turnors. 64%-malig-nant tum 36%-heni~n conditions. Mate ~~~ by ae:e with canr.er patients 

Same as with regard to male 

trois. 43% had mal!~ant 

57% benign tumors. 

Patients with other formE ot ca 

conand 

ncer (I) Interviewed by one person. 

except Cor oral cavity and lung. s; a.• (2) 10% ot male cancer cases histolog- ically confirmed and 4% of female cancer cases. well as various benign dise!ISt•s 
TABLE 13.-Szunmary of results of retrospective studies of tobacco use and cancer of the esophagus 

Percent non-smokers 

Investigator. year, and reference 

Cases Controls 

Percent heavy smokers 

Cases Controls 

Perr"n t Inhalers among 

smokers 

Cases Controls 

Sadowsky et al. 1953 (301) •.•.• ----------------------------- 3.8 .•. ------- 13.2 •• ------- -------------- -------------- -------------- --------------

Sangvhi et al. 1955 (306) ........... ------------------------- 5.5 ... ------- 17.3 .. -------

Wynder et al. 1957 (385): 

Average num her of bidls 

smoked 

15.3 14. I 

M.... .•. . . .. .. ... ... . . . . ... . .. .. . . .. . .. .. .. ... ...... .. 13......... •. 24 ..•..••.... -------------- .....•.••••.•..• -----..•.........••..••... 

L----------------------------------------------------- about~----- about 92 ••••• -------------- -------------- -------------- --------------

Relative risk: ratio to non-smokers 

All smokers 

4.0 

3. 6 

Heavy 

smokers 

2. I •••••••••••••• 

2. 0 --------------

Stas7.cwskl 1900 (326, 327) .•. -------------------------···-·· 0............ 18........... 95.8 59 87.5 80 -------------- 16 

~~--~~~-1---~-1-----~1-----~1------- Schwartz et al. 1961 (315) ..... ------------------------------ 3 .......•.•.• 17........... Total amount smoked 39 38 6. 6 --------------

Wynder and Bross 1961 (374): 

(I) American males .........•.•. ----------------------- (2) American females.---------------------------------

(3) Indian males ••..•••••• ---------------------------•. ( 4) Indian females •.••••• -----------------••••••••••••• 

dally (cigarettes) 

16.8 16.0 

5____________ 15___________ 48 33 -------------- -------------- 41. .......... 78___________ 27 16 -------------- -------------- 13 ___________ 28 ___________ -------------- -------------- -------------- -------------- 78 ___________ 94 ___________ -------------- -------------- -------------- --------------

3. 4 

4. 1 2. 0 

4. 5 

1.8 

1.9 
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 l 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. This level of 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 

1 385) 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 tobacco 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. :~.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 been discussed earlier but it should be 

emphasi1ed 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 (389) found the relationship to be 

significant. 

Three of the studies examined other forms of smoking. Schwartz et al. 

( 315), in France where cigar smoking is negligible, separated pipe smokers 

and mixed smokers from cigarette smokers and found only a suggestion 

of an association with pipe smoking, but the number of cases in this category were too few for meaningful inferences. Lockwood (2201 found significant associations between both pipe and cigar smoking and urinary 

bladder cancer in the male. Wynder and co-workers (389) found no excess 

frequencies of pipe-only and cigar-only smokers among the urinary bladder 

cases. Here, too, the number of such smokers was even smaller than in the 

Danish study by Lockwood. 

Only two studies (220, 389) are concerned with amount of 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 hut Wynder found only a 

suggestion of an excess of heavy smokers among the cases (Table 15). 

lnlwlation was examined in two studies, the French and the Danish (220, 

315). Schwartz et al. ( 315) found a profound effect of inhalation on the 

association between smoking and urinary bladder cancer. When compari· 

sons between cases and controls were made in each of the classes of amount 

smoked, the bladder cancer cases showed a greater frequency of inhalers 

in each class. When inhalation was controlled, the effect of amount of 

cigarette smoking disappeared. Thus the implication is clear that the essential relationship is between inhalation of either cigarette or pipe smoke 

with urinary bladder cancer. Lockwood (220) found statistically signifi219 
TABLE 14.-Sammary of methods wed in retrospective studies of smoking and cancer of the bladder 

Inveatlgator, year, 1111d 

reference Sex Number 

Cases 

Method of selection 

Controls 

Collection of data 

Number Method of selection 

------------1--------------------------------·l----l---------------------l----------------------

Lilienfeld et al., 1956 

(215). 

Schwartz et al., 1961 

(315) .. 

Lockwood 1961 (220). 

Wynder 1963 (389). 

(To be published). 

U.S.A. M 321 Admissions to Roswell Park 

Memorial Institute. 194&-55 over 45 yrs. of age. 

F 116 Same as males 

France M 2H Admissions to hospitals In Paris a.nd a few large provincial cities since 

19M. 

Denmark M 282 All bladder tumors reported to F 87 Danish Cancer Register during 

1942-1956 and living at time of 

Interview In Copenhagen and 

Fredericksburg. 

U.S.A. Fir&t Pl&a~e 

M 200 Admission to several hospital• In N.Y.C. during January, 1957- F liO December, 1960. 

Second Pl&a•e M 100 Admission to same hospital during F 20 1961. 

337 No-disease patients. 

287 Prostate cancer. 

109 Benign bladder conditions. 

317 No-disease patients. 763 Breast cancer 

2H Healthy individuals admitted to same hospital because of work or traffic accident-matched by 5 yr. age group, & admitted during same time to same ho~pital as cases. 

282 A. From election rolls matched with 

87 cases according to sex, age, marital 

status, occupation and residence. 

B. Another control group obtained 

from sample of Danish Morbidity 

Survey (1952-53 & M) compared 

"With respect to smoking histories. 

200 Admission to same hospitals (excluded cancer of respiratory sys- liO tern, upper alimentary, tract, 

myocardiallnfarction). Matched 

by sex and age. 

100 Same as above. 

20 

Interview of paUents hy groups of 

interviewers at time of 1st visit to Institute hefore seen and diagnosed by physicians. 

Interviewed by team of specialized 

Interviewers who interviewed the 

largest proportion possl ble of all cancer patients admitted to these 

hospitals. Cases and matched 

controls interviewed by same person. 

Cases-59 cases interviewed hy 

Clemmesen and 310 hy Lockwood. 

Election Roll Controls-2 Inter- viewed by Clemmesen and 367 hy 

Lockwood. 

Trained Interviewers. 
TABLE 15.-Summary of results of retrospective studies of smoking (irrespective of type) and cancer of the bladder 

Percent non-smokers Peroont heavy smokers Percent inhalers among smokers Relative risk: ratio to non-smokers Investigator, year, and referenoo Sex l----------~---------l-----------~---------1---------~--------------------,----------

Cases Controls Cases Controls Cases Controls All smokers Heavy 

smokers 

Lillenfeld eta!., 1956 (215) ........................... {V ~~ : :::::::::::::: :::::::::::::: ::--·::::::::: :::::::::::::: 2.3 --------------

1.4 -------------- --1--------1-----1------- ---------1--------------------------- Schwartz, 1961 (315) _________________________________ M 11 20 -------------- -------------- ----1----

Lockwood, 1961 (220). _______________________ ., ...... {W 

Canoer Cases ____________________________________ {~ 

Papilloma Cases.------------------------------· {W 

9 17 30 15 

56 66 4 4 ----

11 -------------- -------------- -------------- 59 

8 

55 

54 37 2.0 -----·---····· ---------1---------- 33 9 2.1 

1.5 2.4 

1.0 

24 ---------·---- -------------- -------------· H -------·-·---· -------------- ------------·- 31 -·------------ -------------- -------------· 

14 -------------- ---------·---- -·-----------· 

Wynderet al.,1963 (389) (Phase A and B combined). {W 7 

61 18 86 

47 

6 23 -------------- -------------- 0 ---------·---- --·--·--------

2. g 3.0 

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 I 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 

1220, 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. 

TABLE 15A.-Summary of results of retrospective studies of cigarette smoking 

and cancer of the bladder in males 

---- ----------------~---,-----------c-----

!nwsti~ator anrl Classification of Cigarette Smoking 

LiliPn!chl (cirarctte .~ other) 1215) In55 

Schwart1. (cirarcttc oolyl (31-'l 1~61 

Lockwood (Cigarette is main mode of smoking) (220) 1961 

Wynl\er (rirarettc ,.., other) (3g9) 1963 

PROSPECTIVE STUDIES 

PPrcpnt Cigar<>ttr Smokers 

Cases Controls 

fil 44 

70 

30 15 

85 63 

Relativ~ Risk: Ratio of Ci~arette Smokers to Non-Smoker~ 

2. 0 

2.1 

2. 4 

3. 3 

Six of the seven prospective studies showed bladder cancer mortality 

ratios ranging from l. 7 in the current study by Best et a!., in Canada ( 25) 

to 6.0 in the California occupational study of Dunn et a!. (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 11. 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: l. 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, l.O; 10 to 20, 1.8; more than 20, 2.75. 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, 3.4). Data for cancer 

of the bladder per se were not then available. In the Dorn study, even at 

the 1959 mark in its progress, a distinct gradient was noted. These data 

have recently been augmented by calculations of up-to-date data from six 

of the prospective studies. These reveal a distinct gradient by amount of 

cigarettes smoked daily. The mean mortality ratio for urinary bladder 

cancer among male smokers of one pack or less per day is 1.4, whereas the 

ratio for smokers of more than a pack is 3.1 (Chapter 8. Table 2:1). 

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 mouse anaplastic sarcoma of the uri· 

nary bladder was encountered. The significance of these experiments as well 

as earlier ones reported by Roffo I 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-effect found a 

correlation of increasing risk with amount smoked. Those examining the 

practice of inhalation of smoke have !ound 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 0-64-16 223 
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, 

familv statns, and occupation; and these variables were tested for relationship to smokinl! and inhalation histories. Such relationships, when found, 

were ~Ii!!ht and not to the degree of association of smoking to urinary bladder 

cancer. Information on histological confirmation of all cases of this study 

hv Schwartz was lackin!!. Since the bladder cancer cases in this study had 

originally served as controls in a lung cancer study, some of the observer-bias 

arising from knowledge of the distinction between cases and controls was 

probably neutralized. Furthermore, the results of the early phase of the 

study were consistent with the findings in the entire study reported on later. 

The Lockwood study, executed to elicit environmental factors which might 

be operatinl! 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 smokin~ relationship to both benign and malignant tumors to be essen· 

tially the same. These authors also utilized a second control group derived 

from the Danish Morbidity Survey. Their study control group and the 

probahilitv 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 pros· 

pective study is approximately unity, a finding inconsistent with the other six 

prospective studies. In addition to the finding of an association with smoking 

in female 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 hetween 

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 1177) 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 STUDIES 

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 methodology 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.-Summary of methods wed m retrospective studies of smoking and cancer of the stomach 

---

Cases Controls 

Investigator, year, snd Country Sex Collection of data reference No. Method of selection No. Method of selection 

-------

Dunham & Brunscbwlc U.S.A. M&F 40 Not clear. Patients In Dept. of 40 Not clear. Patients without gastric Not specified 1946 (94). Surgery, Univ. of Chicago. tumor. --- Kraus et al., !957 (193). U.S.A. M 56 Admissions to Roswell Park Me- 677 Patients admitted to Roswell Park Questioned by trained interviewers 

morl!ll Inst., 11/48--ll/51, 25--74 during same time period in followyears of age. ing 4 diagnostic groups: (1) Digestive cancer other than 

esophagus or stomach. 

(2) Cancer--<>ther than digestive-respiratory, urinary, skin, 

hem at. (3) Non-tumor diag. of digestive 

system other than esophagus or stomach. 

(4) Non-tumor diag. other than 

digestive-respiratory, urinary, skin, hemat. 

Each control group matched to cancer group by age and popula- tion size of place of residence. --- Staszewsk\1960 (327). Poland M 136 Patients admitted to Oncological 912 See T ABI,E 11 See TABLE 11. Two-thirds of can- Institute during 1957-59. cer of stomach diagnoses were histologlcally confirmed. --- Schwartz et al., 1961 (315). France M 263 See TABLE 11 263 Patients hospitalized from 1954-1956 See TABLE 11 

with gastric cancer In Paris and 

other large cities. 
TABLE 17.-Summary of results of retrospective studies of smoking and cancer of the stomach 

Percent non-11mokers 

Investigator, reference, and year 

C88es Controls 

Percent bea vy smokers 

Cases Controls 

Percent Inhalers among sn1okers 

Cases Controls 

Dunham and Brunscbwlg 1!Kll (94)________________________ 47.6 47.6 -------------- -------------- ____________ ------------

Relative risk: ratio to non..gmokers 

All Smokers 

0 

Heavy 

Smokers 

---1-----1------- -------------------------- -- ------ Kraus eta!. 1957 (193>-------------------------------------- 19.2 24.2 -------------- ______________ _ 1.3 -------------- -------1-----1----------- ---------- -- -----------

Staszewski 1960 (325)--------------------------------------- 12.6 18 76.6 59 ----------1------------- Schwartz et al.1961 (316>----------------------------------- 16 17 Total cigarettes smoked 

dally 14.6, 15.3 

88.2 1.5 2.1 

37 34 1.0 
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 ( 315, 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 he 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 (p=0.12) (163). 

Two of the earlier reports ( 84, 88) provi.de 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}. 

C arcir(,ogenesis 

Squamous cell carcinoma has been produced in the forestomach of mice 

by the oral administration of various polycyclic aromatic hydrocarbons ( 8, 

19, 59, ll3a, 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). 

Evaluation of the Evidence 

Squamous and adeno-carcinomas have been produced experimentally in 

mice with benzo(a) pyrene and dihenz(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 ciga· 

rette smokers is below the mean total mortality ratio, and for cigar and pipe 

smokers it is approximately the same. Even a gradient by amount smoked 

ia lacking in at least two of the prospective studies. 

Conclusion 

No relationship has been established between tobacco use and stomach 

cancer. 

SUMMARIES AND CONCLUSIO:\"S 

Cancer deaths per year increased seven-fold (in the United States death 

registration area of 1900) between 1900 and 1960-from 10,000 in 1900 to 

80,000 in 1960. Less than half of this increase was due to aging and growth 

of the population. A large part of the increase was due to lung cancer. 

LUNG CANCER 

While part of the rising trend for 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 Cnited 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 separ~te 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'ciation · 

between 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 

~moking 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-1 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 i-ates has increased with the ongoing progress 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 progressivelv with amount of smoking: the pivot level appears to be 20 cigarettes a day. For those who SIT'oke 

pipes and/ or cigars I to the exclusion of cigarettes I, the lung cancer ratios 

are lower than for any of the cigarette smokir:g classes including combinations of cigarettes with pine and I or cigars. 

In extensive and controlled blind studies of the tracheobronchial tree of 

402 rnale patients. it was observed that several kinds of changes of the 

epithelium were much more common in the trachea and bronchi of cigarette 

~mokers and subjects with lung cancer than in non-smokers and patients 

without lung cancer. The epithelial changes observed are ( 1 l los~ of ciliated 

cells, (2) basal cell hyperplasia (more than two layers of basal cells), and (31 

presence of atypical cells. Each of the three kinds of epithelial changes was 

found to increase with the number of cigarettes smoked. Exten~ive atypical 

changes were seen most frequentlY 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 haYe fewer changes th<tn cigarette smokers 

consuming approximately the same amonnt 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, adenocarcinomas 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 

I retrospe::tive and prospective studies) described earlier. Indirect measures 

include: a parallel increase in lung cancer mortality rates and in per capita 

consumption of tobacco; disparities between male and female lung cancer 

rates 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 the-e 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 con$istent; 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 

211 
close in magnitude, attesting to the strength of the association. Moreover a 

dose-effect phenomenon is apparent in that the relative risk ratio increases 

with the amount of tobacco consumed or of cigarettes smoked. From the 

prospective studies, it is estimated that in comparison with non-smokers, 

average smokers of cigarettes have approximately a 9- to 10-fold risk of 

developing lung cancer and heavy smokers at least a 20-fold risk. 

An important criterion for the appraisal of causal significance of an as-

!'ociation 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 

f!enetic 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 

l. Cigarette smoking is causally related to lung cancer in men; the magni· 

tude of the effect of cigarette smoking far outweighs all other factors. The 

data for women, though less extensive, point in the same direction. 

2. The risk of developing lung cancer increases with duration of smoking 

and the number of cigarettes smoked per day, and is diminished by dis· 

continuing smoking. 

232 
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 wa~ 

noted for cigarettes. 

The seven prospective studies show that cigarette smokers have propor· 

tionately 4.1 times as much mortality from oral cancer as non-smokers. This 

is the third highest mortality ratio of cigarette smokers to non-smokers among 

the several specific types of cancer deaths and the fourth highest among all 

causes of death associated with cigarette smoking. For cigar and pipe 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 (a) 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 

l. 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 mor. 

tality ratio (as an average of combined experiences), is not as high as that 

noted for lung cancer, but two of the three major studies with adequate ca~e 

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 which 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 ratio--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 

urinary bladder cancer in the male but are not sufficient to support jud!Zment 

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. 

