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r SMOKING AND fIEALTH I. MODIFYING THE RISK FOR THE SMOKER Sponsored Uy American Canccr Society National Gtnccr Institute WYNIIEK HnFF41.1NN GORI U.S. PEl'ARTMF-NT OF HEM-iH, FIIUCGI flON, \NU tt'F-l.F'ARC I'uhlrc Ncilth Scr'rcc N.ttrunal Inttrtutc% rrl Ilc,rllh Natiunal Canccr Insiilutc DNEW Publication No. (NIFIJ7b-1221 //,, /(

i i PROCEEDINGS OF THE 3RD WORLD CONFERENCE OF SMOKING AND HEALTH New York City, /une 2-5, 1975 WORKSHOP II h1ODIFYING THE RISK FOR TlIE SMOKER {i'orkshop Chairman: Ernst L. Wynder, h1.D. Sponsorcd in cooperation with American Heart Association American Lung Association American Medical Acsociation Health Lducation Council (U.K.) fntcrnational Union Against Canccr National Canccr Institute of Canada National Clearinghouse for Smoking and Health National (Icart and Lung Institute National Intcrat;cncy Council on Smoking and Health Pan Amcrican ttcalth Organization World Health Organization

i I I i SMOKING AND HEALTH I. MODIFYING THE RISK FOR THE SMOKER EDITED (lY Ernst L. Wynder, M.D., Dietrich Hoffmann, Ph.D. and Gio Q. Gori,.Ph.D. W 0 04 W ~ ~ Coordinating Editor: Penny Ashwanden 4~- Grote(u/ochnowledgcment to the Amcricon lleolth Foundation for its ossistoncc in the dcvclopmcnt of these proceedings

PARTICIPANTS Theodor Abelin, M.D. Inst. for Social and Preventive Medicine University of Berne CFI•3012 Bcrne, Switzerland Klaus D. Brunncmann Div. of Environmental Carcinogenesis American Ilealth Foundation Naylor Dana Inst. for Disease Prevention Valltalla, New York 10595 Wilhcrt S. Aronow, M.D. Chief. Cardiology Section Veterans Administration Hospital Long Beach, California 908 15 Dr. Pool Astrup Drp.trfinent of Clinical Chemistry Ril;shospitalct DK-2100 Copenhagen, Denmark Keith P. 6a11, M.D. Brcnt llcalth District C.entral tiliddrescx 1-tospital London NNrld 7NS, England S.tm P. Dattista, Ph.D. Arthur D. Little, Inc. Acorn Park Cambridge, Massachusetts 02140 I red G. Bock, Ph.D. Dircctor, Orch.vd Park Lab. Rus,•cll Park C.lcmorial Institute 666 Clm Street Butfalo, New York 14263 Irwin Bross, Ph.D. Director of Biostatistics Roswell Park Memorial Institute 666 LIm Street Buffalo, New York 14263 W.P. Castelli, M.D. National Hcart Institute 123 Lincoln Street Framingham, Massachusetts 01701 W.H. Cherry, M.D. Department of Statistics University of Waterloo Waterloo, Ontario, Canada N2L 3G I D.M. Conning, M.D. Dcputy Direc., Imp. Chemical Ind., Ltd. Central Toxicology Laboratory Aldcrly Park, Macclesfield Cheshire SKIt) 4TI, Ertgland' Tore Dalhamn, M.D. Institute of Hygiene University of Uppsala Box 587 751 23 Uppsala, Sweden Thomas R. Dawber, M.D., M.P.H. Boston University School of Medicine 80 East Concord Strcct Boston Massachusetts 02118 Louis Diamond, Ph.D. Pharmacodynamics and Toxicology Div. University of Kentucky College of Pharmacy Lexington, Kentucky 40506 V

