Tobacco Documents Online

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SCIEIMFIC ADVISORY BOARD to the Tobacco Industry Research Committee KENNETH MERRILL LYNCH. M.D., Sc.D., LL.D., Chairman President, Dean of Faculty and Professor of Pathology Medical College of South Carolina Charleston. South Carolina RICHARD 1. BING, M.D. Professor and Chairman. Department of Medicine Wayne State University College of Medicine Detroit. Michigan McKEEN CATTELL, Ptt.D., M.D. Pro%sror Emeritus of Phurnmcology Cornell University Medical College New York, N. Y. JULIUS H. COMROE, JR., M.D. Director, Cardiovascular Research Institute University of California Medical Center Sar. Francisco, Ca!ifornia LEON O. jACOBSON, M.D. Professor of Medicine. University of Chicago Dirtctor, Argonne Cancer Research Hospital Chicago, Illinois PAUL KOTIN, M.D. Professor of Pathology University of Southern California, School of Medicine Los Angeles, California CLARENCE COOK LITTLE, Sc.D.. LLD., Lrrr.D. Scientific Director, Tobacco Industry Rexarch Committee Director Emerinrs, Roscoe B. Jackson Memorial Laboratory Bar Harbor, Maine STANLEY P. REIMANN, M.D., Sc.D. Scientific Director Emeritus, The Institute for Cancer Research Director Emeritus. The Lankenau Hospital Research Institute Philadelphia. Pennsylvania WILLIAM F. RIENHOFF, Jtt., M.D. Associate Professor of Surgery Iohr.s Hopkins University School of Medicine Baltimore, Maryland EDWIN B. WILSON. Ptt.D., LLD. Professor Emeritus of Vital Statistics Harvard University Cambridge. Massachusetta ROBERT C. HOClCECT. Ytt.D, Associate Scientific Director

Current Status of Tobacco-Health Studies Preface The c/fort to obtain new knowledge of the origin and nature of the so-called constitutional or chronic diseases is widc-spread. What are the problems? What has been accomplished and what rc- mains to be sought for, discovered and analyzed? Very evidently no complete answers to these questions can yet be given. One may, however, comment on certain evidence of progress and discuss trends and prospects that seem to be worthy of attention. It is hoped that this Report will serve to maintain and stimulate inter- est in, and support of, the vast amount of research that still needs to be done before our knowledge and techniques can control or prevent these diseases. n ~ ~ :.. As Scientific Director. I should like to acknowledge the devoted and unselfish efforts of my associates on the Scientific Advisory Board and also the cooperation and creative contributions of our grantees and scientific consultants. I should also like to emphasize again the vital part in our whole effort played by all members of the Tobacco Industry Research Committee in providing complete freedom of planning and action to those who are responsibk for its scientific researeh program. M C. C. Little Scientific Director The past year has produced an interesting and provocative situation arising from the activities of different research workers independently in- vestigating the pocsible role of smoking as one of many factors being studied in human health problems. What happened in 1959 was the appearance of many more research findings and comments clearly showing the uncertainties and divergence of opinion among doctors and scientists in regard to tobacco and health. Diversity of research problems and speculation about them have existed since 1954, but in the past year they became more marked in articles and discussions referring to smoking. These things, of courae, often characterize any phase of a complex research problem and seem to arise especially at the stage when the urge to solve any problem exceeds the knowledge necessary to enable us to do so. This is not a cause for alarm or fundamental disturbance of any kind. It is the reflection of natural evolution of our knowledge of the prob- lem and its effect upon the thinking of the people engaged in efforts to find its solution. TAEORIES ABOUT TOBACCO As an example of such evolution, we may cite several theories that have been postulated in attempts to explain the limited data that appear to indicate the supposedly harmful effects of smokhtg, especially with respect to cancer of the lung. On present evidettce, any one or some combination of these concepts, or of others yet to be oReted, may be true, or none of them may be. Among these theories are: Tbeory I. T6ere are those seho amRg•e.t there may be rorrino- Rentc .nb.tmrrr. ln to6ecco aeroitce that might enu.e human lung .reneer by dlrtet aetion. Practically the only support for this theory is the reaction of the skin of some laboratory animals, notably certain mice, to the application of concentrated condensates of tobacco smoke produced by one mechanical device or another. Nowever, no substance has been found in tobacco smoke in quantitiet sulTicicnt to account for even the mouse skin reactions that have been re- ported. Also, there are many reports of mouse skin-painting experiments that did not result in tumors. 5

