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intcndficc 111c11i41M 114111111 TO (Name and Location) Ilr _ .I_ H_ Qaf•*PfCAf1 FROM (Name and Location) C_ H_ KPith =-~3'tF+t- Cold Spring Harbor - Banbury Center Meeting DATE GEN 55 (REV.6/74;' 0CtnhQ,- 72,1g79-_ REFERENCE NO. GHK-7g-46 On October 15 and 16, I attended the much discussed meeting entitled "Toward a Less Hazardous Cigarette" sponsored by the Banbury Center of the Cold Spring Harbor Laboratory. The invited attendees (see attached list and program) represented many of the groups outside of the tobacco Industry involved in health related studies, and there was a heavy representation of contractors to the NCI tobacco program. Although It Is claimed that the meeting was initiated as a part of a series of environmental conferences by Dr. James Watson (Director of CSH Laboratory and member of the Cancer Advisory Board), it appears as though Ernst Wynder and Gio Gori were the prime instigators and movers of the conference. Incidentally Gori appears to be partially back In the graces of the NCI working as an assistant to the director, Arthur Upton, but has not regained~titular control of the tobacco pro- gram, whose continuing funding is still uncertain. The program is currently under the wing of Dr. Diarle Fink,Associate Director of NCI. The general tenor of the meeting was somewhat different from previous NCI affairs in that there was less emphasis on the harmful aspects of smoking and the design of cigarettes and more on the improvements that have already been achieved through reduction in tar, nicotine and car- bon monoxide delivery. There.appeared to be a growing realization that "safer" cigarettes were on the market and being used, even among the most virulent anti-smoking advocates. This was brought out in the Monday evening session when answers to three questions posed by Mark Russell were formulated. The questions and answers were as follows: 1. Q: Are the risks of lung cancer from cigarette smoking down? A: Yes 2. Q: If so is this due to changes in cigarettes? A: Probably yes. 3. Q: If so is this due to lowered tar and nicotine or to a lowered carcinogenicity of the tar? A: Both. The answer to the last question reflected a feeling that lowering of tar levels was probably the most important factor, but that reduced specific activity such as that shown In reconstituted tobaccos was also contributory. Most of the material presented by the various speakers was not new, having been given at the last NCI meeting or elsewhere. Discussion was also limited because of time constraints. All the material presented and the discussion were taped and transcripts will be available to the

Dr. J. H. Patterson -2- October 22, 1979 CHK-79-46 participants by November 6. The proceedings will issue In book form on or about April 1, 1980. The first session consisted of five papers dealing with epidemiological studies. Ernst Wynder reviewedhis previously reported studies on lung and other cancer trends In men and women, teenage smoking patterns,and smoking cessation programs. He showed dose response curves for cancer at various sites, myocardial Infarction and chronic pulmonary disease. He claimed that there Is a one-third reduction in lung and laryngeal cancer risk for smokers of filter cigarettes for ten or more years. Questions as to the safety of low tar, high nicotine cigarettes and of flavor additives were posed by him. Cuyler Hammond and Lawrence Garfinkel reviewed American Cancer Society interview data obtained between 1960 and 1972. Hammond reported a significant decrease in risk for lung cancer, coronary heart disease and total deaths for men and women smoking lower tar cigarettes. The decreases ranged from 10 to 40% depending on sex, disease category, and period of time. He thus was able to state that the preponderance of scientific evidence very strongly suggests that reducing air and nicotine will create a safer cigarette. Garfinkel had reworked the ACS Interview and questionaire data from 1959 to 1972 to determine whether switching to lower tar and nicotine cigarettes had in- creased consumption and found no significant change. However he did find that more than half of the people smoking less than a pack a day tended to increase consumption, while only a quarter of those smoking more than a pack a day smoked more on switching to lower tar. On questioning, his definitions of high, medium and low tar were more than 20 mg, 17.5-20 mg and less than 17.5 mg, which are considerably higher than present day concepts of these categories. Dr. Kunze reviewed his studies of Austrian lung cancer patients and controls and advanced a tar exposure index which is proportional to the product of tar level, years smoked, and daily consumption. He found a correlation between lung cancer (Kreyberg i) and this index and proposed that a "threshold" value of 500 was applicable. This threshold is slightly above an index of 400 which would be obtained for one pack a day of a 10 mg cigarette for twenty years. In the discussion of this and preceeding papers, the question of compensation by increasi'ng puff volume and frequency rather than numbers was raised and essentially left hanging. The final paper by Neil Lynch was essentially a rehash of the celebrated Gori and Lynch JAMA paper on thresholds. He was careful to avoid the threshold concept, preferring a "not different from control" approach. ln the discussion Gori felt that the problems caused by this paper were worth it if it had increased public awareness of the relative advan- tages of low tar cigarettes. He opined that he had more troubles from his "friends" than his "enemies." Wynder injected that thresholds were scientifically difficult and politically impossible to establish. The afternoon session consisted of eleven papers on the toxicology of tobacco smoke, ten of which were presented. Relatively little new