I VI Ur, Walter Dontcnwill Rescarch Inst. for the German Cigarette Garctlcnkarnp 38 2000 Hamburg 54, West Germany Manning Feinlcib, M.D. Epidemiology Branch Natiunal Ilcart and Lung Institute Bethesda, Maryland 20014 Lawrence Garfinkcl Amcric.in Cancer Society 777'ihird Avenue New York, New York 1001 7 Tavia Gordon Biometrics Research E3 ranch National Heart and Lung Institute Bethesda, Maryland 20014 Gio 0. Gori, Ph.D. Deputy Director Division of Cancer, Cause and Prevention National Cancer Institute Bethesda, Maryland 20014 M.R. Guerin, Ph.D. Tnhacco Smokc Research Program Analytical Chemistry Division Oak Ridge National Laboratory Oak Ridge, Tennessee 37830 Dr. H.P. Harkc Thcodor Fahr Strasse 27 2 Hamburg 62, West Germany Stephen S. Hecht, Ph.D. Div. of Environmental Carcinogenesis American Health Foundation Naylor Dana Inst. for Disease Prevention Valhalla, New York 10595 P. (PANTS Dr. I.T.T. l liggins Professor of Epidemiology School of Public Health The University of Michigan Ann Arbor, Michigan 48104 Pr.tcr Hill, Ph.D. Hcad, Section Lipid Metabolism American Health Foundation Naylor Dana Inst. for Disease Prevcntio; Valhalla, New York 10595 Or. L. Iljcrn Swcdish Tobacco Industry P.O. Oox 17007 5-104 62, Stockholm, Sweden Dictrich Hoffmann, Ph.D. Chief, Div. of Environ. Carcinogenesis American Health Foundation Naylor Dana Inst. for Disease Prevention Valhalla, New York 10595 Walter W. Holland, M.D. Prof. of Clinical Epid. and Soc. Medicine Department of Community Medicine St. Thomas' Hospital Medical School London, SE I 7EH, England William B. Kannel, M.D. National Heart and Lung Institute 123 Lincoln Street Framingham, Massachusetts 01701 C.I1. Kcith, Ph.D. Cclancse Fibers Company E3 o c 1414 Charlotte, North Carolina 28232 Charles J. Kcnsicr, Ph.D. Senior Vice Pres. Professional Operations Arthur D. Little, Inc. Acorn Park Cambridge, Massachusetts 02140

PARTICIPANTS Hubert Klus, Ph.D. Chemist Austria Tabakwerke AG Vienna, Austria Andreas Koch, M.D. Medical Clinic University of Heidelberg Heidelberg, West Germany H. Kuhn, Ph.D. Research Laboratory Austria Tabakwerke AG Vienna. Austria J¢rgen Lam, Ph.D. Chemical Institute Aarhus University DK 8000 Aarhus C, Denmark. Claude Lenfant, M.D. Director, Division of Lung Diseases National ticart and Lung Institute Bethcsda, Maryland 20014 Charles F. Mattina, Ph.D. Peter J. Schweitzer Division Kirnbcrly•Clark Corporation Lee, Massachusetts 01238 tlenry C. McGill, Jr., M.D. Department of Pathology University of Texas Health Science Center San Antonio, Texas 78229 Gardner C. McMillan, M.D., Ph.D. Div. of Hcart and Vascular Diseases National Heart and Lung Inst. Bethesda, Maryland 20014 Margaret Mushinski Division of Epidemiology American Health Foundation 1370 Avenue of the Amercias New York, New York 10019 Thomas B. Owen, Ph.D. National Cancer Institute Bethesda, Maryland 20014 Oglesby Paul, M.D. Vice President for Health Sciences Northwestern University Chicago, Illinois 60611 D. Bhasakara Rcddy, M.D. Principal and Professor of Pathology Guntur Medical College Guntur (A.P.) 522001, India D.D. Rcid, M.D. London School of Hygiene and Tropical Medicine Kcppcl Street London 1VC1, England Ragnar Rylander, M.D. Dept. of Environmental Hygiene University of Gothcnburg 5•400 33 Gothcnburg 33, Sweden FI. Schievclbcin, M.D. Institute for Clinical Chemistry German Heart Center Lothstrasse 11 8000 Munich 2, West Germany Dietrich $chm5hl, M.D. Inst. for Toxicology & Chemotherapy German Cancer Research Center Im Ncucnheimcr Feld 280 D6900 Heidelberg 1, West Germany Vii

PAR . NTS Irwin D. Schmeltz, Ph.D. Div. of Environmental Carcinogenesis American Health Foundation Naylor Dana Inst. for Disease Prevention Valhalla, New York 10595 J.A. Turner Brent Health District Central Middlesex Hospital London NW10 7N5, England W.A. Setkc, Ph.D. Peter J. Schwcit7er Division Kimberly-Clark Corporation Lee, Massachusetts 01238 Steven Stcllman, Ph.D. Division of Epidemiology American Health Foundation 1370 Avenue of the Americas New York, New York 10019 R.W. Sillctt Brent Health District Central Middlesex Hospital London NW 10 7NS, England Donald Tiggtcbcck Dir. of Marketing, Activated Carbon Div. Calgon Corporation Calgon Center, Box 1246 Pittsburgh, Pennsylvania 15230 T.C. Tso, Ph.D. Agricultural Research Service Northeastern Region U.S. Department of Agriculture Beltsville, Maryland 20705 B. L. Van Duuren, D.Sc. Professor of Environmental Medicine New York University Medical Center New York, New York 10016 Nicholas J. Wald, M.D. Cancer Epid. and Clinical Trials Unit* Dept. of the Regius Professor of Medicine Radcliffe Infirmary Oxford OX2 HE6, England R.W. Williams Epidemiology Branch National Heart and Lung Institute Bethesda, Maryland 20014 Ernst L. Wynder, M.D. President and Medical Director American Health Foundation 1370 Avenue of the Americas New York, New York 10019- Bryan F. Zilkey, Ph.D. Agriculture Canada Research Station P.O. Box 186 Delhi, Ontario N48 2W9 Canada

