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, $ OSCAR AUEA$A-?-'H-T-RICHAIM J-STNG-T HI;NR4 W. BLACKBURN + FRED G. BOCK + JOSEF BROZEK + ANTONIO CIOCCO + J. H. COMROE, JR. + PHILIP COOPER + THOMAS ~ R. DAWBER + HAROLD F. DORN + C. M. FLETCHER + .S LAWRENCE GARFINKEL + WILLIAM HAENSZEL + E. i CUYLER HAMMOND + D. H O F F M A N N + DANIEL HORN + HAROLD A. KAHN + WILLIAM B. KANNEL + CHARLES J. KENSLER + ANCEL KEYS + PAUL KOTIN + LEIV KREYBERG + MORTON L. LEVIN + CECILIE L E U C H T E N B E R G E R+ RUDOLF LEUCHTENBERGER + ARTHUR JAMES LINDSEY + CHARLES C. McARTHUR + GEORGE E. MOORE + JAY NADEL RICHARD DOUGLAS PASSEY + WALTER REDISCH + STANLEY P. REIMANN + GRACE M. ROTH + ROBERT R. SECR'EST + RICHARD M. SHICK + ARTHUR PURDY STOUT + HENRY L. TAYLOR + HAROLD K. TSUJI + BENJAMIN L. 4

TOBACCO AND HEALTH It is generally agreed that there is amarkedassocia- tion between lung cancer and cigarette smoking. More recently significant evidence appeara to link c i g a r e t t e smoking with deaths attributed to coro- nary heart disease, peptic ulcer, bronchitis, and pulmonary fibrosis. In search for proof or lack of -proof of this causal re- lationship, a penetrating, scientific r e v i e w of the entire question of tobacco and health was cponsored jointly by the New York Academy of Medicine and the New York State Acad- emy of Preventive Medi- cine. Discussants included a significant n u m b e r of research investigators who have won recognition for evidence they have coin- piled on one or the other side of the controversy. NO SCIENTIFIC POSITION ON THE QUESTION WAS OMITTED. The discussions recorded here cover ... • Chemistrv and Pharma- colo of Tobacco Smoke • Experimental Pathology of Tobacco Smoke • T h e Interpretation of Statistical and Epidemio- logical Data Relating Smok- ing to Disease • Smoking and Lung Can- cer T200931 • Other Diseases Relating ~ t., c..,..~;...,

TOBACCO AND HEALTH T200932

~ ~ ~ TOBACCO" ~ 0 AND HEALTH ~ Edited by GEORGE JAMES, M.D. Deputy Coritrnissioner, Department of Health Adjunct Associate Professor, Public Health Practice Columbia.University School of Public Health and Administrative Medicine New York City and THEODORE ROSENTHAL, M.D. Assistant Commissioner, Department of Health Clinical Professor of Preventive Medicine New York University College of Medicine New York City CHARLES C THOMAS • PUBLISHER Springfield • lllinois • U.S.A. T200933

i CHARLES C THOIMIAS , PUBLISHER BArtrrMSi'orrE Hovsn 301-327 East Lawrence Avenue, Springfueld, Illinois, U.S.A. This book is protected by copyright. No part of it may be reproduced in any manner with- out written permission from the publisher. © 1.962, by CHARLES C TI-tO1viAS • PUBLISHER Library of Congress Catalog Card Number: 61-15382 With THOMAS BOOKS careful attention is given to all details of manufacturing and design. It is the Publisher's desire to present books that are satisfactory as to their physical qualities and artistic possibilities and appropriate for their particular use. THOMAS BOOKS will be true to those laws of quality that assure a good name and good will. G13, S Printrd in the United States of America CONTRIBUTORS OscAm AvmACx, M.D., Senior Medical Investigator, Veterans Admin- istration Hospital, East Orange, New Jersey; Associate Pro f essor of Pathology, New York Medical College, New York, New York RieIIAnD J. BINC, M.D., Professor and Chairman, Department of Medi- cine, Wayne State University College o f Medicine, Detroit, Michigan HENRY W. BLAcICSVaN, M.D., Assistant Pro f essor, Laboratory o f Ph ysiologieal Hygiene, University o f Minnesota, Minneapolis, Minnesota FIt>rD G. Bocs, Ph.D., Associate Cancer Research Scientist, Biological Station, Boswell Park Memorial Institute, Springville, New York JosEF BaozFnc, Ph.D., Chairman, Department of Psychology, Lehigh University, Bethlehem, Pennsylvania ANTONIO CIOCCO, Sc.D., Head, Department o f Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania J. H. Commor, JR., M.D., Director, Cardiovascular Research Institute, Universit y o f Cali f ornia Medical Center, San Francisco, Cali f ornia PHILIP COOPEn, M.D., Clinical Pro f essor o f Surgery, Albert Einstein College of Medicine, New York, New York; Chief of the Surgical Services, Veterans Administration Hospital, Bronx, New York TnomAs R. DAwwIt, M.D., Member, National Heart Institute, Public Health Service, Department of Health, Education and Welfare, Bethesda, Maryland HAROLD F. DOAN, Ph.D., Chief, Biometrics Research Branch, National Heart Institute, National Institutes of Health, Bethesda, Maryland C. M. FLt+;rcln;R, M.D., F.R.C.P., Senior Lecturer in Medicine, Post- graduate Medical School o f London, Physician to Hammersmith Hospital, London, England LAw$F,NC>; GARFINICEL, M.A., Chie f o f Fieid and Special Projects, Statistical Research Section, American Cancer Society, New York, New York v T2.00934

