Tobacco Documents Online

PHILIP MORRIS U. S. A. lNTER-OFFICE CORRESPONDENCE RICHMOND, Y)RGINIA To: . Dr. T. S. Osdene F"W: • R. Fagan swbLet: . Research Needs on Low-Yield Cigarettes o+te: July 29, 1980 1.) The U.S. Office of Smoking and Health, DHHS, invited some 70 scientists to discuss the research needs on 1ow yi'eld cigarettes. Thi~s was an open meeting and the public was invited on a space-available basis. A l.ist of the invitees is attached. Among the public observers were people from the Tobacco Institute; lawyers from Shook, Hardy and Bacon; observers from Lorillard and R. J. Reynolds. Each participant, but not the observers, was given a copy of the following: (1) working papers submitted by each parti- cipant (2) resource papers that had been published which were used as back- ground. I have copies of all' of them. 2.) The first talk of the session was by Julius Richmond, assistant secretary for health, DHHS, and surgeon general. He ca led this a l~and-mark meeting which would be the basis of his annual report to Congress. He hoped that a consensus would come out of the deliberations on public policy. He was especially concerned about additi'ves in cigarettes, especially since the low-yield ones are said to have new materials that were not present in the older cigarettes. Since the government did not know the nature of these new additives, there was a sense of uneasiness about what effect they might have on the health of the smoker. Dr. Richmond wanted a big effort mounted in the behavioral field. He felt that through such studies there would be a big influence in reducing cigarette consumption. He said that the government deserves credit for the development of'the low-yield'cigarette since the FTC relaxed its strictures on advertising. As a final statement, he mentioned the three requirements that the World Health Organization found necessary for the successful world-wide eradication of small-pox: (1) sound knowledge base and appropriate technology, (2) the socilal strategy for the campaign and (3) the political will to make the committment to act. The implied analogy was quite clear. A copy of hi.s remarks i,s attached. 3.) Since Dr. Frederickson, Director of NIH, failed to attend, his substi- tute was Dr. Tom Malone, deputy director. Dr. Malone had just returned from Geneva where he participated in the General Assembly of the World Health Organization (WHO). At that meeting, a resolution was passed condemni~ng smoking as an impediment that must be overcome if the world was to realize the goal announced: "Health for all by the year 2000." Dr. Malone mentioned the ironic fact that mos t of the ministers of health were heavy smokers. 4.) John Pinney, Director of the Office of Smoking and Health said that a' verbatim transcript of all: the sessions would'be made available to the public. He also announced that the policy of the Department of Health and Human Services on smoking: no smoking in any of the meeting rooms. He N 0 N M+ N ~ GD N ~

-2- ` repeated Dr. Richmond's statement that the proceedings of this work-shop was to be the basis of the Surgeon-General's Report on Smo~ki~ng and Health for 1981. 5.) Dr. Joanne Luoto, Medical Officer of Smoking.and Health defined liow tar- nicotine cigarette as one which delivered less than 15 mg. She then proceeded to give a summary of smoking patterns. The tar to nicotine ratio has not changed'much over the years. All smoking is declining and sex differences are disappering but smoking among males is decreasing while among females it is plateauing. Blacks smoke higher tar cigarettes than do whites. And in general there is increased switching to low-yield cigarettes. 6.) After the coffee break, there was a panel di scussion .l ed by Dr. Jesse Steinfeld. The panel consisted of the chairmen of each of the groups o speciT sts. Dr. Steinfeld was chai~rman of the cancer group; Dr. Castelli, cardiovascular; Dr. Bock, pharmacology/toxicology; Dr. Longo, pregnancy and infant health; Dr. Kimbel, pulmonary; and Dr. Schuster, behavioral. a.) Dr. Steinfeld stated that the tobacco industry, when confronted' by the idea that a p'leasurabl.e experience (cigarette smoking) was deadly, responded by lowering the tar and nicotine delivery. The proper response by the public should be that no-smoking is better than the lower tar-' nicotine cigarette. Also now that tar and nicotine is lower,there is concern about other constituents of smoke: carbon monoxide, aldehydes, nitrosamines, etc. How about considering a Delaney-type i,dea when looking at the cigarette? What relevance is there in animal models? Should we not be studying the interaction of cigarette smoke with other possible noxious substances in the environment like the work-place? Is the harmful effects of cigarette smoke a global one or'are there specific components which are responsible fo r these effects? And one must remember that since the population which smokes is not homogeneous, different characteristics must be taken into consideration. b.) Dr. Castelli, who is the medical officer now in charge of the Framing- ham stu y was by far the most vehement adversary. If it were up to him,, cigarette smoking would be prohibited. He pointed out that the proper end-point in studying the effect of smoking on cardiovascular disease is sudden death. No other end-point is proper. Angina pectoris is not related to smoking. He admitted that the role of CO in cardiovascular disease is not settled and the scientific community is debating it vigorously. Two of his interesting disclosures were the following: (1) The original sample in the Framingham study contained 70% smokers. Only 45% of the children of these subjects are smokers on a comparable age basis. (2) He is colilecting smoking histories on brand basis. c.) Dr. Bock felt that looking at indi:vidual constituents of smoke is not realistic since it may not be relevant to the mixture of compounds that constitute smoke. There must be animal models. He felt that there are good ones for lung cancer and bladder cancer but not others. (Bock feels that skin-paintilng of mice is a proper animal model for cancer). If one accepts the animal model, then one can say how bad any par.ticular cigarette is. What is now needed is a smoking, machine which imitates human smoking. Therefore, should the parameters now used (35 ml, 2 second puff, 1 minute interval) be changed? One should not limit the study of tobacco technology to processing but should include