i ix ACKNOWLEDGEMENTS This book is made up of five parts representing the whole spectrum of current scientific knowledge about the Less Harmful Cigarette, what it is, why it is needed, how it can be manufactured and its effect on cancer, cardiovascular disease and chronic pulmonary disease. Expert contributions have been made covering every aspect of the development, chemistry, biological activity and tobacco technology and results of the Less Harmful Cigare:te. I am greatly indebted to each of the participants for the time and effort they put into their papers and, in particular, to the sub-session chairmen and co-chairmen for moderating the sessions so well: Dr. Dietrich Hoffmann and Gio B. Gori (Relation of Smoke Components to Cancer); Gardner C. McMillan and Wiibert 5. Aronow (Relation of Smoke Components to Cardiovascular Disease); Claude Lenfant and Walter W. Holland (Relation of Smoke Compon- ents to Chronic Pulmonary Disease); and T.C. Tso and Hans Kuhn (Technologi- cal Aspects). Special thanks to my co-editors, Dr. Dietrich Hoffmann of the American Health Foundation and Gio B. Gori of the National Cancer Institute and to my coordinating editor, Penny Ashwanden. Grateful acknowledgcment is made to Ellen Rope, Ellen Parker and Kate Stern who assisted in the preparation of these Proceedings. Ernst L. Wynder, M.D. Chairman - Section II New York City, June, 1976

x PREFACE As has been known for decades, smoking, especially cigarette smoking, is. leading cause of unccessary illness in our society. In spite of intensive cduca- tional efforts which have resulted in a broadened awareness of the health haz- ards caused by smoking and led to a significant increase in the numberofPeople who, have given up the habit, many people continue to smoke and many young people continue to adopt the habit. It is our belief that as long as smoking is condoned by society, people will continue to smoke. It is for this reason that scientific investigators around the world have become increasingly interested in ways in which to modify smoking habits in order to reduce the risks to those who continue to smoke. Towards this end, research has been conducted to determine which are the ingredients in the tobacco smoke which contribute to carcinogenesis, cardiovascular disease and chronic pulmonary disease, and which are the precursors in the tobacco itself. With this knowledge at hand, one can then proceed to reducethe carcino- genic and toxic substances from the tobacco and the tobacco smoke; and through combined chemical and biological studies, tobacco products have been produced which seem to be less harmful than those of a few decades ago as has been shown by epidemiological studies. This monograph presents the current state of the art in this scientific and industriai endeavour. Much progress has been made; much remains to be done. It appears to be a 'utopian' goal for man to ever be able to inhale any substance into his lungs which would be as free from danger as unpolluted air. However, since we live in the real world, in spite of continued health education and in spite of improved programs in smoking cessation, many young people will start and many adults will continue to indulge in this habit. It is for this reason that efforts in the development of less harmful smoking products need to be contin- ued in order to contribute to the day when tobacco-related diseases will no longer occur. Ernst L. Wyndcr, M.D.

i xi TABLE OF CONTENTS PARTICIPANTS .........................................v ACKNOWLEDGEMENTS .................................. ix PREFACE x PART I: GENERAL ASPECTS OF THE LESS HARMFUL CIGARETTE The Epidemiology of the Less-Harmful Cigarette .................... 1 Ernst L. Wynder, Margaret Mushinski, and Steven Stellman Chemical Studies on Tobacco Smoke. XXXVIII. The Physiochemical Nature of Cigarette Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Irwin Schmeltz, and Dietrich Hoffmann Reduction of Nicotine and Tar in Tobacco and in Cigarettes Through Agricultural Techniques ................................. 35 T.C. Tso;-Gio B. Gori, and Dietrich Hoffmann Piltration as a Means of Reduction of Tar and Nicotine Levels in Tobacco Smoke .............................................d9 C.h1. Keith Whole Plant Flue-Cured Tobacco and Tobacco Sheet Cigarette Smoke and Smoke Condensate Characteristics ....................... 57 Bryan F. Zilkey Reconstituted Tobacco Sheets ................................ 6'1 Charles F. Mattina, and William A. Selke Tar and Nicotine from U.S. Cigarettes: Trends Over the Past Twenty years .............................................. 73 Thomas B. Owen Changes in Smoking Patterns in the United Kingdom During the Last Two Decades ........................................81 D.D. Reid i Reduction of Tar and Nicotine in German Cigarettes ................ 85 Dietrich Schm3hl