--~ ~ ~ .. 70 ~ M .~ 0 0 ~ F_+ ~ 00 ~ CJT Repeated experiments in this country and abroad in which laboratory animals were induced to inhale tobacco smoke hovi Joiled to produce a single lung cancer of the type that is prevalent In man. It is generally accepted that lung tissue of mice is more comparable to lung tissue of man, and that smoke directly applied to the target tissue by inhalation is more like the actual process of human smoking than is the application of heavy doses of smoke condensates to mouse skin. There has been growing reaogrtition of the importance of the so-called negative evidence obtained from inhalation experiments. The work of Passey, described in the report of the British Empire Cancer Campaign. issued in the summer of 1959, made this clear and gave actual instances of the experimental work done. Scientists and the public will recognize that there is more direct and applicable evidence in this inhalation research than in the mouse skin-painting type of work. Theory 2. Some persons hold that smoke may aet as an Irrl- tant contributing to the increased probubillty of mdlRnant cbanRes that primarily result from other Intracellalar factors. This theory, essentially based on the assumption that tobacco may have a contributory eRect, has not been studied to any great degree and therefore needs further exploration and testing. The various methods of assaying the effects of tobacco smoke must be investigated further to find out whether the responses of the target tissue are specific for tobacco smoke, or whether they represent a general reaction that may be started by a number of different internal and/or external agents. Theory 3. Some suggest that excessive smoking prodacYs a "general debility" that Inereeses the probability and kadene the appearance of a.nhole array of patlmRenle phenomena. The term "general debility" is a loose one, and supporters of this idea are unable to ddlne it. Debility may be caused in different people at different times by different dreumstances and different agents. It may describe different types and degrees of Internal disturbance and unbalance. Also, "excessive smoking" and "excess" in any other human habit are further variables that make this theory difficult to prove or to disprove. or even to define In a concrete and andyzabk form. What may be "excess" for one person may not, in any appreciable ..ay, affect the physiology d another. If tobacco Is to be classified in the category of agents that produce "genenl debility;" it -will join a whole host of other agents and inAuencett that presumably can do the same. To separate the supposed effects of tobacco from effects of other things will 6 i be a most difficult task and will require a great deal of planning and s-- cumulation of fundamental research to find out what really art the best methods of assay. This particular concept seems to have originated in an effort to intei- pret the reported statistical association between tobacco use An:f vsri.'us ailments for which there was no satisfactory evidence of direct causation. Theory 4. The degree o/ use of tobacco may be dlnlner.ir of types of persoris to/4o Moe different health risks broanse of their Innate natare, or their rete of 11r. 1nR and reoetlons to flie oarlons pliyslrel, mrnrnf and enwtlonal ehdlenRes and stresses of life. The data concerning this theory have been accumulating rather rapidly and from a number of different sources. One is the continuation of studies of human twins, both identical and non-identical, that indicate a constitu- tional factor that may influence smoking habits. Recently four Swedish scientists published a study that in many ways paralleled one Sir Ronald A. Fisher reported last year. Their study came to the same conclusions that he did, namely, that identical twins more often had the same smoking habits than did non-identical twins, even though the degree to which both types of twins encountered a similar environment was essentially the same. Other data have come from several types of psychological tests that are being given to "captive" populations of people to find out the mental and emotional traits of smokers and oompare them with those of non- smokers. A recent paper reported on certain significant mental and emo- tional differences between the two categoriea. Although its author did not interpret it as conclusive that the type of persott is an impottant factor in the situation, the fact remains that a difference was demonstrated. This difference will have to be explained and evaluated along with other asso- ciations of a statistical and aemi-statistkal nature. This last theory really Indicates that "excessive" smoking is iympto- matic of a certain type or types of penon and Is not a prime N•tor in creating or establishing the types of persons who are bad health risk.. Therefore, it is not so appealing to those who are pledged to suMtantiat:nr a causal relationship. We find that we now have at least these four theories, the sMotnte and relative importance of which is uncertain or unknown. We d+. not know, and that is the Important thing to remember. Further reerarch is needed. The present situation Indicates this ttneqoivocafty, and It f•,.n••s the wisdom of the attitude of scientific conservatism. 7