-3- plant genetics to modify tobacco to yield less harmful smoke. And certainly side-stream smoke should also be studied. d.) Dr. Longo stated that toxic substances cross the placental barrier and hence the developing fetus is affected. Perinatal mortality has been shown to be dose-related', more smoking, higher mortality. He believes that there are long term effects in the offsprings of mothers who smoke. These are minimum brain damage and lower I.Q. As he sees the research needs, they are the following: what are the most important toxins in smoke?; by what mechanism do they act?; is there a mutagenic effect?; what is an appropriate animal model?; what is the interaction of. cigarette smoke on other risk factors such as alcohol, anemia, other drugs?; what is the effect of passive smoking,on children? We should be looking at the total dose the smoker gets and no t just the FTC numbers. Dr. Longo suggested that there be a selective warning aimed' at pregnant women and' the mothers of young children. And;lastly, the group ought to consider an ethical or transcientific question - does the fetus have the right to be spared exposure to cigarette smoke? e.) Dr. Kimbel is convinced that the pathogenesis of emphysema is known - lance between elastase released from the excess macro- phages and neutrophiils and'alpha-one antitrypsin. The elastase is released when those cells are exposed to smoke. The oxidizi'ng agents in smoke inhibit the action of the alpha-one antitrypsin. Therefore, it is clear what has to be done. Study the chemistry of elastase; develop synthetic elastase inhibitors; use quantities of human alpha- one antitrypsin therapeutically. Also, he would like to know the major fraction of smoke that is responsible for the harmful effects. And he is intrigued by the fact that many smokers don't get emphysema and he'd like to know how they escape. f.) Dr. Schuster pointed out that the genesis and' maintenance of smoking is the same as any other drug, same as heroin for instance. The genesis is social pressure from peers. Although the initiai experience is aversive,tolerance quickly develops. He is sure that nicotine is the reinforcer as shown by Goldberg's work with monkeys. Withdrawal symptoms (from what?) are alleviated by smoking. Cigarette smoking itself is a psychological reinforcer since it can be indulged anywhere and'is incorporated in a chain of behavior during many activities. Trying to generalize is doomed to failure because of the great variety of people who smoke for different reasons on different occasions. 'Cessa- tion clinics should take these differences in motiva tion into considera- tion. Regardless of what he said previously, Dr. Schuster feels there is a need~ to assess the evidence for nicotine dependence and see whether there is behavorial' compensation as the tar-nicotine ratio changes. And his last question was - does the low-yield cigarette help to initiate the smoking habit? g.) Questions from the listeners were entertained. Dr. Rush, Columbia N University asked about socio-economic effects in the diseases being O considered. Kimbel thought they had a profound effect on the ilncidence N and~ prevalence o respiratory disease. Castelli feIt that as far as the M~ Framingham study was concerned, socio-economic differences were not rele- ~ vant. Garfinkel of th e American Cancer Society felt that socio-economic ~ differences were important in all the diseases being considered. He ~. ciJ a