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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 . . . . . . . . . . . . 263 

Characteristics of the Exposure . . . . . . . . . . . 263 

Composition of Tobacco Smoke . . . . . . . . . . 263 

Regional Deposition or Retention of Tobacco Smoke. 263 

Mouth Retention of Tobacco Smoke . . . . . . . 264 

Retention of Particles by the Trachea, Bronchi, and 

Pulmonary Tissue . . . . . . . . . . . . . . 264 

Retention of Gases by the Trachea, Bronchi, and Pulmonary Parenchyma . . . . . . . . . . . . . . . 265 

Metabolism and Toxicity of Specific Components in 

Tobacco Smoke . . . . . 265 

Clearance of Smoke Deposits . 267 

Effects of Tobacco Smoke on Defense Mechanisms of the 

Respiratory System . . . . . . . . 267 

Pulmonary Hygiene and Ciliary Activity 267 

Mucus Secretion . 268 

Alveolar Lining . . 269 

Phagocytosis . . . 269 

Other Mechanisms . 270 

Histopathologic Alterations . 270 

RELATIO~ OF SMOKING TO DISEASES OF THE RESPIRATORY SYSTEM. . . . . . . . . . . . . . . . 275 

Effects of Smoking on the Nose, Mouth, and Throat . 275 

Smoking and Asthma . . . . . . . . . . 275 

Relation of Smoking and Infectious Diseases :?76 

Chronic Bronchopulmonary Diseases . 277 

260 

Chronic Bronchitis and Emphysema 278 

Definitions . 

Diagnosis .. 

Relationship 

physema . 

Between Chronic Bronchitis and Em278 

278 

279 
RELATIO.l\ OF SMOKING TO DISEASES OF THE RESPIRATORY SYSTEM-Continued 

Chronic Bronchopulmonary Diseases-Continued Page 

Evidence Relating Smoking to Chronic Bronchiti,; a1HI 

Emphysema. . . . . . . . . . . . . . . . . 280 

Epidemiological Evidence. . . . . . . . . . 280 

Prevalence Studies . . . . . . . . . . . . 280 

(l.) Smoking and Respiratory S)mptom,;. 280 

(a.) Chronic Cough . . 280 

(h.) Sputum . . . . . . . . 283 

(c.) Cough ami Sputum . . . 28:) 

(d.) Breathlessnes~. . . . . . 286 

(e.) Smoking and Che:'.t lllne,;,; 287 

(f.) Combinations of Symptom,.;. 288 

(g.) Relationship Between Symptoms or 

Signs and Amount Smoked . . . 289 

(h.) Relationship Between S~ mptom,; and 

Signs and '\lethod of Smoking. 289 

(i.) Ventilatory Function. . . . . . . 289 

Prospective Studies . . . . . . . . . . . . 293 

Clinical Evidence . . . . . . . . . . . . . . 294 

Relationship of Smoking, Environmental Factors, and 

Chronic Respiratory Disease . . . . . . . . . . 295 

Atmospheric Pollution . . . . . . . . . . . . 295 

Basis for Interrelationship and Relative Magnitude 

of Exposure . . . . . . . . . . . . . . . 295 

(1.) Experimental Evidence. . . . . . . 295 

(2.) Relative Magnitude of the Exposure . 296 

Epidemiological Evidence . 297 

Occupational Factors. 298 

SUMMARY . . 300 

CONCLUSIONS 302 

REFERENCES. 300 

Figure 

FIGURE I.-Black pigment and emphysema m lungs of 83 

patients . . . . . . . . 273 

List of Tables TABLE I.-Summary of reports on the prevalence of cough in 

relation to smoking . . . . . . . . . . . . . . 281 

TABLE 2.-Summary of report:; on the prevalence of sputum in 

relation to smoking . . . . . . . . . . . . . . 283 

TABLE 3.--Summary of reports on the prevalence of cough and 

sputum in relation to smoking . . . . . . . . . 284 

TABLE 4.-Summary of reports on the prevalence of breathlessness in relation to smoking . . . . . . . . . . 285 

TABLE 5.-Summary of reports on history of chest illness in the 

past three years in relation to smoking . . . . . 287 

TABLE 6.--Summary of reports on the prevalence of combination,.; 

of certain symptoms in relation to smoking . . . . 288 

261 
Chapter 10 

This chapter presents the evidence on smoking in relation to the development and progression of the non-neoplastic respiratory diseases. The c~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 working 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 ( 107, 

116, 122). Measurements of the median partide 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 m 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 deri,·ed largely from substances 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 probab I y 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 go,·ern 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 parenchyma is about 80-90 percent, even 

when the smoke is held in the lung for a relatively short period, two-to-five 

seconds. When deliberately held for periods as long as 30 seconds, retention 

of particles is almost complete ( 135). 

MOUTH RETENTION OF TOBACCO SMOKE 

Removal of tobacco smoke constituents while 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 he 

removed while tobacco smoke components are in the mouth. 

RETE\TION OF PARTICLES BY THE TRACHEA, BRONCHI, A 'ID 

PULMONARY TISSUE 

Most information pertaining to retention of smoke constituents hy the 

tracheobronchial tree and pulmonary tissue is based on knowledge of physical 

factor>' whiPh 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 very fine particles which diffuse onto the surface. 

The size of virtually all the individual particles in inhaled smoke is 

probably less than t\1 o microns.. Data from a number of laboratories indi264 
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. Diffusion 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 12, 3). Data on sites of intrapulmonary deposition derived from physiological 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 study site dt>position in 

animals. Deposition in a diffuse pattern was obtained in dog;;; inhaling 

smoke from cigarettes impregnated with K 42. 1'\a 24. and As -;(l 1192). 

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 ( 1911. In rabbits. cigarettes impregnated 

with As 76 produced deposition on the larynx, carina. and major bronchi 

but this deposition contributed only a small fraction of the total activity 

retained by the smaller bronchi, bronchioles, and pulmonary tissue 1100). 

From indirect data, therefore, it is most probable that the vast majority 

of cil!arette smoke particles penetrate deeply into the respiratory tract and 

are deposited on the surface of the terminal bronchioles, respiratory 

bronchioles, and pulmonary parenchyma. 

RETE!\TIO:\' OF GASES BY THE TRACHEA. BRO\"CHI, AND PCLMONARY 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 he of 

significance in production or augmentation of diseases of the bronchi. 

Metabolism 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 12) . 

Hydrogen cyanide is present in cigarette smoke in conct>ntrations 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, 601. Among these factors 

are dilution of the small smoke volume, discontinuous exposurt>, rapid de26S 
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 ( 23, 81). Nitric 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 following 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 80--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 form11ldehyde 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). 

Exposure of guinea pigs to low concentrations of acrolein, which is also 

present in cigarette smoke, caused an increase in total respiratory flow re· 

sistance accompanied by decreased respiratory rates and increased tidal 

266 
volumes ( 143) . It has been found also that 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 metaboli~m 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, howeYer, 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 MEcHANISMS 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 way 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, ci~arette 

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 epithelium i 17, 221. Although all investigations have bPen conducterl in ritro, 

the uniformity of the inhibitory effects in a number of different experimental 

models is impressive. 

Positive ions are present in cigarette smoke. Each cigarette vielrls about 

1010 positive ions: negatively charged particles arP also present i 1211. 

These thermally produced gaseous ions have considerable energy 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 cigarette smoke is augmented and sustained by 

additional exposure to positive ions (112). . 

:\icotine in high concentrations inhibits ciliary motility although concentrations of nicotine similar to those in tobacco smoke do not affect rabbit. 

chicken, or human ciliary function ( 22, 121 '1. In addition, tobacco smoke 

from low.nicotine cigarettes produced no significant difference in ciliary 

response from that obtained with cigarettes whose nicotine content had nut 

been altered ( 121). Hydrogen cyanide, ammonia, acrolein. formaldehyde, 

nitrogen dioxide, all components of cigarette smoke, possess potent inhibitory activity ( 40 I . 

There seems to be little doubt that cigarette smoke is capable of producing 

significant functiona I 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 complex experimental methods, including dosage of 

the particular agent. Ciliary depressant activity in the environment of man. 

is not I imited to the components of tobacco smoke; agents such as ozone and 

sulfur dioxide, which are important air pollutants hut are not found in significant amounts in tobacco smoke, are also potent ciliary depressants. 

Morphologic alteration of cilia of smokers has been described i 31. 32, 

104). The len)rth of cilia in the trachea and bronchial epithelium was measured at autopsy and found to be shorter than in non-smokers. In addition 

the percentage of cells remaining ciliated is lower in smokers than in non· 

smokers ( 9. 10, 104 l. 

Afucus Secretion 

Definitive studies on the effect of cigarette smoking upon the quantitv 

and qualitv of human respiratory tract mucus have not been performed. 

Alteration in the appearance of mucus after exposure to cigarette o-mokP 

has been noted several times. Following exposure to sulfur dioxidP. a gas 

not present in cigarette smoke. ('hanges in the physical properties of mucu~ 

have been observed i .tO I. Whether such changes result after exposure to 

gases present in cigarette smoke has not been established. Morphological 

chan~es observed in the goblet cells and mucous glands at post-mortem 

examination. howewr. support the possibility that mucus produrtion may 

have been altered during life. 

In essence. little has been contributed in this regard since the observation 

about 100 years ai!'o that a marked increase in mucous secretions in the 

trachea and larger bronrhi of the cat occurred after large doses of nicotine. 

268 
Atropinization blocked this effect, indicating that this action of nicotine was 

mediated by stimulation of the mucous glands since goblet cells are not 

under nervous control 1 185). An increase in mucus-secreting cells after 

exposure of rats to cigarette smoke has also been obsened recently ( 130). 

Alveolar Lining 

The alveolar surface is covered by a secretion which stabilizes the alveoli 

and is produced by the alveolar epithelium I 79, 151). Little is known of 

the influence of cigarette smoke on this alveolar lining. The application of 

cigarette smoke to rat lung extracts, considered to represent the alveolar 

lining, 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 surf ace compressibility. These findings differ markedh· 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 ( 13-!). 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. 

Phagocytosis 

The importance of phagocytosis as a mechanism for clearance of deposits 

in the acinus has become more clearly established in recent years. The 

. uptake of tobacco tars by 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 I 119, 121). 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 I 121). 

Early in the exposure period, the clearance mechanism of the lungs is adequate to the task of aggregating and removing pigmented material and 

pif!ment-laden phagocytes; in the final stages of the 2-year experiment, 

especially at the high dose levels, the phagocytic mechanism appears to be 

overwhelmed since large areas of parenchyma are flooded with pigment in 

the absence of phagocytes. A similar suppression of the effectiveness of 

the phagocytic clearance mechanism for the human lung has been described 

in pneumoconiosis ( 41). 

Fluorescent histiocytes have been found in the sputum of cigarette smokers 

but were not detected in the induced sputum of non-smokers I UlB). The 

intensity of fluorescence and the number of histiocytes were in direct proportion to the number of cigarettes smoked. These fluorescent histion tes pre269 
sumably represent the phagocytic cells of the acmus 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 Mechanisms 

Little is known about the role of lymphatics in the removal of tobacco 

smoke deposits. The evaluation of the effects of smoking on pulmonarv 

function tests will be considered in this Chapter in the section on "Chroni~ 

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 aboli~h 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 p!lagocytes 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 ohsen·ations again appear to loom large for respiratory disease in man but further 

definition of these effects and quantitation \viii be necessary before their full 

significance can be understood. 

HrsTOPATIIOLOGTC ALTERATIO."iS INDUCED IN THE RESPIRATORY 

TRACT A:\D '-"' PcLMO:\ARY PARENCHYMA BY ToBAcco SMoKE 

A variety of histopatholof!ic studies from diverse points of view indicate 

clearly that ~moking 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 etiologic 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 glands, leading to blockage and subsequent dilata· 

tion of the ducts. Epithelium lining the ducts commonly shows squamous 

metaplasia. This condition is believed to be very common in pipe smokers 

but usually disappears upon cessation of smoking. 

A somewhat similar morphologic change has been descrihE'd in the larynx 

that correlates closely with the cigarette smokinl! 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-smokE'r (9. 10, 11, 31, 33, 35, 38, 1711. 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 hypertrophy of 

mucous glands and a higher proportion of cells with shorter cilia also were 

observed more frequently in smokers ( 33, 171) . The hypertrophy and 

hyperplasia of mucous glands from miners correlated much better with the 

degree of smoking than with exposure to silica ( 35). Even though the 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, 184). Although 

many cases of chronic bronchitis show other morphologic signs of acute and 

chronic inflammation, these are not as constant as are the glandular changE's. 

Provided further investigation of the pathologic anatomy of chronic 

bronchitis in other countries indicates that the disease is essentially identical 

pathologically, the few British studies on goblet cells and mucous. glands in 

smokers offer the first amitomic support for the relationship between smoking 

and chronic bronchitis suggested by several epidemiologir reports. Conceivably, one or more components of cigarette tobacco smoke have the prop714-422 0-64-19 271 
erty of stimulating mucous cell hypertrophy and hyperplasia in a manner 

similar to that of other unknown factors which appear to be important in 

1 he pathogenesis of chronic bronchitis ( 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. . \!though this hypothesis ( 64) has many attractive 

features, especially in reconciling 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, bronchiectasis 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 a:,!ent 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, 1361. Formalin fume-fixed lungs 

from 83 patients over 40 year~ 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 "rliffuse 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 Pnthracotic. A close correlation was observed 

between the quantity of sm•Jkir.g, 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 ( Fi'!U~C 1). 

Histologic examination·~ of peripheral lung sections has revealed changes 

in pulmonary parenchyma, the severity of which was proportional to the 

272 
BlACK PIGMENT AND EMPHYSEMA IN lUNGS OF 83 PATIENTS 

DEPARTITIONING 

0 + I I I I I 

A.A.A.O A.OOO 0 

••• A.OO 

+ ••• • A. • A.A. •• • •• 

BLACK •• • •• • •• •• 

A.O A.O A.O 0 

A. 

I I ••• • •• ••• •••• • •• 

PIGMENT •••• • ••• • •• 

I I ••• 

• ••• ••• NON-SMOKERS •= <15 CIGARETTES 0= PER DAY >15 CIGARETTES •= PER DAY 

FIGURE l. Source: Mitchell, R. S. (}36) 
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 abnormalities, measured by arbitrary gradations, 

included the following: (a) fibrosis or thicbning 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, 45--49, 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 day 

cigarette smokers; 

1 :i) 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 S-19 years. 

All the changes aboYe 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 studY 

are based in large part upon the findings pertaining to fibrosis or thickening 

of alveolar septa and rupture of alveolar septa. 

In summary, histopathologic alterations in the mouth, larynx, 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 parenchvma 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 SMOKING 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. 

Aggravation 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) 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 res· 

piratory tract, induced by smoking, is lacking. Only in studies of "stomatitis 

nicotina" and of epithelial changes in the larynx has there been adequate 

pathological substantiation of the clinical opinion that alterations are induced 

by smoking. 

SMOKING AND AsTH:viA 

The definition of asthma of the American Thoracic Society will be used 

for the purposes of this report ( 4) : 

"Asthma is a disease characterized by an increased responsiveness of 

the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy. 

275 
"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 obstruction is not causal! y related to these diseases." 

In rare instances, allergy to tobacco products has been ascribed a causa. 

tive role in asthma ( 99, 105, 168, 169, 1891. 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). 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 

I Chapter 8, Tables 19 and 261. 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 epidemiological research. 

Studies adequate for examination of this association are available for only 

two categories of infectious diseases, upper respiratory viral illness ·and 

tuberculosis 130 I. Experiments on transmission of common colds failed 

to demonstrate increased susceptibility in volunteers with a history of cigarette smoking (50). )loreover, common colds were detected among 5,500 

employees over a 2-year period with approximately the same frequency in 

smokers and non-smokers ( 110). In a study of illness 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 (211. Similar results were obtained by questionnaires in an analysis of the frequency of common colds in a group of 

college graduates followed over a 20-year period (85). 

276. 
A number of studies have suggested a substantial relationship between 

smoking and pulmonary tuberculosis (55, 124, 133, 175). The possibility 

that the relationship is not a direct one needs further careful examination. 

Certain social factors, important to epidemiological assessment in 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 32,041 deaths 

( 47). The possibility that mortality data, as presently recorded, may underestimate the role of chronic bronchopulmonary diseases throuf!h 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 smokin-g 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 

211 
emphysema. Since descriptions of both were published long before c· . Iga. rette smokmg became commonplace fl3, 14, 114), it seems reasonable t 

suggest at the outset that cigarette smoking alone is not the only cause ~ chronic bronchitis and emphysema. 

Chronic Bronchitis and Emphysema 

DEFINITIONS 

Many definitions of chronic bronchitis and emphysema haYe been sug. 

gested. For the purposes of this report the definitions proposed by th!' 

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 cou?h. 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, bronchiectasis, as well as certain cardiac diseases, may cause identical symptoms: 

furthermore, patients with chronic bronchitis may have other pulmonary 

or cardiac diseases as well. Thus, the diagnosis of chronic bronchitis 

can be made only by excluding these other bronchopulmonary or 

cardiac disorders as the sole cause for the symptoms." 