xii TABLE OF I~E(vTS Reduction of Tar and Nicotine Levels of Austrian Cigarettes During the Last 15 Years ................................. .89 H. Kuhn, and H. Kius Cigarette Smoke and Tar and Nicotine Levels in Sweden During the Decade 1964-1974 ................................ L. Hjcrii Recent Stw;ics on Less Harmful Cigarettes at the University of Waterloo, Ontario, Canada .............................. 10 W. H. Cherry Less Harmful Ways of Smoking ............................. 111 Irwin D. J. Bross PART 11: RELATION OF SMOKE COMPONENTS TO CANCER Methodology for Determining Beneficial Effect of Less Harmful Cigarettes on Lung Cancer Risk ........................... 119 Lawrence Garfinkel Chemical Studies on Tobacco Smoke. XXXIX. On the Identification of Carcinogens, Promoters and Cocarcinogens . . . . . . . . . . . . . . . . . . 125 Dietrich Hoffmann, Irwin SchmcltZ, Stephen S. Hecht, and Ernst L. Wynder Chemical Identification in Tobacco Smoke of Carcinogens, Promotcrs anc: Cocarcinogens in Tobacco Smoke ................ 147 H: P. ; larkc Discussio<<- Identification of Carcinogens, Tumor Promoters and Cnc.i:cinogens in Tobacco Smoke .......................... 155 ,M.R. Guerin Chcm;cal and Biological Identitication of Tumorigenic Components ofTubacco ......................................... 161 Fred G. Bock, and T.C. Tso Tumor r'romoting Activity of Agriculture Chemicals ............... 175 Fred G. Bock, and T.C. Tso Ch.-nicai Studies on T obacco Smoke. XL. Identification of Carcinogens : n Tob=cco ................. ....................... 191 Stca hen S. f!c:cht, Lrwir, Schn.c{tt, Dictrich Hoffmann, and Enut L. Wynder N ~- - ~_ _ -- ---- -- -- ~3 - . G~ C17 ~ -t~ CT+

TABLE OF CONTENTS xtu Discussion of Chemical and Biological Identification of Tumorigenic Components of Tobacco ........................ 203 D. Bhaskara Reddy Biological Evaluation of Carcinogens in Tobacco Smoke .............. 204 W. Dontcnwill The Biological Evaluation of Substitute Smoking Materials as Exemplified by 'NSM................................... 221 D.M. Conning Cocarcinogenic and Tumor-Promoting Agents in Tobacco Carcinogcnesis (Abstract) ................................ 229 B.L. Van Duurcn PART Iil: RELATION OF SMOKE COMPONENTS TO CARDIOVASCULAR DISEASE Introduction to Smoking and Cardiovascular Disease ................ 231 Wilbert S. Aronow :titethodology for Determining the Possible Beneficial Effect of a Less Harmful Cigarette on the Risk of Cardiovascular Disease ........ 237 Tavia Gordon Relative Risks of Myocardial Infarction, Cardiovascular Disease and Peripheraf Vascular Disease by Type of Smoking .............. 243 Manning Feinlcib, and Roger R. Williams Epidemiologic Studies on Smoking in Cerebral and Peripheral Vascular D isease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 William B. Kannel Epidemiologic Studies in the United Kingdom on Smoking and Coronary Heart Disease ................................. 275 D.D. Reid Smoking and Peripheral Arterial Disease : ....................... 281 Andreas Koch The Interrelationship of Tobacco Smoke Components to Hyperlipidemia and Other Risk Factors . . . . . . . . . . . . . . . . . . . . . . . 285 Thomas R. Dawber

xiv TABLE ONTENTS Discussion of Dr. Dawber's Paper (The Interrelationship of Tobacc~ Smoke Components to Hyperlipidemia and Other Risk Factors). ... 293 Oglesby Paul The Evidence for Nicotine as an Etiological Factor in Cardiovascular Disease .............................. .297 'Helmut Schievelbein Discussion of Dr. Schievelbein's Paper (The Evidence for Nicotine as an Etiological Factor in Cardiovascular Disease) ............... 19 Henry C. McGill, Jr. Nicotine: An Etiological Factor for Coronary Heart Disease ........... 3 Peter Hill Carbon Monoxide and Cardiovascular Disease ..................... 321 Wilbert S. Aronow Discussion of Dr. Aronow's Paper (Carbon Monoxide and Cardiovascular Disease) .................................. 329 Poul Astrup Studies on Carbon Monoxide and Nicotine........................ 331 Poul Astrup Monitoring of Carboxyhemaglobin in a Cardiovascular Clinic........... 343 R.W. Sillett, J.A. McM. Turner, and K.P. Ball Carbon Monoxide as an Etiological Agent in Arterial Discasc-Some Human Evidence ............................ 349 Nicholas J. Wald Evidence for Components Other Than Carbon Monoxide and Nicotine as Etiological Factors in Cardiovascular Disease............ 363 Gardner C. McMillan Significance of Nicotine, Carbon Monoxide and Other Smoke Components in the Development of Cardiovascular Disease .......... 369 William B. Kannel, and William P. Castelli