-4- then asked Castellii to comment on the declining cardiovascular deaths. Castelli said that is was dfiffi:cult to evaluate it but he felt it could' be attributed to lower smoking rates. Regardless of the lower death rates, the morbidity rates were still high (this implies better medical treatment). Geller of NCI asked Longo about the effects of side-stream on the pregnant woman and her fetus. Longo did not have any information on that. 7.) Since there were six groups to choose from, I decided to spend By time with the toxicology/ pharmacology group. Fred Bock, the chairman, put on the record the fact that I was there as an observer. As other observers came in, he put their names on record. Bock asked each member of the panel what he thought should be done and what he thought was well- known now. And the last assignment for the group would be to set up priorities. . a.) Dr. Diamond started by saying that there was virtually nothing known of the pharmaco-kinetics of smoke or of smoke components. This is im- portant because smoking is chronic dosing - small bits over long periods of time. As far as nicotine is concerned, he is convinced that this is what smokers are after and the smoker would not be satisfiled with low levels. This being so, Diamond would like to know the mechanism by which nicotine produces its effects, particularly on the cardiac vasculature. He is thinking of coronary spasms. In that regard, he would like to see studies on the effect of nicotine on prostaglandins, thromboxanes, prostacyclins, etc. Also,he would like to see more work on the pulmonary effects, particularly the elastase - anti-elastase balance. b.) Dr. Battista wanted a definition of a low yield cigarette. What effect~oweri'ng the yield have on the gas phase and on such things as aromatic nitrosamines? Is there such thing as a threshold effect of any of these compounds or-of smoke in general? He is skeptical about nicotine being the reinforcer in smoking. Does low delivery mean a shift in particle size of smoke? If the particle size gets very small, then there will be virtually no deposition on the stem bronchi and hence no bronchogenic carcinoma, but this may lead to cancers in other parts of the lung - adeno and'alveolar-bronchiolar. (These cancers are not considered to be associated wilth smoking.) As far as reproduc- tion is concerned, the harmful substances in smoke may be other than CO and nicotine and this should be investigated. c.) T. C. Tso felt that there was undue emphasi~s on the quantity of smoke to 6e exc usion of "quality." He would like to know the exact role of nicotine in the smoking habit and its effect on health. As far as the smoker is concerned, what is the effect of varying the tar to nicotine ratio? And what is the effect of CO? Is there a threshold? As one might expect, T. C. made a plea for devoting more effort to modification of tobacco to reduce the risk of smoking. And he wants a coordinated effort on this. d.) Dr. Chortyk maintains that to produce the low-yield'cigarette, blends had to change. These new blends may produce large quantiti'es of materials not now considered important. Therefore, it is important to know how people smoke - puff volume, puff number, interpuff interval,

5 etc. because the ratio of compounds in smoke changes with puff volume. He feelis that not enough attention is beiing paid to the volatiles in smoke. If smoke were coilected'in dry-tce and in a series of solvents, then greater quantities of everything would be available. The use of G.C.JM.S. enables one to profile smoke immediately. With such informa- tion, the FTC might label cigarette packs the way food is nutritionally l,abeliled. e.) Dr. Chaplin wanted to know what is desired in smoke because the genetics, particularly of nicotine has been worked out for flue-cured and burley. Make the specifications and- the plant geneticist can del iver. f.) Dr. Hoffman is adamant about not increasing niicotine relative to tar. He takes this position because of the relation of the alkaloids to nitrosamine formation. (Incidentally, Bock takes the same position but for a different reason. He is convinced that nicotine is a co-carcin- gen). Also, Hoffman feels that we should not indulge the addiction. He agrees with Dr. Diamond that we lack the knowledge of the pharmaco-kinetics of nicotine and this lack should'be eliminated. Of great concern is the effect of the new additives in the low-yield cigarette. And a last question intrigued' him - why is lung cancer decreasing but not bladder cancer? of co ecting smoke and estimating yields.. h.) Dr. Rickert of Canada wanted to know how to inform the public about smoke components so that the information is meaningfu!l. He feels that there is very little correlation between the smoking-machine results'and what the smoker actually gets. A person smoking a tobacco cigarette in the same way a person smoking marijuana cigarette gets a far, far greater amount of smoke. He, too, wanted to know about additives. i . ) Dr. Guerin felt that the analytic methods for the low-yield cigarette, particu'ar-'fy the super low yield should be subjected to a "round-robin" among the interested labs. In this way, there might be some meaningful data so that labs can agree on deliveries. There must be studies on side-stream smoke and what might be called ambient smoke. How about using human beings in bio-assay of smoke? j.) Dr. Harris (MIT) wanted to know what short-term bio-assays are uniformly accepted and are there other measurements of risk. He made a plea that the public be given all -the information that is available on cigarette smoke. 8.) Taking off from Harrfs' question about short-term bioassay, Bock started the discussion period. He said that his active fractions (by skin-painting) N are not positive in the Ames test but that his negative fractions are. "Ames 0 is a good test if you want one which is negatively associated:" Tso agreed ~ with the statement saying that Ames' test has not worked on condensate. r Guerin concurred. Hoffman stated that Ames does not work on the urine of ~ smokers even though some smokers produce carcinogenic urine. ~ C1'I g.) Dr. Pill!sbu of the FTC is content to stick with th e current methods ~

