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CJRRENT DIGEST of Scientific Papers Relating to Tobacco Use (Compi!- d and Described for Informational Purposes Only for the Tobacco Industry Research Co, nmittee. The Summaries Are Not Intended to be Complete Scientific Abstracts.) Vol. VIII, [1o. 1 January 1963 Contents 1. Smoking and the Lungs 2. Cancer Research 3. Smoking Surveys 4. Heart and Circulation 5. Other Systemic Conditions 6. American Medical Association Clinical Session 7. National Conference on Air Pollution 8. California Air Pollution Conference (Part 2) 9. Medical Opinions - o 0 o - Attached to this issue of Current Digest is an author's index to Vol. VII - 1962. - o 0 o - 1. SMOKING AND THE LUNGS BOUCOT, KatLtarine R., M.D., Professor of Preventive Medicine and Clinical Professo- of Medicine, Women's Medical College of Pennsylvania, Philadelyihia "In consult=.tion." (Medical Tribune, December 10, 1962, page 13) S',,udies at the Philadelphia Pulmonary Research Project based on 6137 older ~,ten reveal only one proved lung cancer inn a non-smoker and only one in a man who smoked less than 20 years, the author says in replying to a question. "The incidence of lung cancer increases with increasing t.egree and duration of smoking to the shocking figure of one cancer amon,-; every 16 men who smoked cigarettes heavily for more than i+0 years, " : ,he says. '2'lomen have not smoked as long as have men. Forty years ago, teen-aged girls sneaked an occasional cigarette but it was still not considered 'lady-like' to smoke in public.... If smoking is the major factor involved in causing lung cancer, we should see a marked increase in squamous and undifferentiated cancer among women within the next ten years." CONFIDENTIAL: N1INNESOTA TOBACCO LITIGATION TIMN 0230914

2. FITZPATRICK, Martin, M.D., W i1l Rogers-O'Donnell Memorial Research Laboratories, Saranac Lake, New York "Chronic bronchitis." (Current Medical Digest, Volume 19, pages 71-73, November 1962) The msjor irritant to most of today's patients with chronic bronchitis is inhaled tobacco smoke, the author says. Little success is achieved in m_an_agement of the disease without total abstention. MAISIN, J. & TShLEPIS, G., Cancer Institute, University of Louvain, Belgium "Cancer of the _],ung and its treatment." (In Italian; Radiazioni di Alta Energia, Voli:me 1, No. 3, pages 125-138, 1962) Of 29~_, patients with lung cancer in this series, 257 or 85.9% were known to b: cigarette smokers, and information on the others is lacking. There were 291 men and only 8 women in the group; none of the women smoked ci,;arettes. The authors say that women go out less, are less exposed to air pollution, but are just as exposed as the men to .respiratory inf=!ctions. McKEE, Herbert, Swansea, Wales "Smoking and lurrig cancer." (Letter; Lancet, December 15, 1962, page 1277) Disc»z;sing Passey's suggestion that excessive mucus secretion helps to origin.te lung cancer (Current Digest, August 1962, page 8), and Sir R. A. Fisher's (1959) recording of the paradox that heavy smokers run a greater r-.sk of lung cancer if they do not inhale, the author says: "As the heavy s!ioker inhales over the years, basal hyperplasia continues. Cell growth requires anaerobic glycolysis and one would therefore expect that factors re=straining glycolysis would be produced in smaller amounts, until, by accidont, one or more of them were deleted -- i.e., until the potential cance;- cell was formed.... The smoker who inhales draws into his lungs not oril.y tobacco but-oxygen, and the relative overgrowth of potential cance~7 cells is delayed. People who smoke few cigarettes need to inhale much __onger to initiate the cancer; and, in them, accumulated mucus, by inter'ering with the oxygen supply of the potential cancer, acts as prime promot=sr." SIMPSON, J., M.D., DPH, Senior Lecturer in Public Health and Social Medicine, UnLversity of St. Andrews, Scotland "Chronic bronchLtis in England." (Journal of Chronic Diseases, Volume 15, pages 991-1000, October 1962) The correlation of bronchitis in England with air pollution suggests that a,iy occupational risk will have strong environmental connotations bu;, the influence of outdoor work in a densely populated area will be afE'ected in one way or another by individual habits and the way of life, th=~ author says. CONFIDENTIAL: TIMN 0230915 Ml "ESOTA TOBACCO LITIGATION