vi Tobacco and Health WILLIAM HAENSZEL, M.A., Associate Chief, Biometry Branch, National Cancer Institute, Bethesda, Maryland E. CuYLER HAMMOND, Sc.D., Director o f Statistical Research Section, American Cancer Society, New York, New York D. HOFFMANN, Ph.D., Section of Epidemiology, Division of Preventive Medicine, Sloan-Kettering Institute, New York, New York DANIEL HoRN, Ph.D., Director of Program Evaluation, American Cancer Society, New York, New York HAROLD A. KAHN, M.A., Member, National Heart Institute, National Institutes of Health, Public Health Service, Department of Health, Education and Welfare, Bethesda, Maryland WILLIAM B. KANNEL, M.D., Member, National Heart Institute, National Institutes of Health, Public Health Service, Department of Health, Education and Welfare, Bethesda, Maryland CHARLES J. Kr•.NSLER, Ph.D., Professor and Chairman, Department of Pharmacology and Experimental Therapeutics, Boston University School o f Medicine, Boston, Massachusetts ANCeI. KEYS, Ph.D., Laboratory of Physiological Hygiene, University of Minnesota, Minneapolis, Minnesota PAUL KOTIN, M.D.. Department of Pathology, School of Medicine, University of Southern California; Los Angeles County General Hospital, Los Angeles, Cali f ornia LEIv KREYI3ERC, i<1.D., Professor, Universitetes, Institutt for Generell Og, Eksperimentell Patologi, Rikshospilalet, Oslo, Norway MoRTON L. LEVJN, M.D., Professor, Department of Epidemiology, Roswell Park Memorial Institute, Buffalo, New York CECILIF LFUCHTF.NISI•',RCER, Ph.D., Senior Biologist and Cytochemist, Children's Cancer Research Foundation, Boston, Massachusetts RUDOLF LuUCHTrNnERCER, M.D., Senior Experimental Pathologist, Children's Cancer Research Foundation, Boston, Massachusetts ARTHUR JAMES LINDSI:Y, D.Sc., Ph.D., Head of Department of Chem- istry, Sir John Cass College, London, England CIIARLES C. MCAITrIIUR, Ph.D., Psychologist to the University Health Services, Ilarvnrd University, Cambridge, Massachusetts GEoRCr•. E. MooRI;, Department of Surgery, Roswell Park Memorial Institute, Buffalo, New York JAY NADEL, M.D., Associate Staff Member of the Cardiovascular Re- search Institute, University of California Medical Center, San Francisco, Caiiforn.ia Tobacco and Health vii RIeHARD DoucLAs PASSEY, M.C., M.D., D.P.H., Emeritus Pro f essor o f Experimental Pathology, Leeds University; Research Fellow, Chester Beatty Research Institute, London, England WALTER REVISCII, M.D., Associate Pro f essor o f Medicine, New York University School o f Medicine; Attending Physician, The Third Medical Division, Bellevue and University Hospitals; Research Associate, New York University Research Service, Goldwater Memorial Hospital, New York, New York STANLEY P. REIIvIANN, M.D., Director Emeritus, The Institute f or Cancer Research, Philadelphia, Pennsylania GRAcE M. RoTH, Ph.D., Department of Medicine, Lovelace Clinic, Albuquerque, New Mexico; Section o f Medicine, Ma yo Clinic, Rochester, Minnesota ROBERT R. SECREST, M.D., Department of Medicine, Lovelace Clinic, Albuquerque, New Mexico; Section of Medicine, Mayo Clinic, Rochester, Minnesota RIcHARD M. SHIcx, M.D., Department o f Medicine, Lovelace Clinie, ' Albuquerque, New Mexico; Section o f Medicine, Mayo Clinic, Rochester, Minnesota ARTHUR PURDY STOUT, M.D., Pro f essor Emeritus o f Surger y, College o f Physicians and Surgeons, Columbia University HENRY L. TAYLOR, Ph.D., Laboratory of Physiological Hygiene, Uni- versity of Minnesota, Minneapolis, Minnesota HAROLD K. Tsv1I, M.D., Chief Resident, Thoracic Surgery, Bronx Veterans Administration, Bronx, New York BENJAMIN L. VANDwRErI, Sc.D., Assistant Pro f essor, Institute o f Industrial Medicine, New York University Medical Center, New York, New York J. EDwIN WOOD, M.D., Associate Pro f essor o f Medicine, Medical Col- lege of Georgia; Director, Georgia Heart Association Laboratory f or Cardiovascular Research, Augusta, Georgia ERNESr L. WYNDER, M.D., Head, Section of Epidemiology, Sloan- Kettering Institute; Associate Pro fessor o f Preventive Medicine, Sloan-Kettering Division, Cornell Medical College, New York, New York J. YERUSHALMY, Ph.D., Professor of Biostatistics, University of Cali- fornia, Berkeley, California WILLIAM J. ZUKEL, M.D., Member, National Heart Institute, National Institutes of Health, Public Health Service, Department of Health, Education and Welfare, Bethesda, M^rifla.nd T200935