~ ~ ~ . ..~. . ~ 0 0 ~ t'* 5e~~ I-+ 00 I ~ ~ OBSERVATIONS ON RESEARCH in the 1958 Report it was pointed out that the proponents of the theory of a tobacco link to lung cancer had rested their claims on a "tripod" of data - statistics, pathobgy, and animal experimentation. In the past several years each. leg of the "tripod" has been subject to more and more analysis by independent investigators who have pointed out the weaknesses, deficiencies and even contradictions in the results. gtatistka During 1959 additional statistical material reporting an association between smoking and certain causes of death appeared to be much the same as earlier data. There was considerable criticism of the conclusions drawn from this type of statistical work when the original data appeared and this criticism has continued. Two individuals in particular have for some years been closely analyz- ing and commenting on the statistical work and the over-interpretation of it that has been so well publicized. These are Dr. Joseph Berkson, head of the Section of Biometry and Medical Statistics at the Mayo Clinic. Rochester. Minn., and Sir Ronald F'nher, a former Arthur Balfour professor of genetics at the University of Cambridge, England. Dr. Berkson, a member of the American Cancer Society committee that sponsored a numerically large statistical study of smoking and death rates, has published several papers relating to statistical investigations of tobacco and lung cancer. He has said that it was premature to claim on the basis of statistical findings that smoking causes cancer of the lung. Cancer Biologic ProMeny Not Stati.t4+at Cancer, according to Dr. Berkson, is basically a biologic, not a statis- tical, problem, and the statistical conclusions would have to be corrobo- rated fully by experimental and direct observational studies before they could be considered to be scientifically established. There is, he said, virtually no substantial clinical, pathologic or other direct evidence that smoking is the cause of lung cancer. Sir Ronald, in a recent pamphlet containing his various published papers and kctures dealing with smoking, comments pointedly on the statistical work of two British investigators whose data indicated that in- halation of cigarette smoke actually seemed to diminish the chance of lung cancer in the population studied. Sir Ronald, in commenting on this, has aid: "There- is nothing to stop those who greatly desire it from believing that lung cancer is caused by smoking cigarettes. They should also believe that inhaling cigarette smoke is a protection. To believe either is, however, to run the risk of 8 t failing to recognize and, therefore, failing to prevent other and more genuine causes." Statistteal Data 'Logically lnieenipetewt' Other pertinent remarks on the statistical studies have come from Dr. Horace W. Nonon, professor of statistical design and analysis at the Uni- versity of Illinois College of Agriculture, who described the present data on smoking and lung canoer as "logically inoompetent." He further wrote in a recent published communication: "I make a plea for integrity on the part of those affirming that smoking causes lung cancer. Let their various papers and public statements include (1) a frank ac- knowledgement that any such affirmative conclusion is a mere opinion and (2) a familiar standard of comparison, choosing something over which we have, or ought to have, some voluntary control, such as the death rate asso- ciated with the use of the automobile." Additional significant comments have been made by Dr. ). Yeru- shalmy, School of Public Health, University of California at Berkeley, and Dr. Carroll E. Palmer, U.S. Public Health Service's Tuberculosis Program, in a discussion of the statistical work in a rcctnt article on the methodo!ogy of investigations of etiologic factors in chronic diseases. The large number of smokers who do not have lung cancer "testify to the insufficiency of smoking as a cause of the disease," they wrote, noting that "the existence of lung cancer patients who have never smoked clearly indicates that smoking is not a necessary cause." A great deal of research needs to be done to flnd out where the truth lies-if, in fact, it lies in any of the existing conjectures, which it very well may not. There is growing support for the point of view that the statis- tical association claimed by various studies has an explanation or explana- tions that may still not be apparent from our present knowledge. Patholo}ry The second leg of the tripod-pathology-has rested on very limited material. On the basis of a relatively few cases, It was claimed that the lungs of smokers contained characteristic ksions, or spots of damaged tissue, that were considered to be precancerous conditions. In fact, these spots were called "carcinoma in siru" (localized cancer)-in itself a confused and contradictory term. Very early, the Scientiflc Advisory Board to the Tobacco Industry Research Commiitee sponsored a long-time study of the pathology of human lungs by 12 leading pathologists in different parb of the country. All these pathologists found various lesions frequently in lungs of non-smoken as well 9

