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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.