3 Discussing various papers relating smoking to bronchitis and lung cancer, he says: "Todd (T.M.S.C. Research Paper #1, 1959) showed that the countryman, on average, smokes two cigarettes fewer each day than does the l_ownsman. This is not a gross difference (9 against 11), but it does mean a difference of 730 cigarettes a year or 14,600 cigarettes fewer in %0 years and this cannot be ignored in partial explanation of the higher prevalence of aggravated bronchitis in the towns." 2. CANCER RESEARCH APPLEYARD, J. H., B.Sc., and JAFFE, A. A., B.Sc., Ph.D., Physical LaboratDries, University of Manchester, England "ElectricaL charges on the smoke from cigarettes and tobacco." (Physics in Medi,2ine and Biology, Volume 7, pages 195-199, October 1962) 'he authors report on their development of a simple method of measuring ;he net electrostatic charge on aerosols, and, among these, smoke from various types of cigarettes and tobacco. They found that the magnitude ;Lnd sign of the observed charge is a characteristic of the brand of c-•.garettes or tobacco, and that there are striking differences between dii'ferent brands. 'Iritish cigarettes A to E ranged from +22 to +31+ in mean charge per 35 cc. of smoke; a British/Turkish cigarette was +l0 and a Finnish ci,;arette +9. American cigarettes ranged from +13 to -13, and French cigarettes were -22 and -24. Cigarettes rolled from British pipe tobacco ranged from +12 to -8. The effect of a filter tip was neligible, the authors say. "A comparison of our results with the limited statistical data (Royal College of Physicians 1962) on the relation between smoking habits and the incidence of lung cancer suggests that a highly positive charged smoke may be more likely to be carcinogenic than one with a smaller charge," they say. "The correlation is stronger, for example, in Britain bhan in the U.S.A., and for cigarette smokers compared with pipe smokera. It is not possible at this stage, however, to decide whether the sign of the charge, or only its magnitude, appears to be significant. "`'he variation in sign and magnitude of the charge on the smoke of differen; brands may be due to the use of additives, which are absent from British cigarettes. It should be readily possible to control the charge in this way. We have readily obtained a blend of tobacco giving almost zero mean charge, for example, by mixing two brands which initially gave sample-, of opposite sign." CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION TIMN 0230916

4. DeBAKEY, Michael E., M.D., Baylor University College of Medicine, Houston, Texa:>, and BEEBE, Gilbert W., Ph.D., National Academy of Sciences-National Research Council, Washington, D.C. "Medical follow-ip studies on veterans." (Journal of the American Medical Association, )ecember 15, 1962, pages 1103-1109) "MortaLity from 1919 to 1956 for men treated for mustard-gas injury and for pzeumonia during the height of the 1918 pandemic was compared (Current Digest, February 1961, page 1) with that of men with wounds of the extremities to learn whether mustard-gas poisoning or 1918 influenza hid increased the likelihood of lung cancer," the authors say. "For influ=anza, no effect was found, but for mustard gas, the data are consist;_nt with an effect strong enough to double normal incidence." A study now bein.3 organized in twins is concerned with a wide variety of problems in humaa genetics, they say. HUEPER, W. C., M.D., National Cancer Institute, Bethesda, Md. "Environmental aad occupational cancer hazards." (Clinical Pharmacology and Therapeutics, Volume 3, pages 776-813, November-December 1962) Govern_nental, professional and private perties engaged in scientific and practical work in cancer have shown "astounding indifference and studied aloofness" in tha face of the "potentially dangerous development associated with the increasing artifactual carcinogenic contamination of the human environment and of goods produced and used in daily living," the author says. "It was only in recent years that a rather rude awakening from this lethargic state resulted from the acute concern of the general public regarding actual and potential cancer hazards.... (Among these are) the impressive aad