sample="rhetorical" bates="hk_0976068" isource="ctr" decade="1960" class="ni" date="19671000" Tobacco and Health Research 27 Where Shall We Go From Here? 28 It is a pleasure to be here with you tonight where I can see again a number of old friends and have an opportunity to make some new ones. Despite that pleasure, I do not feel a kind of hesitation exactly jubilant about mounting this platform to speak again about research on tobacco and human health. What I have to say is not in the nature of entertainment. I know that you all must be rather weary of the subject and wish that it could be ignored or forgotten, with its reminders of difficult and unpalatable problems. I sometimes feel this way myself, especially when confusions, missapprehinsions, contradictions and misunderstandings seem to be in possession of the field. But these problems cannot be ignored and they are not likely to evaporate in any near future. Whether we like it or not, we must grapple with them. Facing this fact, as we must, we come to the question I have put before you tonight, "Where do we go from here in tobacco and health research? I will try to give you a few answers to this question, as I see them, and some reasons for these answers. Within the last few weeks we have witnessed two events that illustrate the kinds of confusions, missapprehensions and contradictions, that I have mentioned, The first of these events was a series of hearings during the week of August 24 before the Consumer Subcommittee of the Senate Commerce Committee on the general subject of "making cigarettes safer." The other event was the World Conference on Smoking and Health during the week of September 11. No doubt you have seen a number of reports from both. In the hearings on "making cigarettes safer" some extremely divergent points of view were expressed. For example, one witness advocated a "cigarette" made from treated lettuce leaves on the ground that its smoke is entirely free of nicotine. Such lettuce cigarettes do however nonetheless produce smoke, and this smoke, like others produced in a similar manner from plant consists in part of particulate matter. this can be condensed in the form of a into the same kind of dark liquid that has come rather generally though erroneously, to be called "tar". IN the case of tobacco, as luck would have it, another witness at the same hearing reported experiments showing that such smoke condensates from burning dried lettuce have exactly the same kind of action as the painted on the skins of mice as the smoke condensates fro ordinary commercial tobacco cigarettes. Smoke from dried cabbage leaves was also reported to have a similar but higher activity. I shall comment further later upon my dissatisfaction with mouse skin painting as a test method. At this point I will only say that these mouse-skin tests with lettuce and cabbage smoke condensates turned out just as any chemist or biologist would have expected. The advisors of the council for Tobacco Research did not think never thought it worth the cost to in terms of your money to carry out an experiment of this kind. I am inclined to feel that it was a dubious investment of the tax-payers money for anybody to have conducted this test. Nevertheless I am rather glad that it was done since it was one way of demonstrating, that there is nothing albeit rather expensively and unnecessarily, that there is nothing unique in this respect about the leaves of the tobacco plant and that the mouse-skin activity of condensate smoke from plant material does not depend in any way the presence of nicotine. Other special and individualistic view-points were presented at these hearings, which we shall not go into here. It was noteworthy, however, that that good part of the testimony was based upon acceptance of the concept that the goal to be sought in producing "safer cigarette" is simply reduction in the amounts of "tar" and nicotine received by the consumer while preserving enough flavor is preserved to make the product acceptable. Most of the inventories described were arrived at this goal and claims of the investors were stated in terms of nicotine and "tar" delivery without any biological tests to provide any direct basis for claims of greater safety. A few witnesses showed a broader grasp of the problems involved and described more sophisticated long-range programs that hopefully may in time might discover specifics effects attributable to specific smoke components and lead to improvements. affected such constructive plans. But overall, my impression was that a number number of well-meaning inventors have been concentrating entirely upon the reduction of "tar" and nicotine delivery because they have interpreted the various releases form the the U.S. Public Health Service as authority for the assumption that a blue-print for the "safer" cigarette has already been established in these terms. This brings us to the World Conference on Smoking and Health. Its whole plan was based upon the assumption that the use of cigarettes has already been established as a major health hazard. Hence the scientific evidence bearing on the point was not a topic for discussion. Instead the emphasis was placed upon methods for dissuading people from starting to smoke or of persuading them to stop. Some relatively minor attention was given to the question of how cigarettes might be made "safe" or "safer". In this latter discussion, again, the basic assumption that the desired goal is