-6- 9.) Sock wanted to get some consensus on animal models. There was general agreement that mouse skin-painting was a good model for lung cancer and laryngeal cancer. Inhalation in hamsters is also a good model. The dog bladder is a good'model for bladder cancer. There are no animal models for pancreatic cancer, emphysema, cardiovascular diseases, or pregnancy. There might be some use for an in vitro protease-antiprotease model for emphysema. Also, it is possible that one can work out a model for the effect of smoke on prostaglandins and coronary spasm or on the presence of inetabolites of arachadonic acid which is a precusor of prostaglandin. Other in vitro tests might be ciliatoxicity as an.indicator of lung clearance or macrophage inhibition as an indicator of impaired defense mechanism in the respiratory tract. 10.) The Behavior Group had asked for a joint session with the pharmacology/ toxicology group. The topic to be discussed was "dose" of smoke and how was it to be determined. In anticipation of the meeting, the questions to be asked are the following: what puff volume, puff frequency, puff dura- tion, butt length (and should this be a free or a closed butt), how much ventilation or dilution shoul1d be specified. Before the behavior group answered these questions, several members of that group suggested that a study needs to be done to show whether changes in puff volume and puff frequency would change the relative rank of a cigarette as now shown on the FTC charts. As a corollary, it Was suggested that FTC deliveries should be reported by delivery per puff since there was no way of knowing how many puffs a person took on a cigarette. And i'f this is done, how about testing cigarettes by means of a standard number of puffs rather than a specified butt length. This last suggestion was quickly vetoed though the previous ones were considered as valid. ll.), The behavior group.had some of its own questions for the pharmacology/ toxicology group. Assuming that smokers compensate when presented with cigarettes delivering nicotine at a level different from their regular one and since we are considering low yield cigarettes, is there evidence that - "high intensity" of smoking alters the ratio of delivery of the various constituents of smoke? By "hi:gh intensity" is meant greater frequency of puffing, shorter interpuff intervals, increased puff volume and perhaps increased fl ow rate. The answer given by ChortLk was yes. And he cited his own work which showed that when the puff volume was increased, dipentenes went up 150%, phenols 120%, catechols 30% and nicotine 40%. Some 45-55 pyrosynthetic compounds did not increase at all. The behavior group raised the "additives" ques tion and wanted to know the toxicity of these. No one could or would give an answer except to say that this work would have to be done. Their third question was "are there any markers other than nicotine that could be used to indicate smoking status or give some idea of smoke exposure. CO and HCN were considered but rejected as non-specific. Guerin at ORNL prefers to use urinary nicotine rather than plasma nicotine. -Toctl- pointed out that a change i,n particle size distribution which might tacTe- place under "high intensity" smoking might alter the ratio of different smoke components. Kozlowski of the behavior group wanted to know whether the tar-nicotine ratio was changed per puff. He got no answer. 12.) The behavior group asked for a large supply of graded'~cigarettes - cigarettes with a constant amount of tar with varied nicotine and'a group with constant nicotine and'varied amounts of tar. Tom Owen of NCI who was an observer said there were a lot of ciaarettes left over from the -NCI