~ M as in smokers, in persons of both sexes and of all ages and of different places of residence. They did not believe that these Iesions were indicative and diagnostic of precancerous conditions. Confirmation of the need for caution in int4rpreting such studies came this year from Cunningham and Winstanley in England. In pathologic studies of human lung tissues, they were unable to confirm findings of "car- cinoma in situ" or of an association of certain other changes with the smok- ing history of the patients. Aninul Experin.entatbn The third leg of the tripod, animal experimentation, has relied mostiy on continued studies in a few laboratories. It has been reported that repeated painting of condensates of smoke on the skin of certain strains of mice was followed in some of these animals by overgrowth of the skin and, sometime, by cancer of the skin. From such data, it was argued by a few that there might be substances carcinogenic to people in the smoke condensates and, therefore, by inference, in the smoke of a cigarette as consumed by a smoker. On the basis of these animal painting experiments, the theory was pro- pounded to the effect that if the solids in cigarettes smoke were reduced, the amount of skin cancer on mice would be reduced, and the chance of human lung cancer would be similarly reduced. However, an attempt at quantita- tive extrapolation from mice to man would exceed scientific limits. The continuing reports of failure to induce lung cancer in animals with direct inhalation of cigarette smoke itself are considered by many to be more significant than skin painting, because smoke itself is utilized and the tissue challenged is lung, not skin, tissue. In any event, these results have called for a re-evaluation of the smoke-condensate, skin-painting arguments on which, up to now, the whole "third leg" of animal experimentation has rested. Qreatbw o/ A!r Po11.Now Experimental work has indieated that adverse effects on health may result from the prcsence in man's environment of "smog" or combustion products of gasoiine, oil, gas, coal, or other air pollutants. Of course, the existence of these factors does not mean scientists should disregard tobacco and other factors-iither internai or externd-in their investigations. How- ever, the fact that there are other* suspects in lung cancer, cardiovascular disease, and other ailments should conceivably affect and modify the over- interpretation with regard to tobaoco. . A rcotnt study In South Africa suggests air pollution may be involved in the causation of lung cancer. A report by Dr. Geoffrey Dean, published in the Brftish Medlrnf lournul, noted that white male South Africans have i long been the heaviest cigarette smokers in the world and yet they have a relatively low lung cancer mortality rnte. His study, based on 1947-56 male lung cancer deaths in the Union of South Africa by age, country of birth and place of residence, showed that British immigrants to South Africa had much higher lung cancer mortality rates than Union-born men or immigrants from other countries. Dr. Dean said: "The relatively low incidence of lung cancer generatly among the heavy-smoking South African men, the higher and rapidly in- creasing incidence in the growing cities, and the high incidence In the younger age group of immigrants from Britain found in the present study, suggest that the air pollution which occurs in modern industrial life - smoke, smog, traffic fumes, etc.-may be a major factor responsible for the alarming increase of lung cancer in South Africa and Britain, and presumably elsewhere." Dr. Dean's findings are similar to those reported three years ago by Dr. David F. Eastcott, assistant director of the National Health Institute of New Zealand. Dr. Eastcott also found that immigrants from the United Kingdom had a higher incidence of lung cancer than native-born persona of the same stock and that differences in tobacco smoking did not seem to be involved. There is, therefore, an obvious and pressing need for Investigating the possible role of such air pollutants in lung cancer and other diseases. The existence of !hese and other suspected factors Justifies the attitude of bal- anced scepticism toward claims that the problem Is solved and the itsistence on further research adopted by the Tobaeco Industry Research Committee and others. The T.I.R.C. Research Program BASIC PRINCIPLES Certain basic principles influence the long-range planning of the Sci- entific Advisory Board, which is reaponsibk for the recommendations for distribution of research funds from the T.I.R.C. TlKse principles are broad and presnmabfy admissible by all those interested in advancing knowledge of the cause and prevention of those constitutional or chronic diseasd attributed by some, at least in part, to tobacco use. Lung cancer and cardiovascular di.sease are at present emphasized in the T.i.R.C. program, but other diseases nnd research problems also are included. IN+ 00 10 11 -1