FOREWORD SHORTLY after the New York State Academy of ~ Preventive Medicine was founded, there was much discussion about its particular mission for the advancement of public health science and practice. The Academy established a number of committees to explore some of the crucial issues in these fields. One of these committees was asked to investigate the problem of tobacco and health. Although impressed with the wealth of evidence which links cigarette smoking etiologically with lung cancer and other diseases, the Committee observed the reservations with which several respected members of the scientific community viewed this evidence. It also recognized the paucity of data avail- able on the epidemiology of the smoking habit itself and on the measures which might be taken to curtail it. In order to establish a firm baseline beneath any further studies of the smok- ing problem and any recommendations for the control of smok- ing, the Committee urged the New York State Academy of Preventive Medicine to sponsor a two-day symposium which might provide the forum for a brief but penetrating and sober scientific review of the entire question of tobacco and health. The New York State Academy of Preventive Medicine dis- covered that the New York Academy of Medicine had an equal interest in sponsoring a scientific review of this subject and a joint Planning Committee was established. Financial support was received from the Rockefeller Foundation, the New York City Cancer Committee, and the New York State Cancer Society, the latter two being affiliates of the American Cancer Society. The session was held at the New York Academy of Medicine, - September 26 and 27, 1960, with attendance limited to the panel- ists and the members and guests of the two sponsoring organiza- tions. ix T200936

x Tobacco and Health It is generally agreed that there is a marked association be- tween lung cancer and cigarette smoking. Most epidemiologists who have studied the problem believe that the fourteen retro- spective studies, the three large prospective studies, the evidence from pathological, chemical and experimental studies, establish the causall relationship of cigarette smoking to lung cancer be- yond a reasonable doubt. Others believe so strongly that addi- tionall avenues of research must be explored that they see no reason to justify a decrease in the cigarette smoking habit. More recently significant evidence appears to link cigarette smoking with deaths attributed to coronary heart disease, peptic ulcer, bronchitis and pulmonary fibrosis. The public health problem was put succinctly by Dr. Hollis S. Ingraham, conference chairman, who pointed out in his opening remarks: "Should this excess mortality due to cigarette smoking prove to have a causal relationship, it would indicate that cigarettes cause more deaths than any other single recognized lethall agent, including alll the known bacteria, known viruses, bullets, wild animals, chemical poisons or even the American automobile." In its search for the proof or lack of proof of this causal relationship, the Committee selected as discussants a significant number of research investigators who have won recognition for the evidence they have compiled on one or the other side of the controversy. The Planning Committee did its best to insure that each major significant portion of evidence be presented and that no scienti ftc position on the question be omitted. Each partici- pant's address was followed by a lively discussion period, which regretfully cannot be reproduced as part of this volume. The editors wish to express their great appreciation to each of the speakers for his willingness to prepare a careful presentation based primarily upon his own research, and to subject his evi- dence and his views to that persistent probing and ruthless criti- cism which charsacterize the search for scientific truth among men with imbom,ded curiosity and hope for still more ultimate conquests against the ravages of disease. The editors wish to acknowledge their debt to all of their colleagues of both Academies who served on the Planning Com- mittee and most especially to Dr. Harry Kruse, Executive Secre- Tobacco and Health xi tary, Committee on Public Health, New York Academy of Medicine, Drs. Henry Aranow and McKeen Cattell of the New York Academy of Medicine, and to Dr. Morton L. Levin under whose Presidency of the New York State Academy of Preventive Medicine the Committee on Tobacco and Health was born. GEORGE JAMES, M.D. President, New York State Academy of Preventive Medicine, 1960-1961 Chairman, Committee on Tobacco and Health, 1958-1960 TxEonoRE RosENTHAL, M.D. Chairman, Committee on Tobacco and Health of the New York State Academy of Preventive Medicine, 1960-1961 T200937