- 7- studies. At this point, the behavior group said that whatever cigarettes were made available would have to be acceptable to smokers and not be so bad' that no one would smoke them. 13.) Russell suggested that cigarettes be tested by taking 75 ml puffs in 2.3 seconds at 30 second'intervals. This is what 95% of the "desperate" smokers do. Jarvik asked for a definition of low tar which Hoffman defined as less than iT -mg according to the Germans. Russell saiid thl this was true also in the U.K.; 11-16 mg i~s considered "ma'dTe." 14.) Russell gave some information on compensatilon. If smoking takes place in theTaboratory (forced swi tchi ng) there i s only 50% compensation on the average. He doesn"t have any information on how well these smokers adjust to the change. If people switch on their own (market switchiing) then compen- sation seems to be complete. Russell discounts these results because the sample is self-sell, ected. All these studies are done by testing for plasma nicotine. Hoffman objected to this reporting by averages. He wanted to see distributi- o'-ns because he was sure that some people benefit by switching to low yield cigarettes. Russell agreed. 15.) Finally there were some questions about farm practices and how they effect yields of smoke and the various smoke components. It was pointed out that plants will take up only so much fertilizer and leave the excess in the field. Using the Ames test, Hoffman says that mutagenic components increase with higher concentration of f3 in the leaf. Concern was expressed about residues of insecticides, pesticides, fungicides, and suckering agents that are used on tobacco. As far as curing practices were concerned, Tso said removal of soluble proteins reduces biological activity. This was determined by the Ames test. Harris wanted'to: know how indus try reduces tar del'.ivery and he was told that this is done by ventilation, filtration and the use of stems, reconstituted leaf and puffed tobacco. 16.) Bock asked his group to list the priorities of research to be done. a.) Battista submitted the following: i. Interaction of smoke with pollutants such as asbestos, silica, dust, etc. ii. How much compensation does the smoker accomplish by changing smoking habits, if he changes. iii. What do people do who quit smoking - take other drugs? iv. Should nicotilne antagonists be developed? - N v. Develop an animal model for lung cancer. ~ b.) Chortyk submitted these: CA i. Determine the smoking parameters that smokers of low-yield Cn cigarettes use and then test the yiel,d using those parameters C1't instead of the ones currently employed. w . ~

-8- i'i. Bioassay the condensate from these cigarettes. iii. Correlate biological activity with chemical analysis. c.) Chaplin wanted work done on i. The influence of agronomilc changes on smoke components. ii. Determine whether nicotine is a co-carcinogen. d.) Hoffman wanted to i. Encourage the manufacture and marketing of low-yield' cigarettes. Study the pharmaco-kinetics of nicotine and nicotine antagonists. ii. Monitor the "new emerging" cigarettes by chemistry and short-term bioassay such as sebaceous gland suppression and the Ames test. This is very important because it wiil show whether the additives are introducing some harmful substance. Pillsbu wants testing done on all cigarettes by new parameters, e.) - not only the low-yield ones. f.) Rickert suggests that i. Smoking machine parameters be re-evaluated. ii. Gas phase components and their relevance to human illness be studied. iii. Nicotine pharmaco-kinetics be explored. iv. There may be other habituating agents in smoke other than alikalo~ids. v. Body fluids be analyzed for early indicators of disease. . There ought to be more information on additives. vii. There be some revision of how information on yields be communi- cated to the public. viii. Tests should be developed to finding those people who are the susceptible ones to diseases caused by cigarette smoking. g,) Guerin wanted i. Chemical' analysis of low-yield cigarette smoke including side- stream. ii. Studies to determine the risk to non-smokers inhaling side-stream. iii.. Validation of analytic methods that are used to determine yields, particularly of the low-yield cigarette. N C N N G1Z ~ CA m ~