progressive rise in the incidence of cancer of the lung during the past 50 years and its probable causal association with the growing pollution of the general and occupational atmosphere with more or less chemically well-definied carcinogenic industrial effluents and with the rapid growth in the degree of personal air pollution through the cigarette smoking habit." The author lists scores of known or suspected carcinogenic agents and includes in one table compounds suspected of causing arteriosclerotic difficulties, including nicotine. ROCKEY, E. E., M.D., SPEER, F. D., M.D., TH0MPS0N, S. A., M.D., AHIV, K. J., M.D. and HIROSE, T., M.D., Surgical and Pathology Departments, New York Medical College-Metropolitan Medical Center, New York City "Experimental study on effect of cigarette smoke condensate on bronchial mucosa." (Journal of the American Medical Association, December 15, 1962, pages 1094-1098) One-fourth of 1 cc. of cigarette smoke condensate provided by Dr. Fred Bock.was applied to the mesial wall of the left primary bronchus of 130 dogs 3 to 5 times weekly. In 25 dogs the same area was submitted to rubbing manipulations. The bronchial mucosa of 27 non-treated dogs was also examined. C CONFIDENTIAL: TIMN 0230917 MINNESOTA TOBACCO LITIGATION

5. Pap%llomas were produced in two of the dogs treated with smoke condensate, "' orecancerous changes" in 25, "carcinoma-in-situ" in 3, and invasive care'.noma in 1, according to the authors, and none of these changes occur~,ed in the other dogs studied. Inflamma.tory changes developed in ,he dogs of all three groups, but these changes "were not as persistent, a~,id the distribution was markedly smaller in the control dogs than in ~he cigarette smoke condensate group," they say. SHIMKIN, Michae1 B., M.D., Associate Director for Field Studies, National Cancer Institute, Bethesda, Md. "Symposium on chemical carcinogenesis. Introduction." (Clinical Pharmacology & Therapeutics, Volume 3, pages 774-775, November-December 1962) Discussing the symposium in chemical carcinogenesis reported in this jourral, the author says, "In this group of articles, little has been said abr-ut the most actively developing and the most promising approach to The study of neoplastic disease, that of the role of viruses. This biologic, environment of man is shared by other species, and it is no longer teiLable to consider that such entities as the Rous virus of chickens, thz: Bittner virus of mice, and the polyoma virus are one-species laboratory cti.riosities. Indeed, the neoplastic potentials in hamsters of the Simian V-_rus 40 and of the human Adenovirus 12 seem to be close to the very lock of the human neoplastic secret." 3. SMOKING SURVEYS ARNE'IT, John H., M.D., Drexel Institute of Technology, Philadelphia, Pa. "Smoking habLts of students at Drexel Institute of Technology." (Journal of American College Health, Volume 61, page 78, October 1962) In reply to questionnaires given to 1719 entering students in 1960 and 1961, the answers indicated that 508 or 29.6% smoked, the incidence of smoking being 30% in men and 24% in women. In June 1961 questionnaires mailed to all students who were about to graduate brought answers from 312 seniors; 115 or 36.9% smoked, including 37.5% of the males and 29.6% of the females. Eighteen broke the smoking habit while at Drexel, two due to advice from the health service, while 49 acquired the smoking habit at school. "We have thus been worsted by 10 per cent in the first round or our camp?,ign against lung cancer, and it behooves us to change our tactics nexi, season," the author says. "This we plan to do." CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION TIMN 0230918