Cancer and cardiovascular disease are due-to changes in the cells and tissues of living people. Both commonly occur after a person has lived for a number of yean, and sometimes after a great number. There are wide and unexplained individual variations and susceptibilities in this respect. Cancer is usually microscopically local in origin, i.e., in a single cell. Cardiovascular disease commonly originates as a result of changes in tissue or system of tissues, i.e., thousands of millions of cells are simultaneously or coordinately affected. The origin of each category is extremely complex and is undoubtedly due to many independent and interacting causes. It must be recognized and admitted that our knowledge in these fields is markedly imperfect and de- ficient. The multiple causes and influences may operate in different degrees, in different order, and with different relative importance in different human individuals. These general principles should constantly be borne in mind by those supporting research in either fiehd, by those doing and interpreting the re- search, and by those informing the public about prevention, causation, treatment or cure. Because of the number and variety of these principles, research pro- grams should be diversified in order to advance our total knowledge with the greatest possible speed and balance. Any one phase of research or re- search approach is, by the very nature of the diseases, limited in its poten- tial value and in its application to the total problem. FACTORS IN CANCF,R-CARDIOVASCULAR DISEASE Broadly speaking, cancer and cardiovascular diseases involve at least the following fields: C) ~--~ ."~ .~a I~+ t70 00 1. Heredity-what effect does it have on the biochemical and genetic nature of the individual? Some individuals in the same en- vironment develop these diseases while others do not. 2. InJectron-how much do bacteria and/or viruses, either present or previously experienced, influence cell or tissue changes? To what extent do they increase the risk of later disease? 3. Nutrition-how much do the various nutritive materials taken, absorbed, stored or excreted by the individual affect cell or tissue changes? Claksterol Is one substance now under extensive in- vestigation, but vitamin deficiencies and other unbatances may be important. 4. Hormonea-how much do the products of the various glands of internal secretion, transmitted by the body fluids, affect cells or tissues either by amount and rate of secretion or by unbalance? It is known that they have an important role in breast cancer and adrenal cancer, and that men have four to six times as much lung cancer as ..omen. 12 5. Nervous strain or tension-how much do these factors in- fluence the activity and function of cells and tissues of various systems of the body other than the nervous system itself? Ulcer is recognized as a disease in which stress is important. Stress is apparently also in-. volved in cardiovascular disease. 6. Environment-how much do physical or chemical compo- nents of the environment, introduced as foreign non-living agents. affect the cells or tissues? Air pollutants, inradiation, humidity, tem- perature, tobacco, occupational exposure and possibly other factors are involved in this question. Studies of these fields are important to obtain a better and, eventaaQye a complete understanding of cancer causation, and all, or a majority of them, are similarly to be considered in the causation of cardiovascular disease. The Tobacco Industry Research Committee has supported and initiated research in these fields and will expand Its activity as opportunity arises or can be created. DEVF.LOPING LINE;S OF RESEARCH In the past, certain lines of research have been mentioned that seem to give promise of contributing knowledge essential to the understanding, analysis, and eventual solution of some of the major problems related to the cause and development of the constitutional or chronic diseases. These lines of research include: l. Ti..r.r Culture The training of fellows and the development of techniques in in v(rro culture of human lung tissue have proceeded satisfactorily at Johns Hopkins University, the University of Nebraska, the University of Texas, and the Albert Einstein School of Medicine. The discovery by a researcher of at least one entirely synthetic culture medium for mammalian tissue is a welcome and long-awaited key that should open the door to a whole new order of qualitative and qutMtitative analysis of the phenomena of growth in both normal and neoplastic tissues. 2. Slona.ev Distinct advances have been made in Initiating large-scale research designed to provide the careful controls ewntial to successful, quantitative standardization of such widely used methods of assay as skin painting or injection with various agents. Assay by rate of growth of, or reactions to, transplanted normal and neoplastic cells and tissues of known genetic nature in genetically controlled hosts is also well under way. The effects of known challenging agents on the survival of pure clones of Paramecium are also being investigated In the hope that such assay may 13