Dr. J. H. Patterson -3- October 22, 1979 CHK-79-46 Information was presented in these. Sam Battista reviewed his work on the role of agents such as heparin, sodium citrate and fibrinolysin In stopping the inhibition of ciliary motion by thick mucous contain- ing serum. The only new feature was a film showing these effects. Dr. Battigelli of UNC talked about his pathological investigations looking for early indicators of lung disorder. He felt that small airway obstruction and changes in morphology were the best current tools. Louis Diamond reviewed work on the toxicity of nitrogen oxides (mostly N02), and described ongoing experiments exposing rats to com- binations af NO and cigarette smoke. Dr. Stewart was supposed to report on work he had conducted at the University of Wisconsin on carbon mon- oxide toxicity, but neither he nor his paper were present. Dr. Astrup reviewed his work on the effects of CO on heart function and reproduction. He claimed that moderate COHb levels lead to increased vascular permeability, increased serum cholesterol levels, decreased the work load for development of claudication, angina pectoris and led to changes in myocardial function. The only data presented dealt with reproductive effects in rabbits, where .02$ CO in air gave decreased offspring weight (17$) and increased numbers of stillborn or dead bunnies (36% of the litter on day 1, 43$ by day 6). Colin Schwartz,who has taken over from Henry MaGill in the Texas baboon smoking experiments reviewed the mechanisms that might connect smoking with cardivascular disease, and talked generally about the current status of these experiments. After three years of smoking forty cigarettes a day, they are finding reduced serum cholesterol in the smoking animals which is somewhat surprising.. Leucocytes and lymphocytes are increased in the smoking animals, and factor 8 levels are lower in the smokers, which Is taken as a sign of injury. Naomi Harley reported on her ongoing work on Polonium 210. She finds a three-fold Increased level of Po 210 in the lower lungs of smokers and ex-smokers for five years compared to non-smokers, suggesting a deposition of particulates containing the long-lived parent Pb 210. Of more interest in relating to human lung cancer which occurs primarily at the bifurcations in the upper lung are her studies of the bronchial tree of 7 smokers (3 current, 2 ex , 1 non and 1 backslider). The annual radiation dose for the non-smoker was 0.1 m rad/year while that for the smokers ranged from. .06 to 1.5 m rad/year. When comparing these doses with that of uranium miners who receive a dose of about I rad/year, the risk to smokers of cancer from this source appears to be negligible. However one smoker had a"warm'' spot with a cancer risk of 1% comparable to that of uranium miners. Her conclusion Is that Polonium is a very questionable source of lung cancer in smokers. Ben Van Duuren summarized his past work on tumor promoters and cocarcin- ogens, listing familiar materials such as phenol, oleic acid, catechol, pyrogallol and non-carcinogenic hydrocarbons such as pyrene and undecane. Dietrich Hoffmann reviewed his work on volatile and non-volatile nitro- samines which Included no new information. He did note that cellulose acetate selectively removes both volatile and non-volatile nitrosamines.

Dr. J. H. Patterson -4- October 22, 1979 CHK-79-46 Fred Bock repeated his presentation on the supposed cocarinogenic effects of nicotine. Curiously he finds that nicotine metabolites such as nicotine-N-oxide are not promoters and actually suppress tumor formation. Lawrence Garfinkel gave a rather impressive summary of his and Oscar Auerbach's paper in the New England Journal of Medicine this spring. This involved a comparison of lung sections from a group of smokers in the period from 1955-60 with a similar group in the 1970-77 time frame. A dramatic decrease to a point hardly greater than that of the controls was seen for the latter group In the incidence of atypical cells, hyper- plasia and carcinoma in situ. Garfinkel, who is well known as an anti-smoking crusader, felt that this would show up_in years to come as a major decrease In lung cancer. On Tuesday morning, seven papers covering various aspects of the components of cigarettes and'cigarette smoke were presented. One other paper on reconstituted tobacco by Bill Selke was not presented but will be include&in the proceedings. T. C. Tso indicated that the USDA has directed that no further work shoul6be done on improving tobacco pro- duction, but that all programs should be aimed at improved safety in tobacco. He summarized their program aimed at developing a useability index based on correlations between tobacco chemistry and NCI skin painting data. He also discussed the work of homogenized leaf curing and protein extraction, pesticide-free tobaccos and the haploid-diploid studies. Mike Guerin summed up the ORNL program on smoke chemistry, particle size analysis, material balance, and analyses of foreign and domestic brands. He presented data supporting the supposition that the tar obtained from non-filter,.filter, low tar and super light cigarettes was qualitatively the same. Dr. F. Muller of Bayer Industries described their artificial tobacco substitute, RCN. This is called a co-tobacco material and was described as consisting of 50% vegetable carbohydrate, the balance being fillers and combustion regulators. Slides were presented showing tar delivery as a function of tobacco in the blend for RCN', reconstituted tobacco sheet and an artificial tobacco substitute (unidentified). For a 50/50 blend, reconstituted tobacco gave 85%, tobacco substitute 55% and RCN 25% of the tar delivered by an equivalent amount of tobacco. Comparably large reductions in nicotine and phenol were also claimed, but it did not appear as though carbon monoxide, HCN and aldehydes were reduced as markedly as those components. Data showing combinations of RCN and ventilation, and oxygen consumption In blends were presented. It was claimed that their material gave a better yield of flavorants and that nicotine'issued as a free base from blends of tobacco and RCN. Mouse . skin painting data on an RCN predecessor gave a relative activity of 65-70% that of tobacco for a 75/25 blend, and 45-50$ for a S0/50 blend. Other biological tests were mentioned but no data were given. In the discussion Dr. Wynder opined that the problems with these materials, even though they were technically attractive was either economics or the ersatz name-tag. Dr. Gori felt that their safety was not proved