This definition and classification of chronic bronchitis later considers 

complications, listing t!uee: infection, airway obstruction, and pulmonary 

emphysema: 

"Emphysema is an anatomic alteration of the lung characterized by 

an abnormal enlargement of the air space distal to the terminal, non· 

respiratory bronchiole, accompanied by destructive changes of the 

alveolar walls." 

DIAGNOSIS 

The diagnosis of chronic bronchitis is based essentially on descriptions 

of clinical manifestations and is achieved by exclusion. Recollection and 

interpretation on the part of the subject are necessary. There is. no simple 

sensitiye 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 phy~iological changes usually thought to indicate the presence of 

emphysema may result from airway obstruction due to bronchitis (66, 180). 

There is no completely satisfactory method of detecting emphysema by 

pulmonary function testing and no pulmonary function test is specific for 

the detection of pathologic lesions of emphysema (52). The clinical detec· 

tion of emphysema is therefore not a simple matter, especially in the presence 

of chronic bronchitis. 

278 
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, clinieal 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 BRO\'CHITIS AI\'D 

EMPHYSEMA 

Chronic bronchitis and emphysema frequently coexist, although one can 

be present without the other. A clinical 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 I 123). 

An alternative method of assessing the relationship is by study of pathological change. A close 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 respiratory tracts simultaneous] y, 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 ( ll4). Clinical evidence of bronchitis preceded clinical evidence of emphysema in over 50 percent of cases in 

one continuing study ( 137). Others suggest that emphysema may be a cause 

of chronic bronchitis 1531. It seems likely that a common cause, cau:oation 

of emphysema by chronic bronchitis, and causation of chronic bronchitis 

by emphysema are all operating mechanisms, with varying importance in 

different populations and different individuals ( 12~). 
Evidence Relating Smoking to Chronic Bronchitis and Emphysema 

Experimental and pathological evidence bearing on the possible relationship of smoking 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 entitles. 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. 

( l.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 a!. ( 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 ll 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 on the prevalence of cou(l:h m relation to 

smoking 

I ~umh<>r of suhject' Perc<>nt with cough Refer- _______ I _______ _ Author 1

1 

Yt"ar 1 pnce 

, I Smoker" Non- Smok('r<.: , ~on-

; smok£'rs "mok<'rs 

--------------------1-------

Balchum ------------------------------------ 1002 Boucot ... ____________ ________________________ Hlli2 Bower ... _____________________________________ Hlli1 Densen. _____________ ___ _ _ _____ _ _ _______ _____ 1963 

Fletcher: 

Lonilon Transport------------------------- 1001 Post Office -------------------------------- 1001 Flick .. ------------------___ ____ ___ __________ 19!\9 Ol<en: Unitcrl Kingdom.___________________ 1\lliO 

1 

Denmark ___________________________________ 1\lliO I 

i?~b~schuetz-::::::::::::::::::::::::::::::::1 m~! 

(lfi) 

(Z.ol 

(21\) 

(44) 

(R7) 

(fii) 

(68) 

(l4R) 

(l4S) 

(176) 

(1~) 

1.19S 1 

5, 331 

76 i 2, 5.10 

272 

166 

1.17 

Hi2 

132 I, 292 

~1 

2m 

son 

49 

,\14 

30 

10 

.11 

11 

24 

4\lli 

.\2 

2~. ~ 

~1. I 

27. fi 

21.2 

~.6 

1S. 7 

M.R 

32. 1 

IS. 9 

6. 4 

fl.O I 

10.2 

1~. 0 

4. 1 

7 R 

0 

0 

q R 

0 

R. 3 

Lfi 

0 

Boucot and others (25) con~idered 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 vears. 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 emploved in a bank. This studv 

is one of the few which included men and women working under similar conditions. Eighteen per,cent 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 

ege 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 

1. "constantly present for two years or more") are presented in terms of 

281 
years of smokinl!, although the original figures were not published and 

are not included in Table l. 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 who 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 ( 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 182) 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 number 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 was almost three times as great as might have been expected on the 

basis of cough prevalence among non-smokers. For women, the ratio of 

ubserverl-to-expected smokers with the complaint of cough was 2.5 to l. 

The ratio of ohsern·d-to-expected numbers complaining of cough "more 

'e\·ere than slight" was 4.09 for males and 2.74 for females. The difference 

in frequt>nn of the complaint of cough or of cough "more severe than slight" 

bet11 epn smokt>rs and non-smokers is statistically significant at the 0.001 

lt>vel. The studv samplt> was not a random sample of the population, but it 

prm idPs 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 cough than are non-smokers. 

In each of the surveys. ,.rooking was found to be associated with the 

symptom of cough definrd in a variety of ways. The studied populations 

varied considt>rahlv-from ho,.pital 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 diffPrence 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 2lists 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 l. 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 

----------~-~-----;--c~---,----- -----

1 Nu~:ofsuhjccts ~~-~~~u~~~;;ith Author 

Balchum _ .... ________ .... ___ .. ______ .. _____ . Bower. _________ ... ________ .. __ .. _____ .. ____ .. Densen ___________________________ _ 

Ferris: 

Males._. ________ ....................... -- .. 

Females ... --------------------------------- Fletcher: 

London Transport._ ..... __ .... __ .. _ .. _____ . Post Office ___________ .. _______ . _____ . ______ . Flick._. ________________ . _______ .... _ ........ . 

Olsen: 

United Kingdom __________________ .. ______ _ Denmark ....... ____________ ..... __ ... ---... 

1 Percentages standardized for age. 

1 Year 

I 

1902 

1961 

1903 

1902 

1962 

1961 ' ::II 

1960 

Reference 

(In) 

(2n) 

(44) 

(61) 

(61) 

(67) 

(67) 

(68)' I 

(J4R) I (148) 

Rmokrrs 11 ~on- I SmokPrs ~on- smokPrs smok('TS 

------------,---

1,19R 25.1 I 30.4 7n 49 34. 2 2, 5:JO M4 21.9 

~g g~ I : i~: ~ 272 30 If>. 9 

1nn to 1 1~. 1 

15n ! 49 , n4. 7 

H\2 ' 

132 I 

11 

24 

27.? 

11. 4 

11.1 

20.4 

13. R 

I 13. R 

I 9. 4 

7. 0 

10.0 

24. ·' 

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 -1-0.3 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.) 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 varying 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 between smoking 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 in 

relation to smoking 

--- ~------ --------------c- 1 I '

1

, -

~umh('r ofsuhjPets Pt-rcent with ('OUrt 

• [ and sputum ' "-utlwr l'ear i Refer- ~-----~-

1 ene<> I Smokers i :-.ion- I Smokers ~- Xon. 

smokprs I 1 srnok, r~ 

;~:~-~----~-----~-~-~-~-~--~--~--- Males __ _ ___ _ ___ . ... _ .\19.o7

1 

(88) 222 28 2:! 9 • 1 Fei_nalrs__ ____________ ------------~1957 (88) 931 176 17.2 1~. H1ggms: Males_ _ ____________ _ __________ 1958 (93) 75 6 24.0 11 Females ____________________ --------------, 19581 (93) 20 ~- 64 30.0 :

1 1 Higgins: I 

Mairs_ _ __________ --------------, 1959 (90) 315 33 29.8 1

; 1 J!iegins: I Males, 2.'>-34 .. _______________________ -~1959 (92) 282 5& 29. I ,_,_, Males. 55-f,4 __________________ --- _______ !959 (92) 293 29 44.7 :1 1 Payne: , 

Males -- -----------------------------------~1002 g~l 

K~~~~~~-~~:-:~:~:~---~~:~;-_·-:::_:·_~:~:1 ;;~ ;;~; Liebeschuetz _ -------------------------------11959\ (120) 

1,400 

888 8: I 43 

831 

364 

1, 468 

451 

46 

81 

52 

11.0 

6. 0 

51.0 

23. 1 18.6 

7. 2 

-------------------

l 'J 

J.q 

'2.0 

4. I 

4 \l 

" 

The percentages of symptoms noted by Oswald and Medvei ( 150) 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 -H. 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 as both cough and phlegm, of which 

at least one was present throughout the day for three months in the year 

or longer. The preya[ence of Grade II symptoms 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-smoking males, and 2 percent of 364 nonsmoking males. The corre&ponding figures for females were 6 percent of 

888 smokers and 2 percent of 1,468 non-smokers. These Grade II symptoms 

increased in prevalence with advancing age in men, and in women up to 49 

years. lt is interesting to note that lesser degrees of cough and sputum, 

classed as 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 were 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 percent of 388 smokers and 17 percent of 1,468 nonsmokers among the females. 

284 
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 an· limited in one respect, and some in another. 

The degree to which bias has been avoided varies; several of the surveys 

quoted are open to criticism in this regard, but in others considerable pai~ 5 have been taken to avoid any possibility of sug~esting a relationship whirh 

may not trulv exist. It would be wron!! to extrapolate from. say, a hospital 

population to the general public, but the ~roups surveyed vary enough that 

the evidence demonstrates clearlv that cigarette smokers more often report 

symptoms of cough. sputum, or both. than do non-smokers. 

(d.) Breathlessness.-Table 4 summarizes the prevalence of breathlessnrs, 

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 bv pack-years of smokin~t 

experience showed a less smooth gradient than for prevalence of cough anrl 

sputum. 

Den sen and others ( 44), 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 i' indicated by positive answers to specific questions on the 

questionnaire) . 

Fletcher and Tinker ( 67), in a study of Transport Executive employees 

and Post Office employees, had only one non-smoker out of 40 complain of 

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 ( 88) in the agricultural district of the Vale of 

Glamorgan, the author presents prevalence figures for the various symptoms 

among females in two age groups, those under age 45, and those over age 

45. His reason for doing so is the considerable difference in frequency of 

the ~moking 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 was 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 

190 I, breathlessness is more prevalent among the smokers, and the same 

thing applies to the two different age groups of males studied in Staveley (921. 

Payne and Kjelsberg ( 1531, in their survey of a total community, have 

&tated 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 among smokers than among non-smokers. 

Hammond (82) 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 breathlessness 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-smoke;s, 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 /llness.-The percentage of smokers and nonsmokers who reported chest illness in the three years prior to the interview 

TABLE 5.-Summary of reports on history of chest illness in the past 3 years 

in relation to smoking 

Author I Year! 

I Rrfer- I 

--- ~ ---- ~--~-~----

~umhrr of suhjt.'ct~ PercC'nt with elwst illness 

Sll10kl'TS I '>lllOkC'TS 

rnrc Smok<~s-\ ~on:-1 Smohrs ~---;.,.o~ 

----~----- ·-------~----'~---~ -- ~-1 --- ------'- --- Fh'leher: I 1 ] 1 

London Transport _ _ 119fll ~~~~~~ 0ffice _ __ t%1 

\faies _ 19S7 f PlllaJt•s ~ -- --- 19,'ii ll!ggms --- · 

'fales 

Females,~:: litgeins: 

\fales 

Higgins: 

\f ales, 25-34 _ \lairs, 55-04. Paynr: 

\!alPs 

Fl'IUah·s-_ = = == = ~ =--

-------------- ~------

714-422 0-64-20 

19.18 

1958 

I 1959 i 

I 

l\JS9 I 

19.1\J 

19f)2 : 

lni)2 

(fi7) 2i2 (ii7) lfifi 

(88) 222 

(~R) \l:l 

(93) 7.1 (9:l) 21) 

(~II)) :H!i j 

rn1 2H2 

[921 2\l:l I 

(J,\:l) I. 4[)[) I 

(lo:ll KKK 

:w H. 2 l.:l 

10 I :J:l. 7 I 20. () 

z,; 17. 1 I :t ti 

1/f; 1.\1 i t:l 1 

I 

" H\.ll () fi4 Ill. II 10. \~ 

:n 2:~. ~ >i.ll 

.'ifi I 12 ~ 7 I 

2U I .,- :l h \1 ! 

:Hi..f I ll.() 9. I 

1. 41):-\ 15. \) ; 1:to 

287 
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 125-34) as well as the older males (55-

61 l. For female smokers and non-smokers, the prevalence of chest illness 

was about the same. 

(f. l Combinations of Symptoms.~A number of prevalence studies ( 7, 54, 

61, 62, 77, ISO) have 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.~Summary of reports on the prevalence of combinations of certain 

symptoms in relation to smoking 

Author 

Ashford____________________ _ _________ _ 

Edwards_ .................. . Ferris: 

Males____________ .................. . Fe-mairs ______________________________ _ 

Ferris: 

Males _ ______ ---------······-··· Femalf's _____________ -----------------------

Goldsmith----------·········--·····-········ 

Oswald: 

!>fa!Ps ···-··-··········--······-········· Frmalrs _____________________________ _ 

·---------~~~~~~~~~~~~~~~~~~~~~~-

IPPrcPntages standardiz('rl for agr. 

Ashford and his colleagues ( 7) 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 cough 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 rresented the percentage of smokers and nonsmokers with bronchitis. according to clinical assessment by one of ll 

general practitioners cooper:.;ting in the survey. No attempt to standardize 

the diagnosi~ was n'ported. Of 7/IJ smokers, 29. I percent had "bronchitis" 

compared with l9.S 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. l.O) of less than 

(JO percent of the total forced expiratory volume. According to this definition. male smokers ~howed 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. 

In a study conducted in a flax mill, Ferris, et al (62l presented the prevalence of "chronic respiratory disease," defined as productive cou!:!:h 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 phvsician at 

the time of the survev; or F.E.V. 1.0 less than 60 percent of forced vital 

capacity. l:nder this. definition, 42.6 percent of 54 male smokers and 15.0 

percent of 20 male non-~mokers had "chronic respiratorY disease." For 

females. the figures were 10.0 percent of lO smokers and 10.0 percent of 60 

non-smokers. 

Goldsmith and others ( 771. in their studv 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 ( 150). defining "bronchitis" as disability from acute 

exacerbations of chest symptoms, or breathlessness, or both, found a preY· 

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.) 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, 1531. In the majority. the 

prevalence of cough and sputum increased with amount smoked. A recent 

study (82) showed that those who smoked cigarettes of low nicotine content 

tended to cough less than those who smoked cigarettes of high nicotine con· 

tent. Other symptoms and measurements of pulmonary function show a less 

clear relationship between prevalence and amount smoked. 

(h.) Relationship betu·een Symptoms and Signs and J1ethod of Smokin{(.-

The numbers of pipe and cigar smokers in many prevalence studies are so 

small that conclusions about the effects of these methods of smoking are not 

reliable, but they all tend to show that pipe and cigar smokers are likPlv to be 

intermediate between non-smokers and cigarette smokers in prevale~ce of 

symptoms and signs. 

(i.} Ventilatory Function.~Pulmonary tests and the method of presenting 

results, though varying widely, are important features of the prevalence 

surveys. 

In the study by Ashford and others ( Tl of 4,014 coal miners. the forced 

expiratory volume in the first second of expiration I F.E.V. 1.0) of nonsmokers was slightly higher than that of the smokers. and a small but sta· 

listically significant 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 smok 

and 7.8 percent of 243 non-smokers had an "abnormal" test, an F.E.V. i~ 

of less than 70 percent. When the "abnormal" test was compared 11 i;h 

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 increa · 

11 

~lti•• 

pack-years. • 

Ferris and Anderson ( 61) showed a progressive decrease in the 111 ,. . 

F.E.V. 1.0 in successive age groups for male smokers, male non-smoke::· 

and female non-smokers. In males, there was also a regular decrea•r · · 

F.E.V. 1.0 within each age group with increase in the number of ciga;t>tt::~ 

currently smoked. In females, there was little difference in the F.E.V. l.O 

between smokers and non-smokers except in one age group. The Pt>a~ 

expiratory flow rate showed a decrease with age and a decrease within th,. 

age groups with cigarette smoking. 

Chivers ( 36) showed that smoking, age, and height were correlated ,j 11 . 

nificantly with the expiratory flow rate. The older and shorter men had 

greater impairment associated with smoking. 

Flick and Paton ( 68) demonstrated a distinct decline, beginning at about 

40 years of age, in expiratory flow rate among smokers, but no apparent 

change among non-smokers until 70 years of age. 

Fletcher and Tinker ( 67), measuring expiratory flow rates by the Peak 

Flow Meter, found one group of smokers, but not another, had lower valurthan the non-smokers. In a later paper (58), Fairbairn, Fletcher and Tinker 

reported that the Peak Flow Meter appeared to be a less satisfactory screrning test than the forced expiratory volume. 

Franklin and Lowell ( 73), in a study of 1,000 apparently healthy facton 

workers, found the mean expiratory flow rate during the third quarter 1;[ 

maximal forced expiration to be approximately 20 percent less in "hea11 

smokers" than in "light smokers." "Heavy smokers" were defined as thos;. 

who had smoked 30 pack-years or more, and "light smokers" less than 10 

pack-years. 

Higgins (88) showed a decrease in F.E.V. 0.75 among smokers of IS 

grams or more of tobacco per day. compared with non-smokers and with 

those who smoked less than 15 grams a day. For this test, there was no 

significant difference between non-smokers and the lighter smoking group. 