I n ~--1 ~ 0 a I F~+ 00 GD prove to be a rapid, effective, and convenient adjunct to other types of assay. Comparative results of several different types of assay, when the same agents are used in each, may well contribute significantly to our ability to understand the total process of assay more completely. 3. In/f..rnrr.s o/ Conerrrrnt or Previous In/rcttow The question whether neoplasia may occur at or near areas of infec- tion has been raised by many investigators over a considerable period of years. There are at least two broad fields of interest involved that are being investigated both experimentally and clinically at present. A. Do areas of tissue, damaged or altered by previous infection, become subject to malfunction of intercellular or inter-tissue ex- change? Could this in turn lead to chemical unbalance ~resulting in intracellular change or mutation from a normal to a neoplastic type in adjacent or surrounding tissueT B. Do invasive agents, such as non-pathogenic or latent or par- tially inactivated viruses, exist in non-neoplastic cells and, if so, what capacity do they possess for transformation to an active state within the cell that leads to its uncontrolled division? 4. Pryrho.ornotit In//ntner. There has been a continuing growth of interest in the psychosomatic aspects of smoking. The number of discussions and publications in this field has increased markedly, as have plans for, and inception of, new re- search. This indicates that the output of research and its importance in obtaining a well-rounded picture of the smoking habit will grow. There are and will be many difficulties in the development of this field on the basis of direct, observational, and experimental methods. Some of these difficulties will be inherent in the nature of the human material used, such as the establishment and maintenance of adequate fol- low-up techniques so necessary to longitudinal studies. Others win involve careful evaluation of various methods of recording and assaying various psychologieal or ptpchosomatic characteristics and proce,csa. Even now it Is possible to reach certain general conclusions on the relation of behavioral traita to the incidence, deveiopment, and course of the eonstitutional or chronic diseases. It should be recalled that it is chiefly in that group of diseases that certain statisticians have reported association between "excessive" cigarette smoking and pathogenesis. S. Gewer4lw/f.ew.ea The genetic influence is often misunderstood and misinterpreted. For example, it seems to be a eomntOtt error to expect that the genetic (innate) element or factor in this complex problem will be a single, clearcut. Men- 14 delian gene for "smoking" or "non-smoking"; for "lung cancer" or for "r.o lung cancer"; for "cardiovascular disease" or for "no cardiovascular disease." The observed behavior traits of individuals in relation to these dia- eases preclude the existence of a simple uni-genic relation as being of prime importance. Statements of this kind regrettably have led a number of individuals to discount oll genetic influence and lose interest in the evidence of complex but nonetheless real genetic influences at work. This is, of course, a tragic error in analytical technique. Studies of twins, as well as of various psychological ane1 pmotinnal traits, show lhat there can be strong genetic predeliction to certan abilitirs, skills, and reactions. These genetic influences often differ in strength and in tenacity of recurrence and of expressicm--even when en.3r.mancqltal factors are held constant. Individuals may still differ in resfxmse because of their innate characteristics. To complicate matters further, the environment, and the challenges that it presents to implement or to obstruct the development and expres- sion of innate characteristics, usually change radically in various ways, tempos, intensities, persistence, and degree. Some genetic responses occur with clarity and definiteness when the environment presents a clear and fixed challenge. This situation is, however, the marked exception. Much more often there will be counter- play and interplay of the innate and of the environmental influences, re- sulting in a changing, living competition. At one age and under one set of circumstances the innate influences may be in control, while at another age and under different circumstances, environmental influences may determine what occurs. There is no doubt that different individuals have different inherited tendencies to develop at certain rates in various tissues and organs. There are hereditary tendencies for different organs and tissues to age at different rates. All of this complex internal balance and counter balance affects susceptibility to pathogenic changes and disease. 6. Stratn or Ten.lon The stress or tension factor is beginning to assume more importance. This factor appears.at times to be associated with the smoking habit. Also, it is well recognized as a predisposing and/or contributory factor to cer- tain diseases. In evaluation of the strain-tenaon factor, it Is well to remrmbex that sensitivity to recognition of strain varies greatly In individuals. Sn do reten- tion of the effects of strain and of neuropltysioloEical reaction to it. 15