Dr. J. H. Patterson -5- October 22, 1979 CHK-79-46 unequivocally and that the economics were not all that good. Wynder had questions as to the current usage of either RCN or Cytrel, which were answered that RCN was not currently commercial and Cytrel was used In small amounts in Europe. This writer presented a review of filtration and ventilation which showed that almost any level of tar, nicotine and gas phase delivery could be achieved. The presence of ultra-low tar brands was noted as an inddcation of the responsiveness of the tobacco industry, and the barrier was thought to be public acceptance. Dr. William Cain talked about the role of flavor in smoking. He felt that smoking appealed to the chemical senses, and the smoker controlled his Intake to give a certain level of sensation, so that he might draw more heavily on very low tar cigarettes to compensate for loss of sensation. He reviewed the physiological aspects of flavor perception. Edmund LaVoie of the American Health Foundation described their work on bioassay of tobacco flavorants. His primary tool is an Ames test with TA 98 salmonella activated with mouse liver homogenate. Distillates from tobaccos heated at less than 250°C were trapped and fractionated into acidic, basic and neutral fractions which were assayed by this test for mutagenicity. He found that the ether soluble basic fraction was the most mutagenic. The active ingredients were a variety of pyrazines and harmanes. The final presentation in this session was an overview by Gio Gori. The final session consisted of several papers dealing with human studies and economic aspects of smoking. In the first paper Saul Shiffman raised questions about the degree of compensation and the limits of acceptability in smokers moving to very low tar cigarettes. His studies indicates some increase in consumption, an increase in nicotine transfer and a minimum consumption level of twelve cigarettes per day in his volunteer subjects. Michael Russell presented a case for maintenance of nicotine levels as tar delivery was decreased. He showed that sales weighted average nicotine delivery was relatively constant in the U.K while tar deliveries continued a downward trend. He finds little relation between numbers of cigarettes smoked and blood carboxyhemoglobin and nicotine levels. He felt that this was an indication of compensation, and wonders whether people have really reduced nicotine intake. Dr. Jaffe of the New York State Psychiatric Institute presented results from two studies In which incentives (a reduced cigarette price) were provided to panelists for smoking low nicotine ventilated cigarettes. They found that the incentives were relatively ineffective although combination of }A these with a health message helped promote the lower level cigarettes. O He also found evidence of compensation in relatively constant carboxy- 0 hemoglobin levels in all smokers, even those of the very light cigarettes which had a CO delivery approximately one fourth that of the heaviest 0 ~.l cigarette. In the economics area, John Maxwell reviewed the current status of the cigarette market. He estimated total consumption at 610 billion units

Dr. J. H. Patterson -6- October 22, 1979 CHK-79-46 for 60 to 80 million smokers. The low tar (less than 15 mg) segment has Increased from 24$ Tn early 1977 to 40% currently. Carleton at 1 mg of tar is the fastest growing brand with a 72$ growth this year and It should soon be among the top ten brands. Jeffrey Harris of MIT attempted to show via cost-benefit analysis the effects of a stepwise tax on tar and nicotine levels. A final paper by Brian Richter of Enviro Control dealt with the costs of smoke related disease, the costs of abatement programs, and their effects on longevity and its, related costs. This main conclusion was that the elimination of tobacco related disease would not economically benefit society. In summary most of the papers showed distinct benefits related to reduced disease risk from smoking low tar cigarettes. The epidemiological trends established from usage of moderately reduced tar cigarettes available some years ago are quite encouraging. Most of those present felt the sizeable tar reductions in modern cigarettes and the rapidly gowing public acceptance of these could lead to a distinct improvement In smoking related disease. There was an air of self-congratulation among those present and a feeling that safer cigarettes were at hand. CHK: MM cc: H. F. Elsom 156 P. M. Garrett 153 G. J. Johnson 237A R. K. Kunkel 250A J. E. Offerdahl 110 Tech. Information 240 2L C. H. Keith