Peak flow measurements indicated a difference between heavy and light 

smokers. and also between non-smokers and light smokers. In each 10-year 

age group over 45, the peak flow was lower in smokers than in non-smokers. 

but the numbers were small. These differences are not explained by differences in age, social class, or occupation. The difference between smoker> 

and non-smokers in peak flow measurement was not seen in tests of women. 

Higgins I 90) summarized the difference in F.E.V. 0. 75 in a variety of 

different samples of the population. Tabulations for 16 different group:< 

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 groups 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 Breathin~t 

Capacity ) as 50 liters per minute, which was significant at the one percent 

290 
level. By pooling subjects with different occupations in the older age 

groups, differences between light and heavy smokers were apparent, though 

not statistically significant. Higgins commented on a strong trend in the 

prevalence of persistent cough and sputum, with amount of tobacco smoked, 

without a significant trend in ventilatory capacity. His possible explanation 

of the difference is that smokers are more likely to give up smoking or re· 

duce the amount smoked, once their lung efficiency becomes impaired. than 

they are when their only symptoms are cough and sputum. 

In their study of miners and foundry workers in Staveley 192). Higgins 

and his colleagues showed a decrease in the F.E.V. 0.75 in smokers. Non· 

;;mokers, light smokers, and heavy smokers 115 grams per day and over l 

ranked in that order for decreasing F.E.V. 0.75, both in men aged 25 to 31 

and in those aged 55 to 6-l. The difference between the non-smokers and 

the light smokers was smaller than the difference between the light and the 

heavy smokers in the younger age group; in the older age group the dif. 

ference was larger between non-smokers and light smokers. 

Olsen and Gilson (1481 measured the F.E.V. 0.75 in a sample of a pop· 

ulation 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 differ· 

ences were not statistically significant. If non-smokers, cigar smokers, and 

pipe smokers are grouped together, non-cigarette smokers had a significantly 

higher mean F.E.V. 0.75 than the cigarette smokers. 

Payne and Kjelsberg (153), who presented mean values of F.E.V. l.O 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 age group. cigarette smokers had a slightly higher 

mean value than non-smokers. A comparison of the mean values by age group 

for non-smokers and for cigarette smokers shows a decline with advancing 

rears in both, but more rapid in the cigarette smokers. Women also show a 

decline of F.E.V. l.O with advancing years. but this is no more marked and no 

more rapid in the cigarette smokers than in the non-smokers. The reduction 

in F.E.V. l.O 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 flow 

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. 

~mount smoked had no obvious effect. Results were similar for women. 

Revotskie and his colleagues ( 165), who grouped smokers in Framingham 

as never smoked, light smoker, medium smoker, and heavy smoker. found 

that the F.E.V. l.O 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. hut in less clear-cut fashion than the F.E.V. l.O 

measurements. 
Goldsmith and others (77) showed that smokers, regardless of amo 

smoked. have a slight diminution in the pulmonary function test results eunt . . . , \en m the ab,:ence of resp1ratory symptoms. The total v1tal capacity was mu h 

less sensitive in this regard than the F.E.V. 1.0 or the "Puffmeter" readinr 

Longshoremen with "respiratory conditions," and particularly those wiih 

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 pu]. 

monary function tests is more difficult to evaluate from the published surwv, 

than is the relationship between symptoms and cigarette smoking. Pul. 

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 fune. 

tion between smokers and non-smokers. 

In the majority of prevalence surveys, the subjects were not forbidden to smoke Prior 

to pulmonary function testing. Since acute alterations due to smoking might be mi'-

interpreten as due to a permanent abnormality, it is important to examine the magnitu~e 

and significance of the acute effects of smoking on pulmonary function. 

Bickerman and Barach 120) found no comistent alterations in vital capacity or in 

maximum breathing capacity before and after their patients and normal subjects smokrd 

three cigarettes. Simonsson (177) found a small decrease in the F.E.V. 1.0 in 13 of 

16 young subjects after smoking, and the diffNence for the group was statistically •i~­

nificant. No significant change was found in the total capacity. 

Several author' have studied more sensitive tests of airway resistance and lung compliance. Eich. Gilbert and Auchincloss (56) made compliance ann airway resistance 

measurements, using an esophageal balloon technique, on a group of nine healthy adult,. 

five of whom had respiratory symptoms. No difference was detected after one cigarettr. 

r n a group of emphysematous patients. a statistically significant increase in airflow Tr· 

sistance was found, but without significant change in compliance. 

Attinger and others I 8) reportt'd no statistically significant difference in expiraton 

airflow rt'sistance or compliance, but in a later study of subjects with pulmonary diseas~. 

significant phy,iological changes-increasPn mPchanical resistance and increased work of 

breathing-were noted aftpr smoking onP or two cigarettes. 

Motley and Kuzman { 142) stunied the lung volumes, spirometry, blood gas exchan~e. 

and pulmonary compliance in 141 subjects, before and after smoking two cigarettes. Not 

all of these mea>uremenf>; were manP on all subjPcts. Therp was no significant change in 

the mean valuf's of vital capacity pt'rformed after smoking, some subjects showing a 

decrease. and others an increaee. Six of the normal subjects showPd a decreased complianct' aftpr emoking. In 33 subjects with cardiac or respiratory disease, 17 had a si~­

nificant decrPasP in compliance aftt·r smoking. The authors fdt that a decrease in pulmonary compliance was the only notablP abnormality which followed smoking acutelv. 

Forced Pxpiratory volumr and airflow n•si•tancP studiPs were not included. 

Miller ( 134a), who constructed pressure-volume work loops, demonstrated increased 

airflow rPsistancp and unen·n wntilation, resulting in increast'd work of breathin~. 

This author coneludt·n that inhalation of ci!!arPitP smokt' !!ives rise to a significant 

negree of unPwn n·ntilation. which is n•spomible for the obsened decrease in dynamir 

compliance and increasPd t•lastic work of hreathin~. 

Nadel ann Comroe tl46J showed a mean decrease of 31 pt'rcent in the ratio of airway 

connuctance to thoracic gas volume after inhalation of cigarette smoke, the changes being 

hil!hly significant statistically. ann similar for smokers and non-smokers. Repeated testing aftpr smoking ,.;hnwpd tht' respon>P to last for from 10 to 80 minutes. Without inhalatio-n. no significant chang<' in the conductance to thoracic gas volume ratio occurred. 

Inhalation of Isuprel aerosol before smoking prevented the increase in airway resistance. 

and whf'n given after cigarette smoking 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 differt>nce in airway 

Tt>•i•tance between non-smokers and cigarette smokers is apparent only when the actual 

.-timates of airway resistance are compared with predicted values based on lung volume, 

hecause of a reciprocal relationship between airway reoistance 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 smokin{:! upon pulmonary function 

are expressed mainly through increase in airway reFistance, 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 te><ts usf"d in surveys 

,ufficiently sensitive to detect the acute effects. Th~" differences in re=-ults of pulmonary 

function tests between smokers and non-smokers, therefore, are guater than can be 

arcounted for by acute effects from a recently smoked cigarette. 

PROSPECTIVE STUDTEs.-In six of seven prospective studies, chronic bronrhitis and emphysema contribute markedly to the excess mortalitv amon~ 

rigarette smokers; in the remaining study the mortality ratio was increased 

hut to a lesser extent. In all these studies, mortality ratios for chronic 

bronchitis and emphysema have been calculated !see Tables 19. 23, 26 in 

Chapter 8, Mortality). Cigarette smokers in these studies died of chronic 

bronchitis and emphysema 6.1 times more frequently than non-smokers. 

In the large study of U.S. veterans ( 49) the obsen·ed 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 

16. 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 ll5 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 were 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 

to chronic bronchitis or emphysema, or found in smokers more frequently 

than in non-smokers. And very little is known of the incidence rates of such 

symptoms and signs in the different categories of subjects constituting population samples. This is unfortunate, as prospective studies of morbidity in 

~opulation samples can best measure the possible health hazard of smoking. 

:--everal studies are under way, but some of the important information will 

concern 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-year follow-up study on ventilatory 

ca_Pacity in a population sample in a mining district in Wales. In nonnnners this measurement fell more over the five years in smokers than in 

n~n-smokers, and within the smoking group there was an increasing fall 

With amount of smoking. When the miners and ex-miners were c-onsidered. 

293 
the pattern was less clear. In three of the four groups, the F.E.V o ~- f • ,j ,) 0 

the smokers fell more than that of the non-smokers or ex-smokers; but th 

fall was usually greater in the light than in the heavy smoking group. Th: 

authors pointed out that when the original sample was selected, no follow. 

was intended, and that the sample was not very suitable for this purpose. Up 

~hus; morbidity d~ta are insufficient at pre~ent to be of value in thr 

esttmatwn of the posstble health hazard of smokmg. Prospective studies · 

populations followed over long periods offer the best opportunity for filji 1

:

1

: 

the major gaps in knowledge about the relationships of smoking and chront 

bronchopulmonary diseases. 

CLINICAL EVIDENCE 

Several studies concerned with individual patients rather than defin~d 

populations form the basis for the clinical evidence. 

A current and continuing study of an "emphysema registry" with entn 

based on clinical and physiological evidence, has been reported ( 138!. Of 

131 patients with diffuse pulmonary emphysema, 20 had findings at necrops 1 

of widespread alveolar destruction. Clinical differentiation was made int;, 

three groups: a "bronchitic" group in whom a history of cough was present 

years before onset of dyspnea on exertion, a "dyspneic" group in whom 

cough and dyspnea occurred at about the same time or in whom dyspnea 

occurred first, and an "asthmatic" group who gave a history of episodic 

dyspnea or asthma for years before the onset of uninterrupted dyspnea. 

When the sample of patients was adjusted for age and sex, 95 percent were 

smokers as compared with an expected 80 percent based on smoking habit> 

of Americans. In a later report (137), the number of patients had increased 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 continued smoking. 

Studies of series of patients by others (l, 125) have also noted the frequent association of cigarette smoking with emphysema. A number of 

clinical studies indicate the frequent association of cigarette smoking in 

chronic bronchitis 1106. 117, 1-19!. 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 ( 751 ; 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 he 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 bronchitis 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, establi~h 

or exclude a causal relationship. 

294 
Relationship of Smoking, Environmental Factors, and Chronic 

Respiratory Disease 

ATMOSPHERIC POLLUTION 

BASIS FOR INTERRELATIONSHIP AND REL\TIVE MAGNITUDE 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 mariy 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, chemical. 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 "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 leYels. and fewer death~ than 

the 1952 London smog. 

Innumerable components with potential biologic effects are present in 

tobacco smoke and as atmopheric pollution; some components are common 

to both. At present, information concerning the effects on the respiratory 

system is available for relatively few of these components. In an earlier 

chapter 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 cha11ges 

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 

been 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 ir h_alation of I ppm. produces chronic 

bronchitis and bronchiolitis in rodents, especially rats. but no detectable ef295 
fects are produced in dogs ( 179) . Under conditions of acute exposure, 

somewhat more than 1 ppm. of ozone produced increased airway resistance 

and decreased diffusing capacity in man ( 76). It is not known whether 

chronic low-level exposure to ozone produces lung damage in man. 

The ingredients of motor vehicle exhau~ts most likely to have biologic 

effects are aldehydes, hydrocarbons. oxides of nitrogen. and carbon monox. 

ide. Guinea pigs exposed to ultra-violet irradiated exhaust gases have 

enhanced susceptibility to infection and bronchospasm ( 2, 144). No data 

are available on the long-term inhalation C!f low concentrations of irradiated 

exhaust gases or photochemical smog and its effects on human pulmonary 

tissues. 

At present, it has not been demonstrated that other components common 

in air pollution are associated with pulmonary lesions similar to those found 

in the chronic respiratory diseases of man. 

( 2.) Relative Magnitude of the Exposure.-Estimates of the relative mag. 

nitude of exposure to constituents common to both cigarette smoke and 

atmospheric pollution are made diffcult by the complex nature of the characteristics 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 frequentlv 

repeated in the discontinuous exposure to cigarette smoke; air polluta~t 

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 accuratrly 

calculated at present. htsight may be gained, however, into the relativ~ 

magnitude of exposure to two components, carbon monoxide and the oxides 

of nitrogen, common to cigarette smoke and atmospheric pollution. The 

smoking of 30 cigarettes per day is estimated to provide a 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 carboxyhemoglobin 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 carboxyhemoglobin 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 smoking as compared with atmospheric pollution. 

The average concentration of nitrogen oxides in ambient air is 0.3 ppm. in 

the Fall quarter in downtown Los Angeles. The oxides of nitro!!'en present 

in cigarette smoke vary from U.S to 665 ppm.: moreover. virtually complete 

absorption occurs after inhabtion ( 231. During periods of cigarette smoking, therefore, a substantially !!realer exposure to nitrogen oxides would be 

expected (76). 

Since cigarette smoking i~ likely to occur on every day of the year and 

periodically throu!!'hout 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 l'nited 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. When'a" 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 hulk of the population of the United States. 

EPIDEMIOLOGICAL EVIDENCE.-Most investigations of epidemiolopc design 

have not been directed toward determination of the relative importance, 

or the combined effects, of cii!'arette smoking and atmospheric pollution in 

chronic respiratory disease. Discernible effects of ci~arette 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 he considered here. 

The prevalence of cough and sputum in the United States appears to be 

determined much more by the amount and duration of cigarette smoking 

than by atmospheric pollution. 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 smoking history. the frequency of respiratory 

symptoms and alterations in pulmonary function tests correlated well with 

past cigarette smoking history; in contrast, study of these men during the 

season in which Los Angeles atmospheric pollution was high did not result 

in detectable response attributable to the atmospheric pollution ( 173). 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 

~xcess mortality remains even after removal of possible differences in clas-

;ification and misinterpreted diagnosis ( 63) _ Moreover, differences in to1acco consumption do not appear to be sufficiently large to account for the 

~xcess 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 eviqence of airway obstruction are more frequent in cigarette 

mokers, the frequency of more advanced forms of chronic bronchitis does 

297 
not increase \\·ith increasingly heavy smoking (65). Atmospheric poll . 

tion in the United Kingdom exerts its effects primarily among chronic br u 

chitics ( 117) almost all of whom are cigarette smokers ( 64) · it al•o .nn. , , I> a 

mal or factor in the urban-rural di~erences in prevalence and mortal ill 

( 3 1, 65. ] 54, 160). When those findmgs are considered together with othP 

e.vidence documenting the role of atmospheric pollution in chronic bronch'tr lh 

(28, 76, 161), it seems probable that atmospheric pollution and ci"att'ltf· 

smoking in the United Kingdom are at least additive and possibly sy~eraj,_ 

tic in their deleterious effect on the respiratory tract. '" 

Thus the epidemiological evidence on the relationship of cigarette smuk. 

ing, atmospheric pollution, and chronic respiratory disease clearly indi('at 1-.., 

that the dominant association in the United States is between cigar!'ttt• 

smoking and chronic respiratory disease. In the United Kingdom, disal.lin .. 

respiratory conditions and death are more likely to occur among per>un: 

who smoke cigarettes and are exposed frequently to atmospheric pollutantthan in those exposed to either alone. 

OCCUPATIONAL FACTORS 

Occupational exposures provide other possible etiologic factors in t)w 

production of chronic bronchitis and emphysema. There is little convindn!! 

evidence on specific relationships. Nevertheless, epidemiological studj1., 

(reviewed in 123, 128) provide information on the relative importance of 

cigarette smoking and occupational exposures in selected groups. 

In a study of 4,014 Scottish coal miners ( 7), the prevalence of respiraton 

symptoms among non-smokers was appreciably lower than among smohr~ 

of the same age, and the ventilatory function of non-smokers in all agf 

groups was significantly higher than that of the smokers. Among smokm 

of 50 years of age and above, the prevalence of pneumoconiosis tended to br 

lowest among the men who smoked the most and highest among men whn 

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 eliminah· 

some persons with symptomatic pneumoconiosis from study groups should 

also be considered in the evaluation of these studies. 

In a sample of 1,317 men aged 40 to 65 who worked in a variety of nondusty and dusty environments, a greater prevalence of bronchitis ( daih 

cough for at least the preceding six months, productive of one teaspoon of 

sputum per day) was found in moderate and heavy smokers (27). Betweer1 

the non-smokers and the heavy smokers, a significant difference was found 

at all age levels, and also between non-smokers and moderate smokers excepl 

in the oldest age group. Although effects from dust exposures could bt> 

noted, it appeared that cigarette smoking was the domi11ant 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 cigarette> 

smoked daily ( 36). 

298 
In a study of L274 steel workers, non-smokers had a comparatively low 

incidence of chronic cough, regardless of their job classification or conditions of work or residence. There was a direct relationship between chronic 

cough and the number of cigarettes smoked dailv in each occupational 

cate~ory (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 du~t. and 

estimated inhaled quantity of dust. The effect of smoking "far out-shadow~ 

any effect due to age or occupational exposure to dust" I 621 . 