Y n ~ ~ 0 ~ CG O 0 The genetic makeup of the individual and the type and strength of environmental stimuli are again the factors that determine behavior reac- tions to strain, tension, fatigue, frustration, competition, and a whole host of the component problems of modern life. The rate and amount of cigarette smoking follow very closely the exposure of certain individuals and populations to situations involving increasing or decreasing stress and strain. For exampie, in World War 11 there was a marked rise in per capita cigarette consumption both among civilians and military personnel. There is evidence suggesting that the smoking of an individual is deter- mined by his inner reactions as shaped by extremely complex and varied genetic and environmental factors. In other words, the smoking habit may be a rt/frction of traits rather than a determiner of them. This subject de- scrvcs further exploration. SUMMARY AND CONCLUSIONS It will be readily .een from the discussion of various aspects of to- bacco and health that the subject is broad and the problems complex. The fmportant point Is that an amrmulation of amounts of circum- smntiaf or inferential data Is nor a substitute for experimentaf and clinical evidence bastd on direct observation. On December 12, the lournal of the American Medical As.rociation, eommenting editorially on "Smoking and Lung Cancer," said: "Neither the proponents nor the opponents of the smoking theory have sufficient evidence to warrant the assumption of an ali-or-none authoritative position." There are many persons, both intelligent laymen and scientists, who will agree with that statement. They will not accept a simple cause and effect relationship in cancer and cardiovascular disease unless such a relationship can be proved by something more than disputed statistics, transferred inter- pretation from animal work, or limited autopsy findings. Neither will they reject a possible rok for tobacco along with other environmental exposures. until evidence permits a true evaluation. BelirJs Upheld Br Past F,:prri.nces The experiences of the past six years amply justify and support these beliefs held by the Tobacco Industry Research Committee and others: 1. Any rok of cigarette smoking in lung cancer and certain other diseases has not been proved m causative. 2. If tobacco has any role, it is uncertain, unidentified, and un- analyzed. 3. Much more teseareh is needed to help clarify and define the 16 significant problems, and to determine the best way to find the answers to them. 4. A/f evidence, including that which demonstrates the Rapc and uncertainties and contradictions in our knowledge, should be pre sented to the public honestly and fully. The individual can form his own considered opinion only on the basis of compf.•te in/ormation. A Balanced Attitude The Tobacco Industry Research Committee believes in the creation ' and maintenance of a balanced attitude toward the tobacco and hewlth situation. It does not believe that the situation has been solved, that the prob- lem has been taken care of, and that the answers are known. We do know that the problems in cancer and cardiovascular diseases are tremendously complicated and the chance of finding a simple answer is small or non- existent. Let us be perfectly sure of what we call established causal factors, and let us be honest in our evaluation of what we advocate-of the soundness and value of evidence--before we attempt to convince the public of any proven guilt or lack of guilt In any widespcead human usage or custom, whether tobacco use or something ebe. While this attitude has been criticized by a few as being obsttvctive, it is actually, from the long-time point of view and for the good of science and humanity, far from being so. It is much better to proceed accurately and slowly w results that will last, than it is to proceed sensationally and rapidly to tentative conclusions and part-truths that may later have to he abandoned. The Tobacco Industry Research Committee will insist on continua- tion of conservative, objective, and painstaking research on which to estab- lish and extend human knowledge in fighting the constitutional diseases. These diseases are and will be man's great peacetime survival problems. 17