TABLE OF CONTENTS xv PART IV: RELATION OF SMOKE COMPONENTS TO CHRONIC PULMONARY DISEASE Long-Term Surveillance of Tobacco Substitutes ................... 383 Walter W. Holland Relative Risks of Various Tobacco Usages for Emphysema, and/or Chronic Bronchitis ..................................... 389 I.T.T. Higgins Types of Tobacco Usaae and Chronic Respiratory D:sease ............. 407 T. Abelin Chronic Disease-The Etiological Factors in Smoke ................. 415 Tore Dalhamn Chronic Lung Disease and Tobacco Smoke Exposure-Concepts on Etiological Factors ..................................... 427 Ragnar Rylander Bioassaying Candidate Less-Hazardous Cigarettes: Methods for Early Detection of Peripheral Airway Dysfunction .................... 433 Louis Diamond PART V: TECHNOLOGICAL ASPECTS OF REDUCING SPECIFIC COMPONENTS IN CIGARETTE SMOKE, AND CONSUMER ACCEPTANCE ~ OF SUCH REDUCTION Chemical Studies on Tobacco Smoke. XXXVII. Determination of Tar, Nicotine, and Carbon Monoxide in Cigarette Smoke. A Comparison of International Smoking Conditions ......................... 441 Klaus D. Brunnemann, Dictrich Hoffmann, Ernst L. Wynder, and G.B. Gori Approaches to the Reduction of Total Particulate Matter (TPM) in Cigarette Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . 451 Gio B. Gori Possibilities for the Reduction of Nicotine in Cigarette Smoke ..........463 H. Kuhn and H. Klus Selective Reduction of Tumorigenicity of Tobacco Smoke. III. The Reduction of Polynuclear Aromatic Hydrocarbons in Cigarette Smoke ...................................... 495 Dictrich Hoffmann, and Ernst L. Wynder i i

xvi TABLE OF qTENTS Discussion: Complexing Compounds Caffeine - PAH ............ . .505 J¢rgen Lam 1 Vapor Phase Smoke Modification-An Under-Utilized Technology .... 507 Donald Tigglebeck Technological Aspects as to Our Ability Toward, and Consumer Acceptance of, Reducing Phenolic Compounds in Cigarette Smoke (Abstract) ........................................... Charles J. Kensler , Cilia Toxic Components in Cigarette Smoke ...................... 51. Sam P. Battista Selective Reduction of Tumorigenicity of Tobacco Smoke. IV. Approaches to the Reduction of Nitrosamines and Aromatic Amines ............ 535 Stephen S. Hecht, T.C. Tso, and Dietrich Hoffmann PART VI: SUMMARY OF WORKSHOP I( RECOMMENDATIONS. ..547 Ernst L. Wynder INDEX ........................................... 555

NOTICE •aY be This materizl ~ prote i ,d by U.S. law (Tit}e r7 THE EPIDEMIOLOGY OF THE LESS HARMFUL CIGARETTE Ernst L. Wynder, Margaret Mushinski, and Steven Steliman Retrospective data on patients with tobacco-related diseases and controls in- dicate a reduced risk for lung, oral cavity and larynx cancers in male, long-term filter smokers and for lung and larynx cancer in long-term filter smoking females. This reduction is due in part to lower "tar" yield of filter cigarettes (the "less harmful cigarette"-LHC) and in part to the increasing number of ex-smokers. Nicotine is implicated in the etiology of peripheral vascular disease and more re- search is needed in the epidemiology of myocardial infarction and emphysema in relation to smoking. Mortality data from England and the U.S. also support the reduced risk for lung cancer associated with smoking the Li-tC and the data indicate a decreasing death rate in the younger cohorts of men. Further refinement of the LHC and its effects are of obvious importance and continued attention should be paid to the effects of these cigarettes on chronic pulmonary disease, emphysema, and heart disease. The tobacco and health problem continues and new approaches are obviously necessary in order to cornbat this public health dilemma. A multi- phased approach is suggested which would include increased anti-smoking educa- tion, increased and more prominent smoking cessation programs and clinics in hospitals and other medical facilities and the further development of a truly less hazardous tobacco product. INTRODUCTION From the very first, epidemiological studies on tobacco-related lung cancer clearly demonstrated that this disease was quite rare among nonsmokers and that its incidence directly increased as the individual's consumption increased (1-3). Similar correlations have been shown for other tobacco-related cancers (4). The established dose-response relationship of these cancers to tobacco smoke exposure has provided the basis for the likely assumption that as smoke exposure decreases, either by smoking less or by smoking a cigarette lower in smoke yield, the risk of developing tobacco-related cancers decreases proportionately. An obvious problem in measuring or predicting the risk of developing cancer is the long latency period between first exposure to a carcinogen and clinical manifestation. Often there is an interval of many years. For example, a long term heavy smoker who gives up smoking has an increased risk of lung cancer for at least ten years over that of a person who has never smoked (5). The average age of a male lung cancer patient today is approximately 60 years old. Since this per- son has been smoking for about 40 years, his smoking history includes a com- bination of the old high "tar" cigarettes and the newer low "tar" cigarettes, with the latter type having been smoked for considerably less time than the former. For this group, therefore, the influence of or relationship between smoking only