maximum reduction fo "tar" and nicotine while still producing a product that confirmed smokers might accept. In his keynote address, Surgeon General William H. Stewart stated (partial quotation): stated "The 1966 cigarette is, on the average, substantially safer than the 1960 cigarette; it contains about two-thirds as much tar and nicotine. This competitive response to public concern has resulted in positive public benefit." Again he said: "For the tobacco industry and its advertisers there are a number of productive courses of action awaiting only the decision to help society cope with a problem that cannot be washed away. Among them are a sincere and wholehearted effort to develop a cigarette that is both as low in hazard and as acceptable to the smoker as science and technology can make it, ---- The door to cooperation has always been open. It remains open." Such statements led one writer to characterize the speech as "an olive-branch held out to the cigarette industry." Dr. Daniel Horn, Director of the U.S. Public Health Service National Clearinghouse for Smoking and Health, in leading a panel discussion, took a rather philosophical view toward smoking. He devoted much of his talk to a review of man's search for stimulants and tranquilizers: He said in part, "Throughout history people everywhere have researched for natural products in their environment which would provide them not only with sustenance and shelter but certain pleasurable effects as well. In his research for gratification man has experiments with things to drink, snuff, smoke, chew or swallow. -----. We must face up to the fact that the cigarette caught hold because it fulfilled certain functions that needed to be fulfilled for a great many people. The cigarette offered an accessible, inexpensive way to deal with a variety of problems --- if there were no harmful consequences, it would have served mankind well. We simply had the rotten luck to have discovered after all these years that the harmful effects are overwhelming----" . (Partial quotation) The Council for Tobacco Research did not participate as such in this World Conference because its primary topic did not lie within our area of concern or competence of the council were perfectly free to participate if they saw fit to do so and several did. But the council, as such, does not take any position as to whether people should or should not smoke and it does not participate in advocacy, our function is entirely descriptive. Vast numbers of persons have smoked cigarettes in the country since the turn of the century. Vast numbers of persons are smoking them at the present time. The indications are that vast numbers will continue to do so for a long time to come. Hence our task of seeking the observing and describing the effects of smoking, good or bad, continues to be relevant and important. We have never assumed or asserted that cigarette smoking is free from any hazards. If we were sure fo this, there would be little need for a program. Indeed, I do not suppose that any cigarette smoker in the country since the turn of the century has ever assumed or believed that smoking was completely harmless. He was told otherwise by his parents, teachers, scout leaders and other adult advisors who probably tried to discourage him from smoking. We all know that there are definite hazards in eating, drinking, athletic sports, swimming, drinking beer and taking a bath. But the the cigarette smoker had hoped that pleasures and benefits of smoking might would outweigh any dangers that he might incur. Dr. Horn has acknowledged the benefits, though a full account of them has certainly not yet been rendered. Is he right in his conclusion that :"the harmful effects are overwhelming"? This is still the key question and we do not think that it has yet been answered for reasons that I will explain. When Dr. Stewart's call for cooperation from the industry, seems to me anachronistic. The industry long ago understood not only cooperation but leadership in seeking reliable answers. They did so first by setting up and forming The Council for Tobacco Research as an independent commission of scientific and medical men to conduct investigations into any and all aspects of tobacco use and human health. Later they made a very substantial contribution, without strings attached, to the American Medical Association for a similar but program. * polled the Tobacco Industry Research Committee. It was certainly their hope and expectation that these programs would in time and mistakes and hazards of cigarette smokers that are real, elucidate their mechanisms by laboratory and clinical studies and trace them to specific ingredients of smoke. The gambled, so to speak, that such a down of any real hazard would probably show the way toward its elimination. Was this not an intelligent and honest attempt to provide an approach to what Dr. Stewart calls for - "A sincere and wholehearted effort to develop a cigarette that is both and as acceptable to the smoker as science and technology can make it." Meanwhile, in their own company laboratories they continued the highly sophisticated work of identifying and determining quantitatively as many individual smoke components as possible with thecondensable and non-condensable. They sought means of eliminating the filtration or otherwise, some of these components that can be presumed to be unneccesary or undesirable, even though that was without waiting for any real evidence