The studies by Higgins and his colleagues (87. 88. 89. 91. 921 show that 

smoking and occupational exposure are both related to the prevalence of 

chronic respiratory disease hut do not allow quantitative assessment of their 

relative importance in the population~ 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 studie; on the production of respiratory symptoms is rather 

convincing ( 123). 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 pulmonary 

ventilation, as measured by the F.E.V. l.O in individuals without X-ray evidence of silicosis. A decrease of 23 percent occurred with the process of 

aging 20 years. For heavy smokers I those who smoked for 25 years or more 

and now smoke more than 20 cigarettes a day), 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 associated with 

smoking was equivalent to half the effect of heavy smoking, or about five 

years of aging" (128). 

The population at risk from occupational exposure is relatively small compared to the population of cigarette smokers. Among occupational groups, 

cigarette smoking is an important variable that must be considered in all 

299 
studies ~f c~ronic broncho~ulmonary di~ea~. In most studies, but not all, 

the relat1ve Importance of c1garette smokmg 1s greater than occupational ex. 

posures in the production of symptoms and signs of chronic bronchitis or 

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 partie!~~ 

in the respiratory system of man is about 80-90 percent complete with breath 

holding of two-to-five seconds. Particles penetrate deeply into the respira. 

tory tract and are deposited on the surface of the terminal bronchiol~ 

respiratory bronchioles, and pulmonary parenchyma. Little information ;~ 

available concerning the specific toxic properties of the particulate phase 

components. Gas phase components probably have a diffuse though not 

uniform pattern of distribution. It seems likely on the basis of the physical 

characteristics of gas absorption and distribution, that a substantial portion 

is retained along the upper bronchial tract. Certain of the gases known to 

be present in cigarette smoke are capable of producing pulmonary damal!e 

in experimental animals and man. 

Cigarette smoke produces significant functional alterations in the upper 

airways. Like several other agents, cigarette smoke can reduce or abolish 

ciliary motility in experimental animals. Post-mortem examination of 

bronchi from smokers shows a decrease in the number of ciliated cells, 

shortening of the remaining cilia, and changes in goblet cells and mucou, 

glands. The implication of these morphological observations is that func· 

tiona! 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. 

sica! 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 decompensatt·' 

under the stress of protracted high-level exposure to cigarette smoke and In· 

bacco smoke components accumulate in the pulmonary parenchyma of 

experimental animals. 

The acute effects of cigarette smoking result in an increase in airway rr· 

sistance but clinical expression of this change in pulmonary function is not 

common. The chronic effects of cigarette smoking upon pulmonary function are manifested mainly by a reduction in ventilatory function as measured 

by the forced expiratory volume. 

Histopathological alterations occur as a result of tobacco smoke exposure 

in the tracheobronchial tree and in the lung parenchyma of man. Change' 

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 alreolar septa and fibrosis, have a remarkably close association with past history of cigarette smoking. These changes cannot be related with certaintY 

to emphysema or other recol!nized diseases at the present time. 

Chronic bronchitis and pulmonary emphysema are the chronic bronchopulmonary disease~ of greatest health significance. Epidemiological evidence 

provides the most important information relatinl! cigarette ~mokin~ to 

chronic bronchitis and emphvsema. All seven of the major prospective 

'tudies show a higher mortality rate for chronic bronchitis and emphvsema 

among cigarette smokers than among non-smokers. In the few studie>' that 

ha1·e examined mortality rates separatelv for the two conditions. chronic 

hronchitis or emphvsema, both rates are higher among cigarette smokers 

than among non-smokers. In one of the studies. the risk of mortalitY from 

chronic bronchitis was four times greater among cil!arette smokers than 

among non-smokers. Emphysema was listed as a cause of death 13 times 

more frequently among smokers in one study. and 71/:? times more frl"quentlv 

among smokers in another study. 

Extensive prevalence studies. based largely on prevalence of specific 

~rmptoms 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 ~he clinical expressions found in chronic bronchitis. The results of the 

prevalence surveys. however, offer less direct evidence relating cigarette 

'moking to pulmonary emphysema. as clinical rliagnosis of this disease is less 

exact. Breathlessness, which may result from emphysema or airwav obstruction in chronic bronchitis, is associated with cigarette smoking in males. 

particularly in the older age groups. but not females. Similarly. a consistent 

a>sociation of cigarette smoking 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 majority of clinical studies have noted a relationship between cigarette smoking and chronic bronchitis and emphysema. Cigarette smoking is 

a more ,common habit in the United States among patients with chronic 

hronchitis 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, the noxious agents from cigarette smoking 

are much more important in the causation of chronic bronchopulmonary 

di~ease.than are those present as community air pollutants. In the l'nited 

Kmgdom, persons who smoke cigarettes and are exposed frequentlY to atn:ospheric pollutants are at greater risk of developing disabling respiraton 

disease and death than those exposed to either alone. 

301 
The relative importance of cigarette smoking also appears to he much 

greater than occupational exposure as an etiologic factor for the chronit 

bronchopulmonary diseases. 

Cigarette smoking does not appear to cause asthma; in rare instances. 

allergy to tobacco products has been ascribed a causative role in asthma. 

like syndromes. 

Evidence does not support a direct association be~ween smoking and in. 

fectious diseases of the respiratory system. The category, influenza and 

pneumonia, contributes moderately to the excess mortality of cigarettr 

smokers but other data are not available to extend this observation. Th, 

association of cigarette smoking and tuberculosis does not appear to be a 

direct one, but both are associated with the use of alcohol. 

Only for "stomatitis nicotina" and the epithelial changes in the laryn\ 

i~ there sufficient documentation to substantiate the clinical opinion that non. 

maliimant alterations in the mouth, nose, or throat are induced by smokin!!. 

The changes in the mouth are more often associated with pipe smoking but 

disappear after cessation of 1'-moking. 

CONCLUSIONS 

l. Cigarette smoking is the most important of the causes of chronir 

bronchitis in the l"nited States, and increases the risk of dying from chronic 

bronchitis. 

2. A relationship exists between pulmonary emphysema and cigarettr 

smoking but it has not been estsblished that the relationship is causal. Tht 

smoking of cigarettes is associated with an increased risk of dying from 

pulmonary emphysema. 

3. For the bulk of the population of the United States, the importance of 

cigarette smoking as a cause of chronic bronchopulmonary disease is much 

greater than that of atmospheric pollution or occupational exposures. 

-L Cough, ~putum production. or the two combined are consistently morr 

frequent amonf! cigarette smokers than among non-smokers. 

5. Cigarette smoking is associated with a reduction in ventilatory funrtion. Among males, cigarette smokers have a greater prevalence of breathlessness than non-smokers. 

6. Cigarette smoking does not appear to cause asthma. 

7. Although death certification shows that cigarette smokers have a moderately increased risk of death from influenza and pneumonia, an associatio11 

of cif!arette smoking and infectious diseases is not otherwise substantiated. 

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3ll 
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312 
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313 
Chapter 11 

Cardiovascular 

Diseases 
Contents 

INTRODUCTIO.I'I . . . 

Page 

317 

PERTINENT PHARMACOLOGY. 317 

GENERAL OBSERVATIONS ON CORONARY HEART DISEASE . . . . . . . . . . . . . . . . . . . . 320 

SMOKING AND CORONARY HEART DISEASE . . . . . 322 

SMOKING AND NON-CORONARY CARDIOVASCULAR 

DISEASE . . . . . . . . . . . . . . . . . . . 325 

CHARACTERISTICS OF CIGARETTE SMOKERS . . . . 326 

PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION 

TO CARDIOVASCULAR DISEASE 327 

SUMMARY . . 327 

CONCLUSION . 327 

REFERENCES. ~8 

List of Tables 

TABLE 1. Death rates per 100,000 from arteriosclerotic and 

degenerative heart disease by sex and age, United 

States, 1958-{)0 . . . . . . . . . . . . . . . . 321 

TABLE 2. Ratios of mortality rates for coronary heart disease, 

male smokers to non-smokers, by age and amount 

smoked, in selected studies . . . . . . . . . . . 324 

316 
Chapter 11 

INTRODUCTION 

It has been suggested repeatedly that smoking may have 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 the~e dis· 

orders is coronary artery disease, and the present chapter deals mostly ''ith 

this subject. The chapter begins with a summary of information ahnut the 

acute effects of smoking on the cardiovascular system. This is followed bv a 

brief account of coronary disease, its frequf'ncy in different kinds of people. 

and the many factors known or thought to affect the likelihood of its develop· 

ment. The aim here is not to re\ie~\ nitically our knowledge of coronary 

disease but only to give background for what follows. Next is summarized 

the information currently available from ~tudy of large population groups 

on the association of cigarette smoking with an increased tendency to have 

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 l. 7 for coronary 

heart disease among cigarette smokers in the seven prospective studies repre· 

sents from 32.9 percent to 51.7 percent of all excess deaths, whereas the 

much higher lung cancer mortality ratio of 10.8 from the same studies repre· 

sents only 13.5 percent to 24.0 percent of total excess deaths (Chapter 8. 

Tables 19, 25). 

PERTINENT PHARMACOLOGY 

The acute cardiovascular effects of smoking in man and experimental 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. l\icotine 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. When nicotine is given intravenously in in· 

creasing doses to dogs or cats the first effects, at about 1 microgram/kg body 

weight, are increased breathing and sympathetic stimulation, with 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 produces an increased urinary excretion of 

catecholamines (84, 99). 

Smoking 1-2 cigarettes causes in most persons, both smokers and nonsmokers, an increase in resting heart rate of 15-25 beats per minute, a rise 

in blood pressure of 10-20 mmHg systolic and 5-15 mmHg diastolic (76, 78, 

85, 86), and an increase in cardiac output of about 0.5 1/min/sq.m ( 75). 

There is a decrease in digital b[ood flow and a consequent drop in finger and 

toe temperature ( 31, 78, 103). The decrease 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 (2). With continued "steady state" smoking the coronary 

flow and cardiac oxygen utilization are maintained at the resting level in 

both normal subjects and per~ons 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, i>' 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 myocardial ischemia. Rarely in per5ons with true 

angina. an attack of pain is precipitated by smoking. An ill-defined syn· 

drome consisting of chest pain. palpitation, and shortness of breath. known 

as "tobacco angina". has been described as occurring in smoker5 who do 

not have organic heart disease. but it is rarely diagnosed today I 73, 82). 

Extrasvstoles and other cardiac arrhythmias have been reported to be caused 

by smoking. but such cases appear to be unusual. 

The ballistocardiogram obtained from a high-frequency table is sometimes {"hanged by smoking a cigarette from a normal pattern to one said to 

be typical of coronary disease 178, 911. This phenomenon is rare in healthy 

persons below ;)0, becomes increasingly common with advancing vears 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 ballistocardiographic changes on smoking have been 

variously interpreted as resulting from impaired myocardial contractility 

I 78'1, 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 

fatty acids in man (50), apparently mediated hy 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 by 

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 ( 5, 68). A decrease in platelet survival in vivo has been found 

after smoking ( 68). Cigarette smokers have been reported to show substan· 

tial decreases in hematocrit, hemoglobin, and platelet counts after abstinence 

of l-2 weeks (25), but hemoglobin concentrations are alike in smokers and 

non-smokers of the same population group ( 4). 

Attempts have been made to induce atherosclerosis in rats by the chronic 

administration of nicotine for periods up to a year without success (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 

107{ 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 

714-422 0-64-22 319 
diseases which have been related to smoking, however, do not in l!eneral 

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 I. 

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 understanding, seem likely to account for the observed 

association of cigarette smokinl! with an increased incidence of coronary 

disease. 

CENERAL OBSERVATIONS 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). In 

1961 there were 1,70L522 deaths from all causes in the United States. Heart 

disease deaths numbered 663.391 of which 502.351 were due to arterio· 

sclerotic heart disease. 

The disorder consists of obstruction or narrowing of the coronary arteries. 

reducing the blood supply to the heart muscle. The underlying cause of the 

obstruction is coronary athern;;clerosis. hut an acute coronary artery occlu· 

sion is often caused by the formation of a blood clot in a diseased artery. 

The common manifestations of coronary disease are angina 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 by inability of the heart to pump enough blood to satisfy the 

demands of the 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 ( 4f>, (>2 I. The reported death rate of 

arteriosclerotic heart disease, 1\·hich is primarily coronary disease. is higher 

in the United States than in other countries. It is also quite high in :\ew 

Zealand, Australia: South Africa, Canada, and Finland. and moderateh hii!b 

in Great Britain. The death rate in Norway, Sweden, and Denmark is roughh 

half that in the high death rate countries I l.') 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 general population of this country ( .')2). 

Because of changing diagnostic skills and revisions in nomenclature of 

disease, it is difficult to be certain of the change in incidence of coronaq 

disease in the United States 0\er the past few decades, but there is a general 

opinion that the incidence is increasing 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'/c over the rate 

in 1940, it has been estimated that less than lS~c of the increase represented 

a real change in incidence of the disease, the remainder depending upon 

changes in diagnosis, in nomenclature and in the age of the population (59). 

Since 1955 the death rate from coronary disease ( ISC 420) and from 

arteriosclerotic and degenerative heart disease (ISG 420 and 422) has continued to increase gradually. In 1960 the age-adjusted death rate from 420 

and 422 was 330 per 100,000 for white males and 1:i0 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 1105). 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 

personality 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 from arteriosclerotic and degenerative 

heart disease* by sf'x and age, United States, 1958--60 

A!!" Croup '\1aJ,., 

Under 35______________________________ 3.3 

35-44 --------------------------------- 90.2 

45-54 --------------------------------- 353.7 

55-64 --------------------------------- 928.5 

65-74 --------------------------------- 2129.2 

75 or over_ _____________________________ 4765.1 

*Includes ISC numbers 420 and 422. 

F~maJ,., 

1.2 

18.3 

79.3 

314.5 

1082.0 

3738.4 

Both s,,x,., 

2.2 

53.3 

213.5 

610.2 

1569.5 

4179.7 

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 ( 7). Others (58, 72, 90) 

have not found that executives are more prone to coronary disea~e than nonexecutive personnel. Physicians have been said to have 3 or 4 times as much 

coronary disease as farmers or laborers 137), and general practitioners to 
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 

prone 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 tl1e 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 bet:ween 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 documentatjon for these statements is given in 

the following paragraphs. Particularly important is the information in 

Chapter 8, Mortality. 

English et aL ( 26) found the incidence of coronary disease in male 

patients at the Mayo Clinic about 3 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 ( 81) 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 year 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 Wynder and Lemon (104) in a study based on 

hospital admissions to haYe ~ignificantly less coronary disease and to develop it later in life than the general male hospital population. Haag 

and Hanmer 1 ~~) reported that employees in the tobacco industry. \1 ho 

tend to smoke heavily. had a lower death rate for cardiovascular disease 

than the gPrwral population in 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 1161. 

Large-scalP prospective studies of mortality in British physi,:ians I Doll 

and Hill, 211. United States males 50-69 recruited by volunteer workers 

322 
I Hammond and Horn, 38, 39, 40. 42) and V.A. Life Insurance policyholders 

i Dorn, 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 I not entireh cigarettes) 

and the mortality from coronary disease. The as~ociation occurred in the 

:~5-5·1 Year age range, but not in older men. Hammond and Horn found 

a similar graded relationship between coronary death" and cigarette smoking. the death rate being more than twice as great in men who smoked 

over a pack a day as in non-smokers. 1Vlen who had stopped smoking for 

more than a year at the start of the study had a coronary death rate lower 

than those who continued. 

Studies on special groups of men, such as longshoremen ( Buechley et al. 

Ill members of a fratunal order I Spain and ~ athan. 89) and industrial 

employees (Paul et a!. 11) which. in the latter two instances. incorporated 

clinical coronary disease. as well as coronary deaths, a I so have ~hown a 

relationship between coronary disease and smoking. The relationship was 

closer for men under 51 than for older men, and closer for myocardial 

infarcts and death than for angina pectoris (70, 89). 

The long-term prospecti\·e studies of cardiovascular disease in Framing· 

ham ( 19) and in Albany I 24 I which have featured a paim:taking search at 

regular intervals for clinical manife~tations of disease. ha\'e. on JlOOlini!' the 

data (Doyle et a!. 23) shown a threefold increase in the incidence 

of mvocardial infarction and coronarv deaths in men who are he a\\. cigarette. smokers as compared to non-s~okers. pipe and cigar smoke;s. and 

former cigarette smokers. In the pooled data the incidence of angina pectoris did not show a significant association with cigarette smoking. The 

lack of this particular relationship had been ~uggested on the basis of 

clinical experience (White and Sharber. 1021. 

An apparent interplay of fa,ctors relating to smoking and or·cupation 

turned up in a short-term study of the development of coronary heart di~­

ease in a general 1\orth Dakota population (Zukel et al., 107). Farmers 

had about half the incidence of myocardial infarction experienced by others. 

Tn farmer~. 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 heavih than males in other occupational groups. 

In Chapter R Mortality, there is summarized the most recent information available from 7 large completed or current pro~pectiH· ~moking 

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 ~mokers to non-smokers is 1.7 (range 1.5-2.0). 

Table 2 presents data from some of the large prospective studies on the 

ratio of mortality rates due to coronary heart disease of male smoker,; to 

non-smokers, by age and amount smoked. The ratios tend in general to 

increa~e with amount smoked and to decrease with arh·ancing age. 