2 WYNDER, MUSHINSKI AND -TELLMAN the low "tar" cigarette and the development of lung cancer cannot precisely measured. One must take into account the number of years and inten. v of high "tar" cigarette smoking and weigh this in relation to the length of tin the per- son has smoked the lower "tar" yield cigarettes. Such a formula woulc 'low in- vestigators to determine an exposure level for each individual based or. aecific smoking histories. The effect of this latency period is likely to differ for cardiovascular ~•ents because, for these diseases, at least a portion of the effect of smoking appt. s to be an acute one. The effect may also be different for emphysema, a conc on which seems irreversible, once a certain stage of pathology has been reachec t the present time, no data are available which have measured the effect of sm• ing the less harmful cigarette (LHC) on the development of emphysema. A fc studies have been conducted illustrating this effect on cardiovascular disease more specifically, peripheral vascular disease (PVD). The data available on tobacco- related cancers is more extensive, however. In respect to tobacco carcinogenesis, two major events have taken place re- garding the "less harmful cigarette": a) smoke condensate yields of American cigarettes and, indeed of cigarettes throughout most of the world, have been re- duced during the past 25 years and, b) the carcinogenic activity of "tar," both from filter and nonfilter cigarettes, as measured on mouse skin and reflected by its chemical constituents, is lower today than it was 25 years ago (6, 7). On this basis, one may predict two epidemiological developments: Firstly, the risk of de- veloping cancer for low "tar" (largely filter) cigarette smokers (at least for those who have smoked filter cigarettes for ten years or more) will be lower than for those who have continued to smoke high "tar" (largely nonfilter) cigarettes. Such a reduction would be due to the fact that the "tar" yield of filter cigarettes is generally lower than that of nonfilter cigarettes ( Fig.1). The carcinogenic activity of such cigarettes, however, is not different when measured on a gram for gram basis on mouse skin (8). It should be explained, however, that even those who now smoke nonfilter cigarettes should have a lower risk than those who smoked nonfilter cigarettes 25 years ago because these cigarettes also have a reduced "tar" yield than previously was the case. Secondly, the risk will be lowest for those in the age groups in which the LHC has been smoked for the longest period of time. Thus, when we compare the death rate from lung cancer in the early 1970's with that of the early 1960's, we should observe a reduction or a slower increase among the younger male population and a continued increase among the older male population. Such a change will be less noticeable for women because even though they have smoked the less harmful cigarette relatively more often and for a long- er period than men, there are significantly more women smokers in even the younger cancer affected age group now than there were 15 years ago (9). With these basic assumptions, let us determine whether they can be substan- tiated by available data. On the basis of ongoing studies being conducted in eight cities in the United States, we find that the rates of lung cancer among long-term filter cigarette smokers are somewhat lower for all cancer sites for which we have obtained sufficient data to permit statistical analysis. This includes cancers of the lung, oral cavity, and larynx (Figs. 2-4). We have been able to demonstrate a

EPIDEMIOLOGY OF LESS HARMFUL CIGARETTE 3 FIG. 1. Filter and nonfilter tar yields in U.S. cigarettes, 1958-1973. FIG. 2. Relative risk of lung cancer (Kreyberg 1) for current filter and nonfilter cigarette smokers-men-New York, Los Angeles, and Houston, 1970-1973. wv.n.rv., ro~cro.+o+a~o-tn FIG. 3. Relative risk of oral cavity cancer for male cigarette smokers by number and type of cigarettes smoked daily.

4 4Nr. Iv75 FIG. 4. Relative risk of laryngeal cancer for male cigarette smokers by number and type of - cigarettes smoked daily. , similar reduction in risk for lung as well as for larynx cancer among women long- term smokers of filter cigarettes (Fig. 5) (9). These data, similar to those reported by Bross and Gibson (10), show that filter cigarette smokers of ten years or more have reduced risk of developing lung, larynx and mouth cancer compared to those who have continuously smoked nonfilter cigarettes.This finding can be attributed at least in part to the lower'rtar" yield of filter cigarettes. An additional benefi- cial influence must be given to the finding of an increasing number of ex-smokers. Obviously, the earlier in life smoking cessation takes place, the sooner the can- cer risk is reduced. Thus, more attention should be paid to strengthening the smoking cessation message as well as making such clinics more widely available. .e ~ ®.or rwa. Lq ~~.=0 Z~.Sp .~uyr K+ a.. arettes smoked daily. WYNDER, MUSHINSKI AND FTELLMAN 'Risl reYtM to 1.0 fer ransTae.n ]I. ,s. ,eur..t *o Lo ro+.~ ~ortn FIG. 5. Relative risk of lung cancer for female cigarette smokers by number and type of cig- We are, of course, also interested in determining the risk for individuals who smoke cigarettes of less than 16 mg'rtar." Clearly, there are differences in "tar"