that that they contribute to the production or aggravation of any The industry alone made available a variety of relatively low "tar" and nicotine cigarettes to most public demand created by the implications of U.S. Public Health Service and other agencies rightly or wrongly " that this is the type to be desired for "society." I think there has been no lack of very relative and constructive cooperation. of a nature. If, however, the present plea for cooperation implies acceptance of all the current doctrines, veiw-points and concerns dogmas of the U.S. Public Health Service, there must be reservations. We of the Council are eager to cooperate energetically and effectively toward attainment of the ultimate objective. This, we conceive to be a substantial reduction or delay in the toll of each constitutional diseases as lung cancer, cardiovascular ailments and chronic lung diseases in a population still smoking that cigarettes and enjoying the pleasures and benefits to which Dr. Horn alluded. We feel that our cooperation toward this end, will be most effective in the long run if we maintain and exercise our independent judgement rather then adopt any "party line" embodied by others. There is time this evening for only a few examples and illustrations of what I mean. First let us take Dr. Horn's statement that the harmful effects of cigarettes are "overwhelming". On what evidence, actually, do he and his colleagues base any such statement? Their method basically is this. The death rates of cigarette smokers and of non-smokers are compared and found to be higher for the smokers. A figure for the "excess deaths" among smokers is then obtained as they say, "by subtracting from the number of deaths occurring in a group of smokers, the number of deaths which would have occurred if that group of smokers had experienced the same mortality rates as a comparable group of nonsmokers." The resulting figure is that which they advance in their publicity as the "excess deaths associated with cigarette smoking." They do not speak of these "excess deaths" as caused by cigarette smoking but a careless reader is likely to assume that this is what is meant. because, I suppose.they know that this is not justifiable,It seems to be what Dr. Horn does mean when he speaks of the harmful effects of cigarettes as "overwhelming". The fallacy in this procedure concluding that the "excess deaths" are caused by smoking is obvious to the any thoughtful man in the street and to many a bright high-school student, as I have discovered by actual test. It has been pointed out by every one of the two dozen or so statisticians with whom I have discussed the matter. The fallacy is simply this: If we knew that the cigarette smokers were alike in all other respects and that the only difference was in their smoking or non-smoking, we could might be able to conclude that this difference in mortality was caused by the smoking. But we know just the opposite from such relatively meager studies as have been made so far. And as more studies of this kind are accomplished, the evidence increases that different physical and emotional characteristics and habits of life are associated with cigarette smoking and non-smoking. Cigarette smoking may well be an or reflection of combination of such characteristics and The needs which Dr. horn pointed out being met by smoking certainly very in degree and intensity from person to person and the smoking group population would be expected to include a group whose life-expectancy is relatively low because of the intensity of their physical and mental malmajadjustments. This situation would might be reflected in recorded death-rates among the whole group of smokers if their smoking helped in some degree to reduce relieve these maladjustments. I recall a study which showed that people who use tranquilizers have much higher death-rates than those who do not. The author did not conclude that tranquilizers kill people but rather that some of the people who need tranquilizers are sick enough to affect the statistical picture of the group by dying relatively early. Similarly it was shown that people who regularly spend ten hours a night in bed have higher death rates than those who average only seven hours of sleep. It was not concluded that too much excessive sleep will kill people, but I rather that among the long sleepers there are enough people whose excessive requirements are due to illness to affect the mortality statistics of this whole group. This would not reflect the longevity of such people to be improved by restricting them to seven hours a night. So far as the epidemiological method of approach to these problems is concerned, I cannot see any difference between the cases of sleeping habits, use of tranquilizers and of cigarette smoking. I am not denying the possibility that cigarette smoking may actually cause some excess deaths. I am only saying that this kind of study does not tell us whether or not this is the case or give us any idea of how many such excess deaths are attributable to smoking. That is why the Council constantly stresses the need for new studies of quite a different character and is trying to lead the way by demonstration projects. We are giving assistance to a very substantial study of human factors associated with relatively long life and with relatively early death. A tremendous number and variety of observations are being made upon the subject of this study. Smoking habits are only