Results of Research The progress of the research program has been reflected in a con- stantly growing number of published papers that are abstracted individually and listed elsewhere in this Report. Nevertheless, in order to provide some perspective of the plan and scope of the program and of the prescnt state of knowledge, it seems pertinent also to summarize the findings and tech- niques in several important fields of investigation. At some points the sum- maries may touch upon work whose results have not yet been published in full. Naturally, not all the work under way or completed is discussed here. These summaries are: 1. Smoke Inhalation Studies; II. Lung Pathol- ogy; III. Carcinogenicity and Bioassay; IV. Tissue Culture; V. Cardiovas- cular Research; V1. Psycho-physiological Studies, and VII. Miscellaneous. I. Smoke Inhalation Studies The T.I.R.C. has sponsored a number of studies in which experimental animals were induced to inhale cigarette smoke. Some of these are far enough along to indicate certain findings. In one study scientists exposed mice of two strains to cigarette smoke inhalation in a machine which controls the puffing conditions to simulate closely the manner of human smoking, for periods approaching the entire normal lifespan of the animals after weaning. No lung cancers of the type prevalent in humans were produced. Lung adenomas of the type that occur naturally in these mice occurred no more frequently than In unexposed mice. Another researcher studied the effect of smoke inhalation by CF, mice which were also painted on the skin with the potent carcinogen, methylchol- anthrene. No synergistic effect was observed. In a third study two scientists set up the necessary machinery for intro- ducing fresh cigarette smoke directly into the lungs of dogs through artificial openings in their tracheas. The smoke was produced under carefully con- trolled conditions of puffing volume, duration and frequency in order to assure that the composition of the smoke would resemble closely that of smoke normally inhaled by humans. The study was continued for more than three years and individual dogs received smoke of 10-20 cigarettes daily for many months. No lung cancers developed. In another laboratory sdendlb have tefttetly'nudertaken to subject mice to cigarette smoke Inhalatiott ftR teoAkwMt difletent purpose. Having found that the susceptibility of mice to lung adenomas of the type that can be induced by feeding them urethane depends upon the supply of niacin, they wish to determine whether any ingredient of tobacco smoke can influence the effective supply of this vitamin either directly or indirectly. Another investigator has done the most extensive study that has been sponsored by T.I.R.C. on effects of cigarette smoke inhalation by mice. Groups of female CF, mice were exposed five times a week to the smoke from four to six cigarettes over a period of nearly two years. No invasive carcinomas of the lung were found, although some mice developed a bron- chitis. The occurrence of adenomas in these exposed animals was no greater than that normal to the strain without smoke exposure. Il. Lung Pathology Work in the field of lung pathology has been of two types: studies of human lung tissues acquired at autopsy, and studies of animal lungs follow- ing controlled smoke exposure. STUDIF,S OF lIUMAN LUNG TISSUF,S Early in 1955 twelve pathologists located in hospitals in various parts of the country from coast to coast undertook a coordinated study to deter- mine what kinds of abnormalities occur in the lungs of human subjects that come to autopsy. The incidence of such abrarmalities was to be determined and the relation of the incidence to age, sex, occopation, residence, environment, and cause of death was to be determined as far as possible. Six classifications of cellular eonditiorn aere adopted and about 2000 lungs were collected and examined over a period of two and a half years. It was found that data could not easily be pooled because of differences in the classification of tissue sections by different observers. These differences were revealed by circulating two slide collections under code for independent classification by several pathologists. Preliminary conclusions from this study were: 1. There was no age difference in the prevalence of changes, classed as "hyperplasia or etxtaplasia,° at any age above 25 ye*rs. Less than 30 percent of all cases studied, htcluding both sexes and all ages, had mucosae classed as "normal" in all the sections that were examined. 2. Males showed changes depart}nt from "normal" more often than females, but both metaplasia and hyperplasia did occur fre- quently In females. 3. Cigarette smoken le Atla tttttdy tended to have fewer "normaf" sections than non-anoteH. ,,~ 4. By a rough di.Wo/~M ll~up0l~ !n'tt) "hazardous" (etose which may have a high dtiltth ti1/e frottt ltsfti tancer), those In farm- ing, and others, tto oorehtlAt bd~t~,bf ntetaplasia or hyperplasia appeared In sny of tltele @tmt OOltpt.I • Ig 19