EPIDEMIOLOGY OF LESS HARMFUL CIGARETTE 5 yield among filter cigarettes. In general, the "tar" yield of filter cigarettes has de- creased during the past 15 years. Cigarettes with 16 mg or less of tar, however, have not been smoked by a sufficient number of people for a long enough period of time to give us reliable information on the risks associated with these cigarettes alone (Fig. 6). FIG. 6. Brands delivering 16 mg tar or less-market share vs. year. At present there are no similar data for emphysema nor for myocardial in- farction. Data from the National Heart and Lung Institute suggest that the death rate from myocardial infarction is decreasing (11). If this is the case, it remains to be shown whether this is due to improved treatment of hypertension, reduction of serum cholesterol levels, more ex-smokers among adults now than in the past, or a reduction in the nicotine levels of cigarettes. This result cannot be due to a reduction in carbon monoxide in cigarette smoke because this component has not been reduced in the last 25 years, nor has it significantly differed for filter and nonfilter cigarette smoke. Obviously, the epidemiology of myocardial infarc- tion is relatively complicated because it is related to several known risk factors. We have, however, obtained data on peripheral vascular disease (Fig. 7). These data suggest that the risk of developing PVD is lower among filter cigarette smokers than for nonfilter cigarette smokers-a finding which suggests that nico- tine is indicated in the etiology of this disease (12). Koch has obtained similar 1 data in an independent study in Germany (13). EFFECT ON DEATH RATES The risk• associated with the LHC can also be measured by comparing'death rates from tobacco-related diseases in the 1970's to those of the 1950's and 1960's. According to previous assumptions, such a reduction should be demonstrated particularly for the younger male population. Additionally, a greater reduction should be indicated for men than for women since, as we have previously stated, what has been gained by more women than men smoking the LHC has been lost

6 WYNDER, MUSHINSKI AND STELLMAN 1L7Y4d b:T:RRS fw.6~1 •O. f/VER llllllll,iV•1121 w0 1 • RISK REIATIVE TOIOMG TERM f1lTEP SMOKEIK ..+, nre FIG. 7. Relative risk of peripheral vascular disease for male cigarette smokers by type of cig- arette smoked. by having more women smoke in the cancer susceptible age group than in earlier years. As expected, Figure 8 shows that filter cigarettes have been smoked more by younger people for a relatively longer period of time than older people. ~ Y r » 1+ ..« ..,.. ..,. .~..~ FIG. 8. Distribution of filter and nonfilter smokers among current smokers. Based on British data comparing lung cancer death rates for 1960 and 1971, Doll has shown that these rates are lower for younger cohorts of men (14). Such a trend, however, is only beginning to be seen for women for reasons outlined above (Figs. 9 and 10). Together with Dr. Gori we have compared lung cancer death rates from the United States from 1958 to 1974 and can report similar findings (Figs. 11 and 12) (15). Clearly, the slope of increase in the risk of lung cancer is decreasing in the younger age groups during recent years. While these findings are partly

EPIDEMIOLOGY OF LESS HARMFUL CIGARETTE 7 . M1 W-1 n. n-i b1 z x t R S Y r...aw... ,+.1r: 1 aos-w. nr. FIG. 9. Change in lung cancer death rate in England and Wales, 1960-1971, males by age.* i - ~ 1 S x 3 n .~. e...<. .~.... r~w-w....a FIG. 10. Change in lung cancer death rate in England and Wales,1960-1971,females by age.' related to an increase in the number of ex-smokers in these age groups (Fig. 13), they can only be explained in their totality by the development of the LHC.This is particularly so because the number of ex-smokers in the age group 40-60 has remained relatively constant; although, obviously, the age at which smokers stopped smoking is of importance. - The effect of the LHC can also be studied by examining the tobacco related cancer rates in different population groups, although such evaluation is compli- cated by-the finding that groups that prefer the LHC usually also contain fewer cigarette smokers and more ex-smokers. The lower rate of lung cancer among New York Jewish males is consistent with fewer cigarette smokers, more ex-smokers and more filter cigarette smokers in this population. The contrasting rate of lung cancer among low and highly educated males provides another example. The group of college educated males contains fewer cigarette smokers, more ex-smok- ers, and relatively more long-term filter smokers and fewer nonfilter smokers than the group with less education (Fig. 14). In our present sample of 593 male lung cancer patients, 9.8% were college educated compared with I8% of the hospital