h.) Harris emphasized that i~. Studies should be made on the components of side-stream smoke. ii. Bioassays should be done with smoke components. iii. Serious consideration should be given to who should do the testing. i.) Bock's list of priorities is as follows: i. Change the parameters on smoking. machines. ii. Evaluate high nicotine - low tar cigarette for carcinogenic potency by skin-paintilng. Pay special attention to ni.trosamines. , iii. Develop tests which would indicate approaching diseases iin man that are alliedged to be induced by smoke. 17.) After much discussi.on, Bock put the report of the pharmacology/toxico:logy group in order and he made the forinali presentation the next day with all the other chairmen. a.) Pharmacology/toxicology - Bock presenting: , I. Routine and frequent surveillance of current and new cigarettes for specific chemical constituents such as nicotine, benzo(a)pyrenes phenols, catechols, nitrosamines, CO, HCN, I+IDx, FWCO and radionu- cl~ides. Continued testing for biological activity by skin- ." painting, sebaceous glands assay, mutagenesis, effects on airways - and lung parenchyma, ciiiatoxicity. II. Determine the parameters of smoke intake by cigarette smokers including puff volume, puff duration, puff frequency, inhalation profilie, etc. This should include measurements on smokers of various types of cigarettes. III. Evaluate the pharmacodynamics and health effects of nicotine and its metabolites to include co-carcinogenic effects; forma- tion of nitrosamines specific to tobacco; etiologic.role•in chroniic obstructive pulmonary disease, cardiovascular disease and deleterious effects on pregnancy and infant health. IV. Systematically investigate the effect of varying smoking machine parameters on relatiive and absoliute yields of smoke components. V. Determine the influence on health related parameters of raw product modification including genetic manipulation, culture and curing practi.ces such as homogenized leaf curing, close- spacing, fertilization, use of pesticides. VI. Characterize the physical and chemical properties of mainstream and sidestream smoke from cigarettes delivering less than 10 mg tar in current FTC tests. VII. Validate and develop analytic methods.

- 10 - VIII. Other recommendations: b. 1.) investigate the interaction of smoking with occupational and o ther environmental exposures. 2.) determine the threshold, if any, for CO on cardiovascular disease, pregnancy,psychonator performance. 3.) determine the extent to which smokers compensate when they swi tch to 1 ow-yi eld ci garettes. 4.) continue evaluating health effects of gas phase components in human beings. 5.) evaluate possible habituating factors in smoke other than nicotine. 6.) develop early indicators of tobacco-related diseases. 7.) develop more effective methods for disseminating information on smoke delivery. 8.) evaluate the effects of passive inhalation of smoke from various types of cigarettes. 9.) develop low tar, low nicotine reference cigarettes. ) Dr. longo'on pregnancy and infant health State of the art is as follows: 1.) There are no data to show that the fetus is less harmed by low- yietd cigarettes than by regular cigarettes. 2.) Children born of mothers who smoke, on the average, weigh 200 grams less at birth than children born of mothers who don't smoke during pregnancy. 3.) Prematurity is 36-47% higher among children born of mothers who smoke compared with the off-spring of mothers who don't smoke during pregnancy. 4.) Perina tal mortality is 20-35% higher in the children of mothers who smoke. 5.) Parturition difficulties are more 1ikeTy (30-70% higher) i'n mothers who smoke during pregnancy. Recortmendations were as follows: 11.) Industry is wrong in promoting low-yield cigarettes as safer.. 2.) On the pack there should be a specific warning addressed to pregnant women.

3.) Since smoking in mothers is associated with hyperkinesis, sudden infant death syndrome, excess hospitalization of children, minimum brain-damage, and birth defects, there should be epide- miologic studies to examine the differential effects of different cigarettes relati'ng to CO, cotinine, HCN on these conditions. Suggestions about government action: 1.) Since cessation of smoking is beneficial, pregnant women should be a special group on which to concentrate. 2.) Physicians should' be counsel,ing pregnant women and the Office of Smoking and Health should be supplying physicians with informa- tion and proper techniques for counseling.- ~ 3.) All human models should be eliminated from ads. 4.) CO content of smoke should be published. 5.) Long term consequences to children of mothers who smoke should be examined in current data files. 6.) Study mechanisms by which complications of pregnancy are induced by smoking. 7.) There ought to be studies on the biochemistry of the placenta. c.) Dr. Castelli reporting for the cardiovascular group: 1.) Current data on low tar-nicotine cigarettes do not show any bene- fit over the high tar-nicotine in cardiovascular diseases. There is very little reliable information. 2.) Epidemiologic studies are needed for in-depth analysis of tobacco usage. Gas phase of cigarette smoke should be measured as well as parti cul ates . 3.) intervention trials should be mined for data. 4.) There ought to be surveys that look for "hard" end-points on the impact of low tar-nicotine cigare ttes. 5.) In all studies, neighborhood controls.should be used rather than the usual age-sex control. 6.), There ought to be an emphasis on international studies. 7.) Animal model!s are needed to study the mechanism by which cigarettes produce their detrimental effects. Compounds other than nicotine and CO should be considered. 8.) Office of Smoking and Health should develop a technical resource center and design a universal questionnaire that would be used everywhere. It should be prepared to disseminate valid informa- tion rapidly.