one. We are trying to find out how other characteristics and life habits tend to be grouped with smoking or non-smoking. The handling and of such numerous of data requires the development of new computer programs capable of doing more quickly the kind of statistical of factors that used to be done by multiple regression analysis or discriminant function analysis. We have therefore undertaken also to support the development and application of more and better and faster computer programs. for such purposes. The methodology developed in these studies will be available for use by other researchers investigating various government agencies and other agencies concerned with similar problems. Already it can be said that cigarette smoking or non-smoking by a group of subjects tends seems to "summarize" groups of other characteristics and habits which can serve statistically as "predicters" of relatively long or short life without inclusion of smoking other factors are candidates for of possible causal effects. We regard these pioneering studies as intelligent cooperation. So far we have been discovering overall mortality rates in smokers and non-smokers of cigarettes. I want to say a few words more specifically about coronary heart disease. This, as you know, is one of the prime causes of death among American males. The so-called "excess deaths" from this disease among cigarette smokers calculated as described before, constitute a large fraction of the total "excess deaths" reported for the cigarette smoking population group. All the comments we have made before about attributing these such "excess deaths" causally to cigarette smoking are applicable here as well. This was recognized by the committee that reported to the Surgeon General in 1964: They had at that time: "male cigarette smokers have a higher death They said at the time rate from coronary artery disease than nonsmoking males, but it is not clear that the association has causal significance." You will understand that I agree with the conclusion for reasons that have been explained. Moreover, I cannot find in the data provided by continuation of the epidemiological studies any justification for a change in the conclusion. On the other hand there are several recent studies that tend to reduce the possibility likelihood that this is a causal relation. I can think off-hand of two in which a number of factors other than smoking were tested for their ability as a to contribute to a profile description to capable of as a valid "predictors" of coronary artery disease. In these cases cigarette smoking did not help contribute to the predictive power of the profile and was discarded." But probably the most significant new contribution is the recent to the Swedish twin study. Identical twins are the nearest thing we have in the human species to the litter-mates of dogs, cats, mice, rats, etc. Their genes are the same so that they have the same hereditary and tend to be much more nearly alike in live-habits than fraternal twins or ordinary brothers and sisters. They even tend to be much alike in smoking habits, which fact is one of the good evidences for the belief that constitutional make-up has an important effect in determining whether and how people smoke. Nevertheless, the Swedish twin registry turned up a considerable number of pairs of identical twins one of whom had smoked cigarettes for a substantial period while the other had not. Extensive study of the cardiovascular systems function and function of these twins showed no significant difference between the smokers and the nonsmokers attributable to smoking. This conclusion finding might be more convincing have been finally conclusive if he number of twin pairs had been a little larger and if the study had been continued over a period of years. IT is expected that this there will be follow-up at intervals. and if A similar study of a larger number of twin pairs is urgently to be desired and I recommend to our U.S. Public Health Service that this be given a high priority in their plans. It could well give might just provide some quite definitive answers to the kind of difficult questions we have been discussing. even now the statistical Meanwhile properly designed studies in animal models can probably help fill the gap since it is possible to use litter-mates (that is twins) in such studies and to make sure that all environmental factors are kept the same except for the one where effect is to be assessed. The Council is planning further work along such lines. In the recent Public Health Service Review, entitled The Health Consequences of Smoking, considerable attention is also given to the analysis of laboratory and clinical studies of the effects of nicotine, smoking or of smoke constituents on the heart and arteries. Many of these studies were sponsored by the Council. They include studies investigations of coronary blood flow, thrombus formation, serum cholesterol, free fatty acids in the serum, and the amount of anterisclerosis found post-mortem. This was, in effect, a search for plausible effects and mechanisms that might plausibly explain how and why smokers show a higher mortality from coronary artery disease. It was quite properly hedged with many "possiblys" and "perhaps" and "conceivablys". In my opinion none of these offers say mechanisms or effects so far describe offers any convincing explanation of the statistical picture. I will mention just one by way of illustration. Council