I 8 WYNDER, MUSHINSKI AND STELLMAN 4oo r 6 7 360 h a sor WNRE FEMALES t$60 176s 1sa 1les tl7o1lTJ tsso 1l6a /flo 1MS 1l701l73 FIG. 1 1. Deaths from malignant neoplasm of trachea, bronchus, and lung. matched controls (Fig. 15). In a recent study on larynx cancer the differential by education was similar. IS THERE A SAFE CIGARETTE? From a theoretical point of view, it is unlikely that man will ever be able to inhale any substance, other than unpolluted air, without at least some possibility of its being injurious to his health. On the other hand, it appears realistic to as- sume that if the inhalation of respiratory, irritants does notexceed certain dosages, and if these are limited to components known to have minimal activity at a given dosage level, then it is possible for one to inhale substances such as tobacco smoke up to such a dose without producing a measurable health effect. The attainment

EPIDEMIOLOGY OF LESS HARMFUL CIGARETTE 9 a w 4.0r as iSl m ww aa u 1.9 1.0 0 E 0 .1 i .1 FIG. 12. Five-year slopes change in death rates from malignant neoplasm of trachea, bron- chus, and lung. 1 p ~ W tI1 ~ -Fs w Wlltt£ MA1Ft FIG. 13. Distribution of smoking status among male controls by decade (N = 4225).

10 WYNDER, MUSHINSKI AND STELLMAN <wtt 1•••f])1 Q.N.wwnc _ra~bOH..'.• awact ~ •t Iw.)y1 FIG. 14. Distribution of smoking status among male controls (aged 40-80) by educational attainment. FIG. 15. Distribution of educational attainment for lung cancer cases and control. of such a"negiigible" risk is, of course, what all of those working in the area of the LHC are striving for. In establishing such a cigarette, it is obvious that we must separate its effects on chronic pulmonary diseases, such as emphysema, from cardiovascular diseases and from the various tobacco-related cancers. Because our experience at present, in tobacco carcinogenesis is greater than in the other areas, let us discuss this con- cept from the point of view of carcinogenesis. As we have presented, experimental- ly and epidemiologica{ly, it has been well demonstrated that there exists a dose response relationship between exposure of tobacco smoke and the development of cancer. As early as 1950 we showed that individuals smoking 10 cigarettes or less per day had a relatively low rate of lung cancer (16). Experimental studies reported on in 1957 showed that no tumors resulted when 2.5 or less grams of tobacco "tar" per year were applied to the skin of mice (17). Our most recent epidemiological data suggest that individuals having smoked low "tar" filter ciga- rettes up to 20 per day may have a risk not much different from those who have never smoked, provided they have not previously smoked cigarettes with high "tar" yiefds. As expected, these data indicate that there exists a dose level at which ciga- rette smoke, with its relatively weak carcinogenic properties, does not increase

EPIDEMIOLOGY OF LESS HARMFUL CIGARETT'E 11 the risk of lung cancer or other tobacco-related cancer to any measurable extent. Undoubtedly this dosage level depends not only on the "tar" yield of cigarettes, but also on the manner and duration of smoking, as well as on the chemical make- up of the "tar: " One purpose of the epidemiological studies now in progress meas- uring the risks of tobacco-related cancers and other tobacco-related diseases is not so much to precisely determine the threshold level for tobacco carcinogenesis, but rather to determine what in a practical sense this level is. It may well be that this threshold level is relatively high for tobacco-related cancers, lower for tobacco- related cardiovascular diseases, and lower still for emphysema. Significant efforts in the area of the LHC should be directed not only to a continued decrease in "tar" and nicotine yields which, from a practical point of view, must be consonant with whatever satisfaction is seemingly derived from smoking, but must also be directed towards identifying the specific components in the smoke and their pre- cursors in tobacco itself that are responsible for the various tobacco-related dis- eases so that they can be selectively reduced. CONCLUSIONS Work of those concerned with tobacco-related diseases should no longer be directed so much towards determining whether tobacco usage initiates these dis- eases, but should better emphasize the identification of smoke components re- sponsible for these diseases and the dose level at which these cigarettes would be relatively "safe." It is hoped that these studies, which require the cooperation of private investigators, the Department of Agriculture and the tobacco industry, will lead to the day when man will obtain the factors he seemingly receives now from smoking without risking his health. In spite of our efforts towards these goals, we continue to recommend strong- ly that young people do not begin the smoking habit and that all physicians and health care centers encourage and appropriately assist adult smokers to cease the habit. However,, we are realistic enough to recognize that as long as society con- dones smoking as an acceptable habit, a great number of young people will start and older people will continue to smoke. In science, as in so many other areas in life, while striving for the ideal, one must usually settle for that which is realistic. We therefore suggest a continuation of a multiphased approach to the tobacco- health problem to include (1) anti-smoking education, (2) smoking cessation pro- grams, and (3) the development of less harmful smoking products. It is through these methods that we hope to advance the day when tobacco-related diseases will be confined to an absolute minimum, the principal goal of all involved in to- bacco and health research. ACKNOWLEDGEMENTS This study is in part supported by NCI CA-12376-04 and ACS CI-175Q.

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