The data from the first 22 months of Hammond's 141 I current study 

help to ~how the ~ize of the coronary problem. For thi~ purpose. actual 

numbers of df'aths may he more informative than mortalitv ratios. Of nearh· 
TABLE 2.-Ratios of mortalit:f rates for coronary heart disease, male smokers 

to non-smokers, by ag'' and amount smoked, in selected studies 

HAl\L\1:0!\"D AND HORN-19.58 (42) 

~------ -- -------------------

Ci?arettrs smoked per day 

BFECHLEY, DRAKE, BRESLOW-1958 (8)• 

--------·-----------

35-44 ----------------------------------- --- ------· --------- 2.0 

2.8 

1.8 

0.9 

45--54 

55--64 

6.5-74 

FRAMINGHAM STUDY-1963 (47) 

----~---------------.---------------c------

---1 30-1>2 

(less than 20) 1.5 (20 anrt over) 3.2 

----~---. ------------ --'------------'---- ----

DORN-1959 (22) 

-----------------.---------.-------.--------

----- ---1 Total (age adjusted) __ I. 32 I. 76 1.75 

~-----'------~-------

DOLL AND HILI~1956 (21) 

Grams or tobacco smoked per day 

Age Oroup 

' I I ~ 1-14 Grams 1 15--24 Grams 25 or more Grams 

3-.. 5--54-_- ·--· -------------------------------i~~~--~--3.-3---~----4-.2--· 55-64 __________________ _ __ , 0.9 I 0.6 • 1.0 

65-74. ------------ ---1' 1.0 0.9 1.:! 7.1+ ----------------- --- 1.3 1.5 1.6 Total (agL' arlju<t<'•li _ _ .

1 

I. I ' I. 1 1.4 

*P,·r~onssmokin~ 1 pack pt>r day or mort' f'omp;ur(l with those smoking lPss than 1 pack prr day (indu1linc 

non-:;;mokPrs). 

10.000 deaths of men a!!ed 45-/<J. 4() percent were ascribed to coronar) 

rlisease. .'il.l percent of the 2.()30 "exce~s deaths" associated with cigarettt> 

smoking were caused by coronary disease. In approximate terms, nearly 

half of middle-aged and elderly males in the United States die of coronary 

disease. About half of the,.e males smoke ci!!arettes. Cigarette smokPrs 

haw heen found in se\eral studie~ to have 1.7 times as high a coronan death 

rate as non-smokers. If cigarettes actually caused the additional coronan 

deaths of smokers, they would account for many deaths of middle-aged and 

elderly males in this country. Like other studies (19. 21, 22. 23. 4.21 this 

one shows that the ratio of !'mokers' coronary death rates to those of nonsmoker,; inneascs progre,si1ely 11 ith the daily cigarette consumption. In 

addition. at each le1 PI of con~umption the ratio increases with the amount of 

inhalation reported hy the smokers. Others (21, 23. 26, 89) han· indicaterl 

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. The mortality ratio was 3.09 in the a~e range 

40-49, and in successive decades "as 2.20. l.SS. and 1.38. 

Men who stop smoking haYe a lower death rate from coronary disease 

than those who continue ( 23, 42, 47). In the study of Hammond and Horn 

( 42) the decrease in death appeared onlv 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 over-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 

male,;, especially in middle life, in population groups whose members appear 

so far to he ,-imilar except for smokin~Z 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 whether it is closely 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 smoking than is myocardial 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 de\ elopment 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 incrt>a"ed prevalence of hypertension 13, 4, 19, 47, 49). 

The study of Hammond and Horn 140, 42) did not sh01' an increased death 

rate from hypertension in smokers. However, Dorn 122 1 found that the 

death rate of cigarette smokers from hy pcrtension \\ ith heart disease was 

1.53 times that of non-smokers, and from hvpertension without heart disease. 1.41 times that of non-smoker". Hammond's current stlllh sho\\ s 

similar figures I 411. ::;moking ha:- not been found to be associated with 

an increased mortality ratt> from chronic rheumatic heart disea~e I 22, 41. 

42). 

Hammond and Horn I l2) found a moderate innca~e in the mortalit} 

rate from cerebral \ ascular disease in ci~Zarette smokers as compared to 

non-smoker,; I ratio 1.:30 1. Dorn 1 22 1 reportl'd a ratio of 1.33. and Hammond ( 411 a ratio of 1.+:1. Althoul-!h non-s\ philitic aortic aneurysm is a 

relati\el) infrequent cause of death. the mortalit\ ratio for smoker~ to nonsmokers in thi" diap:nosl ic C"ategon is larp:e in relation to the ratios in ntl1Pr 

cardima,.;cular disordt>rs. In the stuch of Hammond and Horn l·l21 it 

was 2.72. and in Ham1noml'~ current "tudv 1411 it is 3.1 0. 
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 ( 4S) . 

Buerger's disease, or thromboangiitis 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 resumpf.on of smoking. The existence of Buerger's 

disease as an entity separate from arteriosclerosis obliterans has been recently challenged 1 I Ol), but wEll defended ( 61). 

It is apparent that much mere 1\·ork "ill have to be done to determine 

what relationship may exist bet1\·een non-coronary occlusive vascular disease, aneurysmal disease, and smoking. 

CHARACTERISTICS OF CIGARETTE SMOKERS 

If it could be shown that ciE;arette smokers and non-smokers had significant constitutional differences apart from any differences that might be caused 

by smoking itself, then a possibility would 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-smoken by a number of investigators (6, 18, 49, 63, 

95), but others have found no relationship (l, 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, 49). 

A few personality differences have been reported between cigarette smokers 

and non-smokers. Friedman's type A men f the coronary tvpe) tended to be 

heavy smokers ( 33) . Smoken are said to be more easily angered and to eat 

more when under stress 194). They have been reported to marry oftener. 

to change jobs more frequentlY. to be more often hospitalized, and to participate more actively in sport~; than non-smokers ( 60) . 

Thomas 1 94. 951 ha" rep01 ted that the parents of medical students who 

smoke have a significantly higher incidence of arteriosclerotic and hypertensive cardiovascular disease than parents of non-smokers. ClearlY. this 

finding is open to more than c·ne interpretation. 

Smokers tend to have a higher heart ratf' than non-smokers ! 3. 94 I. 

The matter of constitutional predisposition to smoking has been investigated in twins. It has been found I 27. 28. 321 that the smoking habits of 

monozygotic twins are si).mifirantly more alike than those of dingotic twins. 

even when members of a twin pair are brought up separately. 

326 
In spite of some bits of suggestive evidence the existence of basic 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 ( 441 . 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 

~imilar 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 ciga· 

rette smoking and coronary disease has causative meaning than to suspend 

judgment until no uncertainty remains. 

CONCLUSION 

:Vlale 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 
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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. A mer 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 lipids 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 2.34: .35--43, 1957. 

65. Morris, J. N. Recent history of coronary disease. Lancet 1: l-7, 

1951. 

66. Morris, J. N., Heady. J. A., Raffie, P. A. B. Physique of London bus· 

men. Epidemiology of uniforms. Lancet 2: 569-570, 1956. 

67. Morris, J. N., Heady, ]. A., Raffie, 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. ]., 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, 0., 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. Pel!, 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. }., Frank, M. }., 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 0-64-23 
Contents 

RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE 

Conclusion . . . . . 

References . . . . . 

TOBACCO AMBLYOPIA 

Conclusion . . . . . 

References . . . . . 

SMOKI~G AND CIRRHOSIS OF THE LIVER 

Conclusion . . . . . . . . . . . . . . . . 

References . . . . . . . . . . . . . . . . 

MATERl\-AL S"\10KING AND INFA~T BIRTH WEIGHT 

Conclusions 

References . . . . . 

SMOKI:"l"G A:"l"D ACCIDE~TS 

Conclusion 

References . . . . . 

List of Tables 

TABLE 1. Summary of methods used in retrospective and cross337 

340 

340 

341 

342 

34,2 

342 

342 

343 

343 

343 

344 

344 

345 

345 

sectional ,.;tudies of peptic ulcer and smoking . . . 338 

TABLE 2. Summary of results of retrospective and cross-sectional 

studies of pepvc ulcer and smoking . . . . . . . 339 

TABLE 3. Expected and ohilerved deaths and mortality ratios for 

ulcer of stom1ch and duodenum among current 

cigarette smok·~n;, from seven prospective studies . 339 

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 eross-f'ectional study, the frequency of peptic 

ulcer has been determined in a population of individuals with varying smoking 

habits ( ll) . 

Tables 1 and 2 summarize the methods used and the results of these studies. 

These studies demonstrate an association between cigarette smoking and 

peptic ulcer which appears to be greater for ga~tric 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 hean- smokers 

in the study of Doll ( 7) and no consistent relationship with amount smoked 

was observed by Trowell ( 18) . 

In the cross-sectional study of Edwards, et a!. 1111, 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 stu die:; (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 ( 46/0, 5.1 and 4.3). For 

duodenal ulcers the mortality ratios are more modest ( 2.2, 2.3 and 1.1). 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 over-all average mortality 

ratio is about the same as for the three large studie5. Consequently. it appears likely that the excess mortality of cigarette smokers from peptic 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 but in view 

of the small number of deaths this elevation is not statistically significant. 

Doll, et al., ( 7) conducted a clinical trial of the effect of stopping smoking 

on the healing of gastric ulcers. The results were assessed hy measuring 

radiologically the reduction in the size of the ulcer niche. Patients advised 

to stop smoking had an average 78r;r redpction in the size of the ulcer, compared to 57'7< for those who continued to smoke. In \iew of the probable 

existence of other factors which may have concomitantlY been introduced 

in the approach to thP smoker;;. and the compln naturP of the ht>aling process, it is difficult to interpret this observation. 

337 
TARLE L.-Summary of method8 used in retrospective and cross-sectional studies of peptic ulcer and smoking 

! 

~,fl-Gast~r~~~- -~ ~.:tit•I:t~ adi~it~r~l-~<~,:.: --.~;~~-~PlPetP~~:~om fro~~t~~ ~--;~r~crro:r;tles::t~avte ---P~e•tveircwBen~tf DuodPrt'll 1191:~ an<l 1926. Only cases g('fleral admissions-Inalt•s, ' · with compktp smoking his- agpd 20-flO. Brigham Hospital. 

tory sPlected. 2. Ulcer diagnosis probably 

________________ --1 wpll established. 

Country 

Banwtt, (21 l\1:2/ l'.>-l.A. 

Cast'S I Controls I 

~"-:l --~~~o~~f~~<'ction --

Collection of data 

:-.To. 

:\I 

- ---,--·--- --

I 

!\Jot stated 400 SPlPcted at random from wards 1. Intcrvif'Wf'd hy invrstigator. 

of a general hospital. 2. Ulcer diagnosis confirmed 

by X-ray and/or surgery. ------! 

Trowpll, (lXI 1\1:!4 I England !\1 I 50 Duodt>nal 

i 

Mills, (141 19.'>0 U.S.A. M fifi Not stated 275 Sample of population in No d!'lails giwn. 

Columbus, Ohio. --------------------------------------1---1--- Allibonc and Flint, (II 1958 ~:ngland M&F 107 Consecutive admissions to hos- pital of patients with gastric and duodenal hemorrhage or perforation. 

107 Matchpd by age, sex, and Patients and controls inter- time ofa<lmission from acute viPWl'<i hy same observer. 

Doll, Jones, and Pygott (7), 

1U58 

England M&F :!27 Gastric; 338 

Duodenal. Ulcer patients in Doll and I, 143 Ifill Lung Cancer Study 

plus ·a<lditional patients in Central Middlesex Hospi- tal. 

general surgic·al cmergNlcy admissions. 

Patients with non-ulet>r dis- easrs. Each case matclwd with 2 control patients of same sex, 5-year agl' group, 

and same type of place of residenc-e. Male patients n1atchNl by social class. -----------------1----------1--1---

E<Iwards, McKeown, and gnglan<l M 1,737 mpn aged fJ() and over on 11 General Practioners' lists were examined and inter- Whitfil'ld (11), 19fi!J viewed by these practitioners. Represents about 84% of all such mpn on thcsl' lists. (9% non-response due to death and/or untraced.) 

- ----------'------'------'------------------

t. Samr interviewers and questionnaire in ca.~es and eon trois. 

2. Ulct>r diagnosis probably well <'Sta blished. 

or 143 consi<lered to have a peptic ulcer, 53 were con- finned by X-ray. 
TABLE 2.-Summary of results of retrospective and cross-sectional studies of 

peptic ulcer and smoking 

Investigator 

Barnett (2) 

Trowell (18) 

Mills(H) 

Allibone and Flint (I) 

Doll et al. (7) 

Edwards et al. (11) 

Amounts Used Percent Non-smokers 1

1 

Percent Hea.-y Smokers or l\\erage 

~ontrols ~=- Cases ----1- Contr_ols__ 

25 I 

Cases 

Total 18 

Gastric !.1 

Duodenal 20 

Duodenal 8 17 Cigarettes: 12.0 prr day Ill. I pi'f day. 

Pipe: 1.6 oz. per WC'('k , 2.1.'} oz. per 

week. 

18 35 

3~ 54 

Gastric Gastri£ M 1.3 4. 7 M 10.6 11. 3 

F 51.1 66.8 F l.l l.l 

Duodenal Duodenal 

M 2.1 b. 8 M 10. 2 12. 7 

F 53.7. 6z.o 1 F 1.9 1.9 

Percent of Peptic Ulcer by Smokin• Category 

N.;over smoked ____ ------------------------ ________ _ Formerly smoked _________________________________________ --_ 

Cigarettes: 1-9 per day ----------------- ----------- 10-19 per day _ -------------- 20 plus per day_ ------------- Pipe __________________________________________________ _ 

Pipe and cigarpttes _____ ------------------------------------

6. 0 

6. 7 

9. 4 

9. 8 

12.0 

6. 5 8. 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 

Hammond and Horn (13) .. _ 

Dorn (8)**- ----------------------------

Hammond (12) 

Doll and Hill (6) ______________________ _ 

Type of t:Jeer 

Number of Deaths I 

Observed Expected 

Mortality Ratio 

---------1-----------------

Gastric. ___________________ 

1 

Duodenal. _______________ _ 

----1------

Both types __________________ _ 

Gastric __________________ _ 

DuodenaL------------------1----

Both types. _________ _ 

4!\ 0 54 

25 I 2. 2 

100 42.1 4. () 

31 I 6. I 5.1 

36 15. 4 ' 2.:l 

!l7 21. "l----3._1 42 9. 7 4. 3 

32 28.9 1.1 

74 38.6 1.9 

Gastric ___________________ -[ 

DuodenaL----------------~ 

Both ty!><'s. ______________ _ 

-----1----1----

Both types ____________________ 14_

1 

___ o_ ~_:_:_:_:_ 

Dunn eta!., Occupational (9) __________ Both types ----------- 121 23.1 0.5 

~::::;\·5~~~~~-~~~)--~-~~~~~~~~:·: ~~-:-:-::-::-:~-:-·:-_ -_-_-::---··-:---_:-:-:: 1----:4-2 I ~ : 1-- :·: ---------------------------------

*Includes ISC numhrrs 540, MI. **The Hammond and Horn data arr from tlwir original published rpport; the other n•sult:-: listrd include more recent data as tabulated for the Committe-e (see Ch:t!Jtl'r 8). 

339 
1\ umerous investigators have studied the clinical and physiological effects 

of smoking on ~astric motility and acid secretion in humans with and without peptic ulcer. Great variation of gastric motility and i'ecretion was 

observed in response to cigarette smoking. 

Some workers found inhibition of ~astric motility ( 15, 17). Batterman 

I 3 i showed three types of re.;ponse in normal subjects and ulcer patients 

after smokin!! one ci!!arette. In one-third no effect was observed. another 

third complete inhibition of motor activity for a time, and in the rest a 

period of hvpermotility was followed by normal or subnormal activity. 

Smokin!! appears to produce variable effects also on gastric secretion. In 

a few studies. gastric secretion increased, while in others no change was 

observed or there was depress; on of secretory activity ( 4, 15, 16, 17). Additional studie~ 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 

I. 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 gc.stro-intestinal tract. In: Wynder, E. L. ed. 

The Biologic Effects of Tobacco. Boston, 1955. Chapter 5, p. 133-50. 

-t Batterman. R. C .. Ehrenfeld. I. The influence of smoking upon the 

managt·mcnt of the peptic ulcer patient. Gastroenterology 12: 575-SS. 

1 <JII). 

5. Best. E. W. R .. Josie, G. H., Walker. C. B. A Canadian study of mor· 

tality in relation to smc•king habits, a preliminary report. Canad J 

Puh Health S2: C)fJ-106, 11)61. 

(J. Doll. lt. Hill. A. B. Lung cancer and other causes of death in relation 

to ~nwkinf!: A ~econd report on the mortality of British doctors. 

Brit \1ed J 2: ]0-;-1-::ll, 1956. 

1. Doll. R .. Jones. F. A .. Pyt:olt, F. Effect of smoking on the production 

ami maintenance of gastril' and duodenal ulcers. Lancet l: 657-62. 

l%B. 