- 12 - Dr. Castelliended' his presentation by saying "it is better to quit than to 'wis tch:" d.) Dr. Kimbel for the pulmonary group: Introductory remarks: Smoking is the majorr risk factor for chronic obstructive pulmonary disease (CO'PD). There is a paucity of reliable data on low tar-nicotine effects. Mechanism of lung i::njury is not completely understood and more study is needed. For this a good animal model is needed. Necommend'ations: 1.) Dose delivered to different parts of the respiratory tract by different components of smoke needs to be determi ned. 2.) Air-flow measurements are needed and they should be secured in currently on-going studies. Special attention should be paid to COPD patients whose blood and urine samples should be stored for future use when proper tests become available to study markers of disease. 3.) MechanisnEof the pathogenesis of COPD should be worked into current in vivo and in vitro studies. 4.) Passive smoking has a low priority. e.) Dr. Gritz reported for the behavior. group. Research is needed in the following areas: 1.) Pharmacology of nicotine as the primary re-inforcer. Nicotine should' be given both intravenously and by inhalation. Self- administration of nicotilne should' be investigated. And tolerance and physical dependance in animals and i,n human beings needs study. 2.) Compensatory behavior must be i nvesti'gated. There should be separate studies on smokers who do compensate and those who don't. t. Swi tchi ng behavi or i s of two types -. free as i n the marketplace and forced or controlled as in a laboratory situa- tion. These are not the same. Experiments should be done with cigarettes of different tar to nicotine ratio. 3.) The current standard'smoking machines are not adequa te since they don't match the current behavior of smokers. What is the maximum possilble yield of the low tar-nicotine cigarette? 4.) Studies ought to be mounted on the toxicology of nicotine an& its role in disease.

- 13 - f.) Dr. Steinfeld reported for the cancer group 1.) Smokers who switch from high to low-yield cigarettes develop fewer cancers. But this may result in an increase of other tobacco-related diseases. 2.) There is a need for longitudinal epidemiologic studies on smoking and health and this should'include identification of brands smoked. Such studies should emphasize occupation, speci- fic age groups and ethnic groups. 3.), A new administrative element within the government ought to be established that would organize centers where people interested in smoking and health could work together. Such centers should have stable funding committed for extended periods. 4.) NIH ought to set up a special study section to review grant requests on smoking and health. 5.) Additional carcinogenic testing ought to emphasize the nitro- samines in smoke. Special attention ought to be paid to flavoring agents and other additives. The group felt that industry should do this work and then make the information public. 6.) Tar from liow-yield cigarettes ought to be studied. 7.)Gas phase smoke should be studied for its carcinogenic properties. 8.): In vitro short-term models for carcinogenesis ought to be validated. 9.) The co-carcinogenic properties of nicotine and acrolein ought to be investigated. 10.) investigate anti-carcinogens such as vitamin A and its analogues. 11.) Establish a register of all compounds found in smoke. 12.) The iinternational studies of NCI ought to be continued. 13.) Genetic markers, particularly-HLA groups, should be investigated for evidence leading to the identification of susceptibility to cancer. 14.) Passive smoking has a low priority. 18.) After these formal reports, discussion was opened. a.) Bock responded to Longo's assertion about the lack of evidence that N pregnancy difficulties are not alleviated by smoking liow-yield cigarettes. O Bock said that since women, in general, never smoked high-yield cigarettes, N there was no opportunity to see what a really loW .delivery cigarette ciga- N rette would d'o. G11 ~ . ~ ~ . ~ . =o