CONTENTS Foreword ' ix ................................•-..._....-•----..........._.........-•..-..............._....... . ~g SESSION I CHEMISTRY AND PHARMACOLOGY OF TOBACCO SMOKE Chapter 1. The Pharmacology of Tobacco Smoke Effects of Chronic Ex- posure by CxAnm J. KiNSLm ................................................... 5 2. Some Observations Upon the Chemistry of Tobacco Smoke by A. J. LiNnsEx .......................................................................... 21 3. Some Aspects of the Chemistry of Tobacco Smoke by BEN- JAMIN L. VAN DWIIEN ................................................................ 33 4. The Effect of Cigarette Smoking on Coronary Blood Flow and Cardiac Work in Normal Subjects and Patients with Coronary Disease by RicHAnn J. &NC .................................... 48 5. Tobacco in Health and Disease Effect on Peripheral Circula- tion by J. Enwmt WOOD ............................................................ 51 SESSION 11 EXPERIMENTAL PATHOLOGY OF TOBACCO SMOKE 6. The Role of Skin Neoplasia in Tobacco Carcinogenesis b y E. L. Wnanm and D. HorrmAN .................................................... 61 7. The Significance of Mouse Skin Tests of Cigarette Smoke Condensate by FxEV G. Bocx and GEOxcE E. Moom : ............ 72 ~ 8. A Correlated Histological, Cytological and Cytochemical Study of the Major Bronchi From MYce Exposed to Cig- arette Smoke by CEcmE LEVcnroNSERcEa and RvnoLF LEVCa3TENSERcEa ----...--••-• ............................................................. 87 xui T200938

xiv Tobacco and Health Chapter Page 9. Neoplasia: Lungs by RIcFrAxn DovcLAs PASSEY ---------------------•-_ 105 1-~'10. Bronchial Pathology in Man by STANLEY P. REINIANN .............. 123 11. Changes in the Tracheobronchial Tree in Connection with Cigarette Smoking by OscAlr AuzRBAcH, AsTFIUIi PvanY STOVT, E. CInYLER HAMMOND and LAwRENCE GAHr•IrIIEL .... 136 12. Histological Types in Relation to Etiological Factors and Trends in Lung Cancer by LEiv KxEYBEnc .............................. 144 SESSION III THE INTERPRETATION OF STATISTICAL AND EPIDEMIOLOGICAL DATA RELATING SMOKING TO DISEASE 13. Smoking and Cancer: Retrospective Studies and Epidemio- logical Evaluation by MORTON L. LEViN .................................. 163 14. Death Rates and Causes of Death of Smokers and Nonsmokers by HAROLD F. Donrr ..........................................................••-----..• 172 15. Statistical Considerations and Evaluations of Epidemiologic Evidence by ANTONIO CIOCCO .................................................... 191 ~" 16. Statistical Considerations and Evaluation of Epidemiological Evidence b yJ. Yr•.BVSrIALNIY ...................................................... 208 SESSION IV SMOKING AND LUNG CANCER 17. The Effect of Smoking and Nicotine on Respiration by J. H. CoArnor, Jn. :,nd JAY NADEL . ........................................................ 233 18. Environmental Factors and Lung Cancer by PAVI. KoTIN ........ 244 19. Quantitative Evaluation of the Etiologic Factors in Lung Cancer bi/ WILLIAM HAENSZEL ........................................... _.-- 264 20. The Personal and Social Psychology of Smoking by CxAIU,Es C. McAnzTlml ............................................................•----......-....--.. 291 21. Smoking Habits of High School Students by DANIEZ. HORN •... 300 I! Tobacco and Health xv SESSION V OTHER DISEASES RELATING TO SMOKING Chapter Page 22. The Effect of Smoking on the Peripheral Circulation of Man: Studies on the Site of Action of bTicotine by GsACE M. ROTFI, Ph.D., RICxABn M. Sxlcx and RoBEBT R. SECREsT .... 311 23. Cardiovascular and Related Characteristics in Habitual Smok- ers and Non-Smokers b y HENRY W. BLACmmN, Josr.r' BaozEx, HENRY L. TAYLOR and ANCEL Ki.ys .......................... 323 24. Tobacco Allergy and Vascular Responses by WALTn Rmiscx.. 352 25. Coronary Heart Disease Incidence and Mortality Among Smokers and Non-smokers by Wu.i.IAm J. Zvm, TxomAs R. DAWBER, WILLIAM B. KANNEL, HAROLD A. KAxN and HAROLD F. DORN ............................•--•---.............--•--..................... 360 26. Chronic Bronchitis, Smoking and Air Pollution by C. M. FLETCHER 380 27. Interrelationship of Smoking and Peptic Ulcer by PxII,Ir Coorm and HAROLD K. Tsull .................................................... 402 T200939