8. Dorn. H. F. Tobac,co consumption and mortality from cancer and other 

dist>ase,... Public Health Rep 7c~: 5t\l-93, 1959. 

340 
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'~ Advisory 

Committee on Smoking and Health. 

J .3. Hammond, E. C., Horn, D. Smoking and death rates-Report on 

forty-four months of follow-up of 187,78.3 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. L \ '\1A 112: 898-9m, 1939. 

] 7. 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: 399-409, 1954. 

18. Trowell, 0. A. The relation of tobacco smoking to the incidence of 

chronic duodenal ulcer. Lancet l: 308-9, 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 pip<> and cigar 

smoking and very rarely with cigarette smokin!!· 

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 sen~itive to tobacco 

(l, 5). 

Objective attempts at experimentation have been extremely rare and most 

of the literature is related to uncontrolled clinical impressions ( 21. 

:l41 
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 

l. Heaton, J. M., McCormick, A. J. A., Freeman, A. G. Tobacco Amblyopia: 

A clinical manifestation of vitamin B-12 deficiency. Lancet 2: 286-

90, 1958. 

2. Potts, A. M. Special report to the Surgeon General's Advisory Commit· 

tee on Smoking and Health. 

3. Schwartz, J. T. Special report to the Surgeon General's Advisory Com· 

mittee on Smoking and Health. 

4. Traquair, H. M. Toxic Amblyopia, including retro-bulbar neuritis. 

Trans Ophthal Soc UK SO: 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 cirrho,is 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 li"er 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 heavy 

consumption of alcohol and nutritional deficiencies are associated with in· 

creased mortality from cirrhosis of the liver. The increased death rate from 

cirrhosis among ~mokers may reflect the consumption of alcohol and associated nutritional deficiencies rather than the effect of cigarette smokin:r. 

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 

l. 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, 1960. 

4. Heath, C. W. Difference;< between smokers and non-smokt>rs. A\1A 

Arch Int Med 101: 377, 1958. 

5. Larson, P. S., Haag, H. B., Silvette, H. Tobacco-experimrntal and 

clinical studies. A comprehensive account of the ''orld literature. 

Balliere, Tindall & Cox, London, 1961. p. 319-321. 

6. Matarazzo, J. D., Saslow, G. Psychological and related charactf'ristic~ 

of smokers and non-smokers. Psycho! Bull 57: 493, 1960. 

7. McArthur, C., Waldron, E., Dickinson, J. The psychology of smoking. 

J Abnorm Soc Psycho! 56: 267-275, 1958. 

MATERNAL SMOKING AND INFA:\T BIRTH WEIGHT 

Five retrospective and two prospective studies have shown an association 

between maternal smoking during pregnancy and birth weight 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 greater neonatal death rate of 

the children of smokers ( 2, 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 'I. 

It is not known whether the lower birth weight of the infants of smokers 

has any clinical significance. In one of the groups studied I 51 there was 

less need for surgical induction of labor among mothers who smoked. 

CoNcLUSIONS 

l. Women who smoke cigarettes during pregnancy tend to haye babies 

of lower birth weight. 

2. Information is lackin~ on the mechanism by which this decrease in 

birth weight is produced. 

3. It is not known whether this decrease in birth weight has anv influence on the biological fitness of the newborn. 

343 
HEFERENCES 

l. EssPnherg, ]. 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 Obste~ Gynec 

81: 988-96, 1961. 

3. Haddon, W. Jr., i\"esbitt, R. E. Smoking and pregnancy: carbon monoxide in hlood during gestation and at term. Obstet Gynec 13: 262-7, 

1961. 

4. Herriot, A., Billewicz, W. F., Hyttt:>n, F. E. Cigarette smoking in pregnancy. Lancet l : 771-3, 1962. 

5. Lowe. C. R. Effect of mother's smoking habits on birth weights of their 

childrt>n. Brit Med J 2: 673-6, 1959. 

6. O'Lane, J. M. Some fetal effects of maternal cigarette smoking. Obstet 

Gmec 22: 181-4, 1963. 

7. Savel, 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 Laeg 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. 

SMOKING AND ACCIDEl\TS 

Smoking has lwm a~~ociated with a variety of accidents. Among these. 

firt>s ha\ e the mo~t obvious and important consequences. 

In a special stuch of bomP accident fatalities in 1952 through 1953, the 

Public Ht>alth SPnict:> and tlw 'iational SafetY Council reported that 231 

I HV ( l of 1.27-l deaths from fires of known origin were due to cigarettes. 

cigars or pipes 11 \. 

ThP 1\letropolitan LifP I n.'-unmce Company reported that of 3.52 rleaths in 

195(> and l !):) 7 muong tht>ir policYholder~ from fues and burns with known 

causes in and about the bome. :i/ 116r i-) were due to smoking ( 2). 

Of pll\siolo)!ical responses rdated to dri,in)!. smokin)! degrades detectably 

only the rliffen·ntial hrightne:;s threshold and this efft>ct increases \\ith 

amount of ~lllllking 1-l1. Th<' epidemiological data a\ ailahle on the effect~ 

of smoking on traffic acr·ident~ are inconcluo;i\·e. 

It has been sho11 n that a len· I of carboxyhemoglobin of.') percent- -a le\ el 

which is not UJH"ommon among hea\y cigarette smokers 13. 6) --depresses 

Yisual perception to a" great an extent as anoxia at 3.000 to 10,000 feet 

altitude I. 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 40: 

6-8, November-December, 1959. 

3. Larson, P. S., Haag, H. B .. Silvette, H. Tobacco: Experimental and 

Clinical studies. Baltimore, Williams and Wilkins. 1 9(!1. Carboxyhemoglobin, 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 Bull 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 OF TOBACCO 

Summary. 

References . . . . . . . . . . . . . 

348 

Page 

349 

349 

350 

351 

352 

354 

354 

355 

356 

356 
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, analogy 

to other habits involving pharmacological agents and, to a much lesser extent, 

on established scientific fact. The latter may be summarized briefly as 

follows: 

l. 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 I 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 

{ollowed by depression which is noted in isolated tissue and organ system&----

has been invoked to explain the widely differing subjective responses of 

smokers, many of whom describe the effects as stimulating ("smoking relieves 

the depression of the spirits"), while others obtain a soothing and 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 an" 

tense and excited." In order to ascribe such biphasic effects solely to the 

direct action of nicotine it would be necessary to discount psychological re· 

sponses and alterations in mood from all other types of stimuli associated 

with smoking or the use of tobacco, an obvious impossibility. Although 

Knapp and Domino (15) ha\'e 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 (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. Furthermore, 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 the\' 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 addiction, 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 

world as the basis for control of potentially dangerous drugs. 

350 
Drug Addiction 

Drug addiction is a state of periodic 

or chronic intoxication produced by 

the repeated consumption of a drug 

(natural or synthetic). Its charac· 

teristics include: 

l) 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 depend· 

ence on the effects of the drug; 

4) Detrimental effect on the individual and on society. 

Drug Habituation 

Drug habituation (habit) is a con· 

clition resulting from the repeated 

consumption of a drug. Its charac· 

teristics include: 

l) 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; 

3) Some degree of psvchic dependence on the effect of the drug, 

hut 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 cra\·ing 

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, 

714-422 0-64-24 351 
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 AnmcTING DRuGs 

Undoubtedly, the smoking habit becomes compulsive in some heavv 

smokers but the drive to compulsion appears to be solely psychogenic sin!';. 

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 !!rades. from the habit pattern of the cigarette smoker who 

subconsciously reaches into his pocket for a cigarette and may even li!!ht hi;; 

lighter before he realizes that he is already holding a lighted ci!!arette in hi;; 

lips, to the heroin addict who becomes involved in crime, sometime~ in 

murder, in his search for drugs to satisfy his addiction. Clearly there is 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 characteristi(' 

and reproducible abstinence syndrome upon withdrawal of a drug or chemical 

which occurs spontaneously, inevitably, and is not under control of the subject. 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 smokin!!, 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 persons 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 arP 

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 

deprivation. 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, theobromine, and metrazol; and for those who are excited, sedatives, barbiturates. 

and the like. Hansel ill) 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 with the usual patterns of diurnal and nocturnal behavior. 

352 
In contrast to addicting drug-s, 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 ( 30) . A !though 

some tolerance is also acquired with repeated use. this is not sufficient to 

permit the nervous system to be exposed to ever-increasing- nicotine concen· 

trations as is the case with addicting- drugs. This in itself mav militate against 

the development of the adaptive changes in nerve cells which create physical 

dependence. 

It is a well-known fact among smokers and other users of tobacco that 

certain toxic effects such as nausea and vomiting. which accompanv the 

initial use of tobacco, disappear with repeated use. This tolerance is only 

relative and excessive use may at any time initiate these signs and symptoms 

even in the heavy smoker or other user ( 6). 

Acquired tolerance may take two forms: 

(a) A low grade tissue tolerance in mucous and pulmonary membranes 

to the irritants in tobacco or tobacco smoke ( 8). This probably involves 

adaptive changes in cell membranes, similar to those which occur with other 

local irritants, and a reduction in sensory nervous input permitting more 

prolonged exposure to those irritants without unpleasant subjective 

manifestations. 

(b) Specific organ tolerance 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 which 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 Cmm OF ToBAcco HABIT 

Measurps directPrl at thP curP of the tobacco habit have been designed 

principalh to morlih- or abolish the psychogenic. sensory. or pharmacologic 

drives 116. pp .. 540-5461. 

In the psvchotlu·rapPutic area these include psychoanalytic technics, 

hypnotism. antismoking campaigns hasPd upon fear of health consequences, 

religion. group psvchotherapy (similar to Alcoholics Anonymous), and 

tranquilizing or stimulant drul"s. 

Modification of tohacco taste hy astringent mouthwashes (silver nitrate 

and copper sulfatf' 1. hitters (quinine. quassia 1. local anesthetics (benzocaine 

lozenges I. "ubstitution of other tastes 1 essential oils and flavors), and production of a dry mouth I atropine or stramonium) are all measures which 

have been aimed at diminishing the sensory drives. 

Administration of oral lobeline. a substance from Indian tobacco, with 

weak nicotine-like actions as a nicotine substitute has had rather extensive 

trial 1 S. 21, 361, and commercial preparations are available. Carefully 

controlled studie~ have failed to establish the value of lobeline ( l, 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. 

SuMMARY 

The habitual use of tobacco is related primarily to psychological and social 

drh·es, reinforced and perpetuated hy the pharmacological actions of nico· 

tine on the cPntral HnYow• system, the latter being interpreted subjectivelv 

either as stimulant or tranquilizin~ dependent upon the individual response. 

\ icotine-free tobacco or other plant matPrials do not satisfy the needs of those 

who acquire the tobacco habit. 

The tobacco habit should he characterized as an habituation rather than 

an addiction. in conformity with accepted \'rorld Health Organization defini· 

tion~. since once estahli~llf'd there is little tendency to increase the dose: 

p~Hhic but not phYsical dependence is de\ eloped: and the detrimental effects 

are primarilY un the indi\ idual rather than society. '\o characteristic absti· 

J~cnce\yndronw is dP\elopcd upon withdrawal. 

Acquired tolerance. e\en though comparatively low grade, is important 

in 11\ercoming nausea and other mild signs of nicotine toxicity and is a 

factor in continued usP of tobacco. 

Discontinuation of smokin!"- although possessing the difficulties attendant 

upon extinction of anY conditioned reflex. is accomplished best by reinforcing factors \1-hich interrupt the ps~ chogenic drives. '\ icotine substitutes or 

supplementary medications have not been proven to be of major benefit in 

breaking the habit. 

354 
BENEFICIAL EFFECTS OF TOBACCO 

Evaluation of the effects of smokinf?: on health would lack perspectiYe if no 

consideration was f!iYen to the possible benefits to he derived from the 

occasional or habitual use of tobacco. A large list of possible physical benefits 

can be compiled from a fairlv 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 comparatiYely 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 ele,·ation 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 intangible 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 70,000,000 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 

continut> to utilize pharmacologic aids in his search for contentment. In the 

best intt>rests of the public health this should be accomplished with substances which carry minimal hazard to the individual and for society as a 

whole. T n 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 l\ arcotic 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 

measureahle onlv in terms of individual behavior_ Since no means of quantitating these benefits is apparent the Committee finds no basis for a judgment 

which would weigh benefits versus hazards of smoking as it may apply to the 

general population. 

REFERENCES 

l. Bartlett, W. A .. Whitehead, R. W. The effectiveness of meprobamate and 

lobeline as smoking deterrents. J Lab Clin Med 50: 27R-81, 1957. 

2. Behrend. A .. Thienes, C. H. The development of tolerance to nicotine 

by rats. J Pharmacol Exp Ther 43: ;)17-25, 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. Ann Intern Med 10: 628-

31, 1936. 

6. Edmunds, C. W. Studies in tolerance, !-nicotine and lobeline. J Pharmacol Exp Ther I: 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 I: 

315-21, 1915-16. 

8. FarrelL H. The billion dollar smoke. A working truth in reference to 

cigarettes and cigarette smoking. Nebraska Med J 13: 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. 

] 0. Freedman, B. Conditioned reflex and psychodynamic equivalents in 

alcohol addiction. An illustration of psychoanalytic neurology, with 

rudimentary equations. Quart J Stud Alcohol 9: 53-71, 1943. 

356 
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. A 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. 

1R. Miley, R. A., White, ~'. 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 NY 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 "1\l"ikotinsucht oder die Kunst, 

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, 1962. 

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. 565-640. 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, 0., Jr., Ochota, L. Smoking and chronic respiratory disorders. Results of abstinence. Ann All erg 16: 455-8, 1958. 

29. Takeuchi, M., Kurogochi, Y., Yamaoka, M. Experiments on the repeated injection of nicotine into albino rats. Folia Pharmacal }ap 50: 

66-9, 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. :'\ew York J Med Si· 

3348-52. 1957. 

34. Wolff, W. A .• Giles. W. E. Studies on tobacco chemistry. Fed Proc 9: 

243, 1050. 

35. World Health Organization. Expert Committee on Addiction-Producin" 

Drugs. Se\enth Report. 15 p. I Its Techn Rep Ser No. 116, l9.'ii.~ 

36. Wright. I. S., Littauer, D. Lobeline sulfate, its pharmacology and us.· 

in the treatment of the tobacco habit. JAMA 109: 649-54, 1937. 

358 
Chapter 14 

Psycho-Social Aspects 

of Smoking 
Contents 

INTRODUCTION . . . 

DEMOGRAPHIC FACTORS 

Age ......... . 

Smoking by Socioeconomic Level 

Occupation 

Education 

Sex .. . 

Race .. . 

Marital Status 

Religion ... 

Rural versus Urban 

Summary ..... 

PERSONALITY AND SMOKING . 

Extroversion and Introversion . 

Neuroticism . . . . . . . . . 

Psychosomatic Manifestations. 

Psychoanalytic Theory . 

Summary ....... . 

TAKING UP SMOKING .. 

Parents' Smoking Patterns 

Intelligence and Achievement . 

Some Hypotheses on the Beginning of Smoking 

Status Striving . . . . . . . . . . . . . . 

Rebellion Against Authority . . . . . . . . 

Smoking as a Response To Stres~ and as a Tension Release . 

DISCONTINUATIOJ\" 

SUMMARY . 

CONCLUSION 

REFERE~CES . 

360 

Pa~r 

~(o) 

~to) 

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:\t,2 

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36:\ 

36:\ 

36~ 

36t 

36.t 

3tit 

36 ~ 

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Chapter 14 

INTRODUCTION 

The smoking habit has been found to be linked with several demographic 

variables (such as age, sex, socioeconomic level, etc.), with a number of 

general behavioral patterns (such as degree and kind of participation in a 

variety of social activities), with psychological characteristics (such as in· 

telligence, school achievement. etc.), and with certain personality variables 

(such as intro· and extroversion. gregariousness. ft>elings 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 psychologit:al-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 111 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. probably less than five percent of the boys and less thar. 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 

361 
percent of children have been found to be smokers. By age 25, estimat , 

of smoking prevalence run as high as 60 percent of men and 36 I)er~ e. . . ,ent of women. There Is a further mcrease up to 35 and 40 years after which 

drop is obse.rved. In the 65 and over age group, prevalence of smoking i: 

only approximately 20 percent among men and four percent among wonH·n. 

These distributions are based on cross-sectional rather than longitudinal 

data and may be subject to considerable change over the years as each "'Pn. 

eration of smokers carries its own smoking pattern into higher age bracket' 

It is also conceivable that increased public attention to possible hazard~ 

of smoking within the last few years has led to some decrease in the numhn 

of smokers, a decrease not evenly distributed among the several age ~roup-. 

Since these statistics were collected several years ago, they may not rrfleq 

current age distributions. More recent but limited data suggest that thPn· 

has been an increment in smoking prevalence at all age levels since the earh 

fifties (7, 13, 23, 26, 31). 

Horn (ll) estimates that 10 percent of later smokers "develop the hal 1it 

with some degree of regularity" before their teens and 65 percent durin" 

their high school years. It seems, then. that the years from the earlv tt>Pn: 

to the ages of 18-20 are significant years in exposing people to the.ir fir,t 

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, education. 

occupation and type of residence. 