- 14 - b.) Castelli stated that the availability of 1ow yield cigarettes would impede quitting and could make the initiation of smoking easier. c'.) Gri'tz disagreed with Castelli and the thought that the availability of liow yield cigarettes would make quitting easier. d.) Lfi insky felt there was a need' to have a good test for studying the changing carcinogenic potential of mixtures. He thought that Pieta and Huberman have tests which would be useful in such studies. e.),Elizabeth Wei'sbur er thought that acrolein might be a promoter. Bock contra 'icte thi's and repeated that,nicotine is a cocarcinogen. f.) Castelli thought that the money for these good suggestions should comerom tTie tobacco industry; or from the smokers in the form of a 5Q~ per pack special tax. g.) Gri ffith wanted to know what compound' other than nicotine was an habituator. Bock had' no answer. h.) Elizabeth Weisburger asked whether it would be worthwhile studying the effect of on enzyme.systems that act as de-toxifiers. Bock agreed but could youlget funding for such study? i.) Wynder pointed out that there was universal agreement that there was a dose-response between exposure and effect - the more cigarettes the greater the effect. Then clearly there must be a "no effect" level. Let's concentrate on determining that level. He then described the work of the American Health Foundation in preventive medicine and he urged that everyone become an advocate for prevention. j.) Lon o would like to see a national birth and death certificate whicld i~nclude information on-smoking. The government should require cigarette manufacturers to release information on additives. He called for studies on the initiation of smoking and this might l ead to techni ques for preventi ng the i niti ati on. k.) Kimbeli believes taht investigators are close to unravelling the pathogenesis of CQPD, particularly emphysema. Suppose it turns out that ci' arettes are an obvious cause. What can be expected' from govern- ment? ~No answer). Stei~nfeld said that if there is a single compound involved, then it cou de renoved. 1.) Jarvik wanted to know whether there is a dose-response curve for accepta 'Ti ity of cigarettes in terms of nicotine. If so, how does this correspond to the dose-response curve for disease? Bock responded by saying that not much is known about the attributes of acceptability. Jarvik answered that if we knew about the levels of nicotine in the body we might be on better ground. m.) Hulle brought up the possible adverse effects of low-yield cigarettes: ~ (1.) inhibit quitting and enhance initiation, (2) epidemiologic studies Q on switching and qui'ttiing%•are-:implJcitly biased since those who quit and N. those who switch are self-selected; are there constitutional differences MA to account for this self-selection; (3)~ there ought to be more attention CA Gl .. ~ . ~ N

paid to social and political factors involved in smoking. n .) Wynder called for- a Manhattan-project type approach to the smoking and ea th question and to preventive medicine in general. o.) Pinney - had the last word. Each participant will see the: transcript of awh t the chairman of his group submits (30-40 pages). Then it will a11 go into the 1981 Surgeon General's report to Congress. What recom-s mendations the Surgeon General and' the Secretary of QHIiS will make to Congress, we don't know at this time. RF/cl a

- 16 - S.ummary Although the cancer group accepted the low-yield cigarette as "safer" in the sense that there was a lower rate of lung cancers among the smokers of these cigarettes, the pregnancy/infant development group could find no evidence for a beneficial effect of switching. The cardiovascular group maintained that the evidence for benefits from switching to low-yield cigarettes is not of good quality. Low-yiel~d cigarettes were considered harmful by the behavioral group because those cigarettes do not supply sufficient nicotine to satisfy the habituated smoker. Hence he has to smoke more cigarettes or else smoke in a fashion which exposes him to excess noxious material! such as "tar" and C0. No doubt was expressed by anyone that cigarette smoke was casually in- volved in cancer of the lung, larynx and bladder; was casually invol,ved in cardiovascular di~sease, chronic obstructive lung disease, infant mortality, peri natal mortal i ty, bi rth defects and compl ilcations of pregnancy. All the participants were concerned that material was being added to cigarettes without being tested for possible carcinogenic potency as sub- stances in their own right or as part of the inhaled smoke. Everyone wanted the identity of these substances revealed. A large majority of the participants expressed'dissatisfaction with the parameters of the FTC smoking machine. They feel that the standard 35 U1 puff of 2-second furation and taken once a minute are unrealistic and give rise to numbers which are much too low. The only specific suggestion I heard' called for a 50 ul puff of 2.3-second furation taken every 30 seconds. There was a uniform call for publication of CO delivery. Several groups suggested that sidestream be studied with same intensity as mai nstream. Yet these same groups gave passi ve smoki ng a 1 ow priori ty.. There was some skepticism expressed about the composition of mainstream smoke from low-yield cigarettes. Several people wanted assurance tha t main- stream smoke from low-yield cigarettes was not different, qualitatively, from mainstream of the ordinary cigarette. Nicotine was heavily stressed by several groups. Some wanted to use it or its metabolite, cotinine, as an i'ndicator of smoke exposure. Some wanted it studied as a co-carcinogen. Some wanted to study it as a rein- forcer of the smoking habit and hence look for ways of administering it without the intervention of the cigarette. Everyone wanted more money for more facilities for more research.