studies have shown that nicotine, tends to increase blood flow in the small arteries that supply the heart muscle itself with oxygen. It The also has a stimulating effect on the heart muscle much like that of mild exercise such as walking up a staircase. This is accompanied by a moderate increase in heart rate, systemic arterial pressure, cardiac outfat stroke volume and muscular contraction. A person whose coronary arteries are narrowed and stiffened by disease may not be able to increase of laboratory and clinical study nicotine, smoking or of smoke constituents and arteries. Many of these studies were sponsored by the Council. They include studies investigations of coronary blood flow, thrombus formation, serum cholesterol, free fatty acids in the serum, and the amount of arteriosclerosis found post-mortem. This was, in effect, a research for plausible effects and mechanisms that might plausible explain how and why smokers who a higher mortality from coronary heart disease. It was quite properly hedged with many "possibilities" and "perhaps" and "conveivablys". In my opinion none of these offers any mechanisms or effects so far described offers any convincing explanation of the statistical picture. I will mention just one by way of illustration. Council studies have shown that nicotine, directly or indirectly tends to increase blood flow in the small arteries that supply the heart muscle itself with oxygen. It The alkaloid also has a stimulating effect on the heart muscle much like that of mild exercise such as walking up a staircase. This is accompanied by a moderate increase in heart rate, systemic arterial pressure, cardiac stroke volume and muscular contraction. A person whose coronary arteries are stiffened by disease may his coronary blood flow normally in reference to nicotine stimulation. The reviewers estimate that smoking by a filter with advanced heart disease may this create a demand for increased oxygen in the heart muscle that cannot be met, and thus bring about a crisis or even death. He may well be right. My comment, however, is that a person so severely diseased as to be endangered in this way by smoking a cigarette would encounter a similar comparable hazard by dancing a slow waltz or climbing a flight of stairs. As we all know, people do in fact experience fatal heart attacks when engaging in these very activities. We do not conclude from the fact however, that exercise is a basic cause of coronary heart. There is evidence rather that exercise, if regular and not too strenuous, will help delay or compensate for the arteriosclerosis. I fail to see any significant difference between mild exercise and cigarette smoking insofar as the particular set of mechanisms is concerned. It does not seem reasonable to me to suppose that such "last straw" effects upon people in a precarious state of disease could have much influence on mortality rates. To summarize then, it seems to me that one very large portion of Dr. Horn's "excess deaths" among cigarette smokers (the ones from coronary heart disease) are very doubtful with respect to any causal implications. They may well be removed from suspicion altogether. This event would greatly reduce the appearance of "overlooking harmfulness" he mentions. To a greater or lesser degree this is true of other diseases included in the statistics. The evidence needs to be thoroughly analyzed in each and every case. Since we have brought up the subject of nicotine, I must say that I cannot understand why it has become customary to link "tar" and nicotine together as related to the "risks" of smoking. The 1964 report to the Surgeon General made a rather review of nicotine pharmacology and drew the following conclusions: "The rapidity of degradation to non-toxic metabolites, the results from chronic studies or animals and the low mortality ratios of pipe and cigar smokers when compared with non-smokers indicate that the chronic toxicity of nicotine in quantities absorbed from smoking and other methods of tobacco use is very low and probably does not represent a significant health problem." I have seen no research reports since 1964 that suggest any change in this conclusion. My only guess is that they nicotine and tar are linked together because the nicotine in cigarette smoke is found in the particulate phase which forms the chief component of smoke condensates. Hence cigarette which yield a relatively small amount of particulate material are likely also to yield relatively little nicotine in the main-stream smoke. Epidermotologists attempting to relate disease incidence or mortality to the amount of daily smoke dosage find that the "tar" and nicotine dosages are associated. To conclude from this kind of association without other that nicotine makes any contribution to the disease is very loose thinking reasoning indeed. Since any case If there is no actual case against nicotine as a health hazard is conceptual in the and since if nicotine for is responsible not very for some of the beneficial desirable effects that smokers seek as it might be good health so being to keep the nicotine content and output of cigarettes relatively high as a health measure. This should might enable the smoker to obtain the effects desired nicotine effects with a minimum exposure to other ingredients of the smoke. If any of these are harmful, the reduced exposure might be beneficial while satisfaction was maintained. This bring me to the last question that I shall try to