Despite the use of different determinants of class status. there is rather 

consistent evidence that smoking patterns are related to socioeconomic ]eyp] 

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. 22. 

27). 

As to separate class-linked variable;;;. income does not seem to be relatrd 

in a consistent manner to prevalence of smoking either in England I ::\91 

or in the U.S.A. (26). There does appear to be some tendency to11anl 

fewer male smokers among thosr with a warlv income helm' $2.000 (as of 

195(>) and. in the older groups only. with an annual income over $S.OOO. 

On the other hand, income does relate positively to the quantity of cigarette, 

consumed. 

OccUPATION 

Almost as many different ways of classihing and grouping occupation:-

have been used a,: there are studies dealing with this variable. making com· 

parisons extremely difficult. Morem·er. most groupings are not wn 

meaningful since theY used broad and comprehensive joh classificationwhich obscure some of the most important occupational characteristic,;. 

For example, the category "professional" encompasses (as do other cale· 

gories) a tremendous range of occupations. These vary widely amonf!' 

362 
themselves with respect to many characteristics that may be significantlv 

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. 1'\onetheless. 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, 1'\ew York. Matarazzo 

and Saslow (23) Etlso 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. Smokers 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 (II) 

reports that a recent American Cancer Societv survey showed an increase 

since their 1955 survey of five percent (from 31 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 rou~hly the same among whites and nonwhites (7) and relations of smoking to sex and age also were comparable 

363 
in the two 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 was 

found to relate to amount, thoup-h not to prevalence, of smoking, this ra('ial 

difference could reflect economic differences between whites and non-whites 

MARITAL STATUS 

Smoking (of any kind) is most prevalent among the divorced and widowt>d 

and least among tho~e who have never been married, except that amon~ 

persons over 45, never-marrieds are as likely to be smokers as the marriPd. 

(7). 

RELIGION 

There is evidence of lower smoking rates within some religious sects whiPh 

condemn smoking (16) and among persons who hold devout religious beliefs. 

For example, less smoking was found among Harvard students who wert• 

religious and whose parents were devout; and non-smokers seem mort> 

inclined to attend church than smokers (3, 22, 37). Both Horn 011 and 

Straits and Sechrest (:)7) report over-representation of smokers amon 11 

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 thPre 

is a direct causal link between religion and abstention, or whether some 

other factors account both for the religious convictions and the abstention 

from smoking. 

RunAL VERsus URBAN 

There are proportionally fewer smokers in rural than in urban areas. but 

the smallest percentage of smokers is within the rural farm population. The 

rural non-farm population is more like the urban population with onlv 

slightly fewer smokers than in the latter. No relationship of smoking to size 

of community has been established. No convincing interpretation can he 

offered in view of the lack of additional data. 

Su:-.n1ARY oF DEMOGRAPHIC FACTORS 

No single comprehen~ive theory to explain smoking is suggested by the;;.· 

demographic data taken by themselve". In facL the only known attempt at 

formulating a theory which is. at lea;;;t partly, related to or based on sul'h 

data revolves arot..nd a hypothesis relating smoking, or not-smoking. to 

introjected culture standards linked to social class norms in our society 

(21,22). 

Nonetheless, there are many. though not always clear, relationships he· 

tween smoking and a variety of social and economic variables. Taken al· 

364 
together, there emerges the picture of smoking as a behavior that has over 

many years become tied closely to manv of the complexitil"s of our present 

~ociety. 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 above. 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 tht> wav in which he reacts 

to and, in turn, creates such forces. in short, a considt>ration of personality 

factors. 

PERSONALITY Al\'D S"\IOKJNG 

All research studit>s on the relation between smoking and personality 

select one or several. more or less distinct personalitv traits or characteristic-s 

for scrutiny. For example. thev mav trv to test hvpothPses on the interrelation between smoking and introvPr<:ion. smoking and nt>uroticism. smoking 

and anxiety. etc. A few studl:'nts havl:' triPd to dPscrihe personality ~vndromes by a synthesis of several suc-h traits. At the present state of knowledge. however, it is more fruitful and more valid to speak not in terms of a 

"smoker personality." hut rather in terms of discrete personalitv c-haracteristics which may be 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 may 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 difficult to saY whPther these 

studies really are yielding contradictory findings. or Khether diffPrences in 

such data are due to the fact that they reflect different variahlPs. In addition, psychological techniques for the assessment of personalitv are still of 

uncertain validity, some possibly of little or no value. For examplP. in a 

number of studies the investigators have made up a priori scales. tests or 

questionnaires without any reported attempts at establishing their reliability 

or validity. 

ExTROVERSIO-"' A~n I NTROVERsro~ 

One of the best-designed studies (L 6) was carriPd out in England using 

representative samples and objective techniques using question' previously 

developed by Eysenck and claimed by him to "have bePn found to be ... 

reasonably valid measures of three personalitv traits, extroversion. neuroticism, and rigidity." ( 6). If one accepts the author's claim that the questionnaire really did measure these traits. a very significant rPlationship was found 

between extroversion and smoking. Heavy smokers Kere more extrm·ertt>d 

than medium smokers; these were more extroverted than light smoker5 and 

365 
ex-smokers; and both non-smokers and pipe smokers were least extrovertt>d 

Two consecutive studies with different representative samples yielded th · 

same results, and the association of smoking with extroversion was als~ 

supported by several other investigators, such as McArthur et a! ( 22 l and 

Schubert ( 34). Another study by Straits and Sechrest ( 37) using the Social 

Introversion Scale from the Minnesota Multiphasic Personality Inventory "" 

a rather small and probably biased sample did not support this findin1!. · 

The general picture which emerges from Eysenck's study and from othn,. 

is one of smokers tending to live faster and more intensely, and to be mnro· 

socially outgoing. 

Several studies, using behavioral rather than psychological test data. su1,. 

port this picture. Davis ( 4) describes young smokers as "more gregariou,. 

and socially advanced" than non-smokers. McArthur et a! (22) report 

similar findings. 

However, a compilation of actual participation of smokers and nonsmokers, respectively, in a number of specific social activities as reported }, 1 

several investigators ( 4, 13, 19, 30) yields conflicting data. Smoker' ar~· 

reported to participate more in such social activities as dancing, courtship. 

ond fraternities-in line with what would be expected of extroverted individuals. As to participation in sports, findings in some studies favor the 

smoker, in others the non-smoker. Non-smokers were found by one inve>tigator to show greater social parti..cipation in organizations and to hold morP 

offices-activities more associated with extra- than with introversion. 

Smokers show greater interest in TV and movies, non-smokers in readin1! 

books. Studies and cultural activities are over-represented among non. 

smokers. 

These conflicts in the data as collected do not necessarily reflect real con. 

flicts, however. Some sports may be of a less gregarious or extrovertrd 

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 rangr 

can accommodate introverted as well as extroverted students. Lumping 

together heterogeneous activities under one broad descriptive term, as donr 

in so many studies on smokers' behavior, may obscure real relationships. 

In any case, while the association between extroversion and smokin1! is 

fairly well supported by available evidence, less certainty exists as to thr 

exact nature of this association. It is possible that extroversion is dirrctly 

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 equallv 

plausible that the extrovert. by virtue of his greater participation in various 

social activities, exposes himself more to social stimuli to pick up ,,nd 

re-enforce the smoking habit. He may also be more susceptible to social 

influence. 

NEUROTICISM 

Several studies. usmg a variety of methods, have investigated variable,. 

related more or less vaguely with 11 hat mav be subsumed under the trnn 

neuroticism. Such variables include neuroticism as a personality trait in366 
£erred 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 (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) . E ysenck et a 1. 

( 1), using a neuroticism-scale, did not finr{ any significant relationship of 

neuroticism either to type or degree of smoking. He does suggest, however, 

that "inhaling may be more prevalent among the more neurotic and 

1otionally disturbed." 

The state of our knowledge in respect to the smoking-neuroticism svn· 

drome can be best summarized this way: 

Despite the individual deficiencies of manv of the studies, despite the 

great diversity in conceptualization and research methods used, and despite 

certain discrepancies in reported findings, the presence of some compara· 

bility between them and the relative consistency of findings lend support 

to the existence of a relationship between the smoking habit and a 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 (l) 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. 

714-422 0-64-25 367 
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 furthe; 

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 exclusiveh: 

in one group and is completely absent in the other" ( 23). Nor has any sing!~ 

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 all 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' 

Emoking 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 

Hornet 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, regar-dless of sex or 

parental habits. But within each year there are significantly more smokers 

in families where both parents smoke than in families where neither parent 

smokes. Various combinations of smoking practices of father and mother 

respectively, also affect children's habits differentially. Horn's findings are 

supported by those of Salber and MacMahon (27) obtained from Newton, 

Mass., high school students. 

This congruity between parents' and children's smoking habits has led 

some investigators to ascribe, explicitly or implicitly, simple and direct 

causal properties to parents' smoking behavior. It has even been asserted 

that the most effective way to diminish smoking radically among children 

would be to decrease smoking among their parents. However, such con· 

gruity could be due to several factors. Parents could exert direct and force· 

ful influence on their children; the attitudes and practices of smoking 

parents could create a general atmosphere of permissiveness in the home; 

conflict between parents' exhortations and their actual behavior could influ. 

ence children's perception of the pros and cons of smoking. Selection of 

social associates on the basis of similar attitudes and behavior norms may 

lead to a social life on the part of the parents involving other families (and 

their children) who smoke, thus providing additional social smoking stimuli 

for their own children. Then, there is the availability of cigarettes in a 

home where parents smoke which could facilitate the child's first steps to· 

wards smoking. Finally, the possibilities of similarity in personalities of 

parents and children cannot be ruled out. 

Even in families where neither parent smokes there is a striking increase 

with age in smoking among children. Moreover, congruity between the two 

generations diminishes with each year from freshman to senior year. That 

this trend of diminishing congruity continues into college is suggested by the 

findings of Straits and Sechrest (37) who 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 striving 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. The 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 interpretatffins 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 

sta,tistical 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 w-as found between achievement 

scores obtained from school grades and non-smoking, and the authors conclude that "the 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). Hornet 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 given school grade can he accounted for 

by their age differences. 

370 
Thomas (38) and Lilienfeld (19) found 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 hi:rher smokin:r 

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 BEGINI\'ING 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-adu.lt-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 amonl! 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 ;;aining 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 de~ire f 

adult status, rna~ play a role in inducing some, and perhaps many. !'hildr~r: to take up smokmg. 

STATUS STRIVING 

Some students of smoking behavior have looked at the dynami!',- of 

"striving for status" in a broader sense, as a manifestation of interrrlatt·d 

basic psycho-social needs. To be accepted by one's reference persons. partir. 

ularly one's peer groups, to develop self-esteem and an acceptable self-irna!!~>. 

and to cope with painful feelings of inadequacy, are such basic psycho-soc-ial 

needs. Of these, striving for adult status is only one aspect. It is entireh· 

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 he 

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 the 

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. Thi~ 

relation between under-achievement and smoking has generally been interpreted in terms of compensation. 

Salber et al. ( 32) suggest, "it may be that children who do not achievr 

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 ( 20, 22, 331. 

The findings from anthropometric studies of students' physiques which detected an association between physical masculinity and non-smoking (35) 

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 (as is more or less 

i"trongly implied by some authors) is not very impressive. For example, in 

all studies reviewed, the fact that a ~tudent does not perform as well as his 

peers in the classroom is accepted as prima-facie evidence that he feels psychologically 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. Nv studies have demonstrated that there is a relation between smoking and under-achievement 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 ( 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, whv 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 carrying 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, hut 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 hahit 

once established. 

Considerable evidence lends credence to this hypothesis. "Nervous'' 

traits, anxiety, and over-reaction to environmental stimuli have been founrl 

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 product' 

stress if the experience is relevant to a person's needs and values. Cartwright et a!. ( 3) found that men often tended to start smoking when thev 

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 explanation could be advanced for the observed increase in initial smoking amon~ 

young men in military service (7). 

More direct, hut 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-producing experiences. As McArthur et a!. (22) point out, such short-lived 

fluctuations in response to brief stress episodes would not be detected bv 

survey methods that elicit information on smoking behavior at only on~ 

point in the smokers' lives or even, as in McArthur's case, at yearly intervals. 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 he accepted with a reasonable degree of confidence. It should he 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 latter, is it effective, 

that is, would tension actually he 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 re· 

garded as an intelligent and desirable thing to do. 

A study carried out in 19.57 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 5ex, and for the 5cientific 

nature of their interests formed the subjects. One consisted of 72 well· 

known lung cancer scienti5ts, the other of experimental psychologists. 

Significantly fewer of the cancer specialists than of the psychologists were 

smokers, and the same difference exi5ted in respect to the number of persons 

in each group who believed cigarette smoking to be a cause of lung cancer. 

But there wa5 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 

5moking 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 expres5ed more dissatisfaction with their 

own smoking, and who exhibited a significantly lower prevalence of 5moking, 

a higher rate of attempted discontinuations, and a higher rate of deliberately 

dimini5hed amount of cigarettes consumed. 

There is no readily available convincing explanation for this finding, 

hut it doe5 demon5trate that the smoking habit is linked with so many 

aspects of a per5on'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 

U5ed 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 trustworthy 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 smoking 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 

uf 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 

i!" 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 hypothesis that smoking 

among adolescents is an expression of rebellion against authority. 

376 
8. No differences in intelligence between smokihg 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. 

ll. 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 existence of predisposing 

constitutional or hereditary factors. 

REFERENCES 

L 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-ll1, 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. NY J Med 58: 2956-9, 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 Di!'. 16: 

383-95. 1963. 

12. Horn, D. Modifying smoking habits in high school students. Children 

7: 63-5, April 1960. 

13. Horn, D., Courts, F. A., Taylor. R. M., Solomon, E. S. Cigarette smokinl!' 

among high school students. Amer Public Health 49: 1497, 1959. 

14. Kissen, D. M. Emotional factors cigarette smoking and relapse in pulmonary 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 Soc Psycho! 54: 235-48, 1961. 

18. Lawton, M., Phillips, R. The relationship between excessive cigarette 

smoking and psychological tension. Amer J Med Sci 232: 397-402. 

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 lnst 22: 259-82, 1959. 

20. Lynn. R. M. A studv of smokers and non-smokers as related to achievement and various personal characteristics. [Abstract] 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, 1. The psychology of smoking. 

J Abnorm Soc Psychol 56: 267-75, 1958. 

2:1. Matarazzo, J. D., Saslow, G. Psychological and related characteristics 

of smokers and non-smokers. Psycho} Bull 57: 493-513, 1960. 

24. Matarazzo. R. :\1.. :VIatarazzo, J. D., Saslow, G., Phillips, J. S. Psychological test and organismic correlates of interview interaction patterns. J Abnorm Soc Psycho! 56: 329-38, 1958. 

25. !\1oodie, W. Smoking. drinking, and nervousness. Lancet 2: 188-9, 

1957. 

26. Sackrin, S .. Conover. A. Tobacco smoking in the U.S. in relation to 

mcome. l_'SDA Market Res Rep l\o. 189, 1957. 

27. Salber, D., Mac'VIahon. B. 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. Change in women's smoking patterns. Cancer. 

In press as of September 1963. 

29. Salber, E. 1., 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. }., and others. Recreational activities and attitudes toward 

smoking: A study of school children. Pediatrics. In press as of September 1963. 

378 
31. Salber, E.]., 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. Smoking 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 

Psychol 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. 1-130. 

37. Straits, B., Sechrest, L. Further support of some findings about the 

characteristics of smokers and non-smokers. J Consult Psycho! 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. l. 

The Tobacco Manufacturers' Standing Committee. London, 1959. 

379 
Chapter 15 

Morphological 

Constitution of 

Smokers 
Contents 

PHYSIQUE OF SMOKERS . . . . 

SOMATOTYPE CLASSIFICATION 

MASCULINITY . . . . 

BODY WEIGHT . . . . 

PROSPECTIVE STUDY 

CONCLUSION . 

REFERENCES . . . . . 

382 

Page 

3S1 

1S:~ 

3S:~ 

:3S4 

:l85 

:lSi 

:lSi 
Chapter 15 

MORPHOLOGICAL CONSTITUTION OF SMOKERS 

PHYSIQUE OF SMOKERS 

Several studies deal with the relation of morphological constitution and 

smoking. In 1929 Diehl (2 i 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) 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 

714-422 0-64-26 383 
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 thie 

study showed a statistically significant association between the strength ~ 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 ~~ 

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 40 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 smoker~< com· 

pared with non-smokers (of which the weight analysis was a part), Thomas 

wrote: "The finding that smokers, especially heavy smokers, have a higher 

mortality rate from coronary heart disease than do non-smokers makes it 

important to determine whether those who smoke are fundamentally different 

from those who do not smoke, or whether smokers and non-smokers are 

essentially alike. If alike, then 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 
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 N~apolitan parentage 

but of American birth and upbringing, Damon ( l) 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 l 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 Harvard 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 genotypically 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 obtain groupings as precisely 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 2+ 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. In 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 "2 + 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 

L 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 I: 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 

U.S. GOVERNMENT PRINTING OFFICE: 1964 o-714-422