discuss tonight. On what evidence is the are people learning this doctrine that the hazards of cigarette smoking are related to the "tar" output based of cigarettes? Attempting to analyze the thinking of the proponents of the doctrine, I find three kinds of on which it seems to me that they mainly depend. The first is the kind of evidence provided by epidermiological studies in which they try to relate disease incidence to the level of exposure to total smoke, that is to the number of cigarettes smoked per day. We have already discussed the difficulties in interpreting such studies. In the present context I want to add the point that the exposures they are talking about are exposures to whole smoke with all its ingredients, whatever conclusions are may be justified from such studies, any effects claimed cannot be attributed to "tar" any more than to nicotine. If they are effects attributable to the inhaled smoke ate all, they cannot be assigned to any smoke fraction or ingredient unless or until there is some evidence to justify such assignment. The second kind of evidence on which the "tar" dogma apparently rests is the cellular abnormalities seen in the lungs of chronic smokers. Whether this changes our or not is a matter of intense debate among pathologists. We are trying to help resolve this question by studies. The point here is that the subjects of this study whole smoke and there is no evidence that the changes mentioned are attributable specifics to the particulate or smoke that which is the principal component of "tar". The second third and chief kind of evidence these proponents of the "tar" dogma are relying upon is the mouse-skin painting work. As I have said before, the trouble with this method is that it applies the wrong material, in the wrong form, in the wrong concentration, to the wrong tissue of the wrong animal to have any clear or simple relation to the human lung cancer problem. The condensates used in such studies do not contain all the ingredients of fresh, normal smoke. The physical form is entirely different from that of smoke. The skin is a very different kind of tissue from the lung, as extensive studies have shown by extensive clinical studies sponsored by the Council. And we have Council-sponsored studies have shown that pipe tobacco and cigar tobacco smoke condensates are as active in producing tumors on the skins of mice as cigarette smoke condensates, even though human pipe and cigar smokers rarely get lung cancer. Unfortunately mice are also quite different from men or monkeys in their susceptibilities to cancer-producing chemicals. We think that we will learn much more about the effects of tobacco smokes on lung tissue by making small animals inhale whole, fresh, normal cigarette smokes repeatedly over long periods, than by skin painting with condensates. It has been a difficult task to design mechanical devices for bringing the about smoke inhalation conditions closely resembling human smoking conditions, But think we are now reasonably close to being able to bring the right material, in the right form and the right concentration to the right tissue, though it is still the wrong animal. So far In the first chronic exposures of this kind with earlier and cruder devices, have not been followed by appearances of lung tumors cancers. It remains to be other than a very occasional one of the types that occur in the seen what will happen with use of the infrared equipment. If no cancers are obtained with a wide variety of animal species, and with various kinds of conditionings to increase susceptibility, we will become increasingly doubtful whether tobacco smoke can act on lung tissue as a direct contact carcinogen. But this will not end the search. There are several methods by which lung cancers resembling the human type can be produced in animals. Using such models, a great variety of factors and influences can be screened to see how they affect susceptibility. Among these factors and influences, tobacco smoke can be studied in context to see whether it could play some kind of an indirect contributing role. And whether or not any contribution by tobacco were found, such studies might well turn up clues to the prevention of human lung cancer. This is our real objective and we have mapped out a broad program of studies along such lines. and would will rejoice if the Government departments eventually see fit to help carry them out. On the other hand, if the animals exposed to inhalation of fresh, whole, natural smoke in the improved equipment should develop cancer of the lung, this result might come bout as a relief. For then it should be come possible to make systematic studies of fractions of the smoke, and identify the responsible agent. Once identified, its removal or prevention should be within the capability of our scientists. Then we might have a cigarette that we could feel quite sure was safe with respect to any cancer hazard. It is a fortunate fact in scientific research, that a variety of different working hypothesis and contrasting can all engender good research. The results of good research can be expected eventually to intermingle, interrelate and provide illumination as well as suggest new and better hypotheses. We hope to continue and intensify our work along such the lines described as have been illustrated here tonight, and as well as in areas that there To Dr. Stewart, I would say that the door has always been open to cooperation. It remains open.