6. BARRET, Kevin A., LRCP, S.I., L.M., DPH, Assistant City Medical Officer, Calgary, Alberta, Canada "High school st?idents' smoking habits." (Canadian Journal of Public Health, Vo1i?me 53, pages 500-506, December 1962) "Because of the increased death rate from lung cancer and the statistical asscciation between tobacco consumption and the occurrence of lung cancer nnd arteriosclerotic heart disease, the Calgary Health Department staft decided to make a survey of the city's high school students' smokir,g habits andd later to undertake an educational campaign in the schools wit17, a view to preventing young people from starting the smoking habit," the author says. A que-tionnaire type survey was given to 7682 students. It was seen that the students started to smoke at an early age, he says. Most students b__came established smokers between 12 and 16 years, the peak for boys bCing at 14 years and for girls at 15 years. There is a high percentage of smokers in Calgary's schools and many of these pupils buy their cigarettes illegally, he says. The highest percentage of sviokers come from upper social class parents. The smokers rate badly in o-oganized sport and very badly academically. They tend to follow the example of their parents in the adoption of the smoking habit. They took their first cigarette out of curiosity and continued to smoke because they de.oived pleasure from it. The vast majority of them smoked filter-tip cigar7ettes and would be prepared to stop smoking if the hazards were proved to 1;hem, he says. Only 20.1% stated that they would not give up the habit. CANADIAN TUBERCTTLOSIS ASSOCIATION BULLETIN, Toronto, Canada "Adults' bad ex;wple is followed." (Editorial; Volume 41, page 3, December 196:?) Answe7s to 8000 questionnaires filled in by school children in grades III to XIII in Kenora, Red Lake, Fort Frances and Dryden Schools indicated that 50 per cent of the children had their first cigarette before they wei-;: eight years old, the editorial says. The years 10 to 15 are the ones in which those children who smoke become regular smokers and it takes about two years to pass from the light to heavy smoking range, Dr. E. R. Langford. reported to the annual meeting of the Ontario Thoracic Society. "Chil•iren are surrounded by cigarette smoking adults and bombarded with :!igarette advertisements," he said. Smoking habits of parents undoubtedly affected children, analysis of the data showed. Academic achievem.ent is in inverse ratio to the amount of smoking. He advocated an effort to persuade tobacco companies to be more responsible in their advertising. Dr. R. B. Southerland, discussing lung cancer as an occupational disease stated that carcinoma-provoking substances were used in some industries but that cigarette smoking is the most commbn causal factor in lung cancer. CONFIDLwTIAL: TIMN 0230919 ,dI~SOTA TOBACCO LITIGATION

HORNER, J. Stuart, M.B., Ch.B., DPH, DIH, Deputy Medical Officer of Health, County Borough of Dewsbury, England "Cigarette smoking and health education." (Medical Officer, November : pages 305-308) This is the complete history of a "comprehensive campaign of health teaching and to evaluate its effects upon the pattern of smoking in a school with 210 boys and 228 girls aged 11 to 19. At the end of five weeks there were no significant changes in the pattern of smoking, although there was some evidence that the boys had been influenced rath than the girls. The author suggests that in order to assure greater accuracy in responses, an initial survey should be followed two months later by the "real" survey, by which means the confidence of pupils is more likely to be obtained. TAYLOR, R. M., M.D., FRCP(C), Canada "The impact of education." (Acta Unio Internationalis Contra Cancrum, Volume 18, No. 5: pages 702-708, 1962) Replies to a questionnaire addressed to a sample of 2000 women in cities and rural areas throughout Canada, compared to a 1954 survey among women in the Manchester area of England, showed that only 5% of the Canadian women cited "cut down smoking" as a possible action to reduce cancer, compared to 3% of the British women in 1954. "So much publicity has been. given to the possible evils of smoking that it might have been expected that more mention would. have been made of the possiblE value of its reduction or elimination," the author says. 4. HEART AND CIRCULATION 63ILENS, Sigmund L., M.D. and PLAIR, Cassius M., M.D., Laboratory Service, Veterans Administration Hospital, New York City "Cigarette smoking and. arteriosclerosis." (Science, November 30, 1962, pages 975-977) The authors reviewed findings in 989 consecutive necropsies Ln men performed between 1958 and 1961. Daily smoking of more than 1 1/2 oa.cks of cigarettes for many years was the criterion used to determine heavy smoker of cigarettes; moderate smokers were those who smoked :~. to 1 1/2 packs a day, and light smokers those who smoked less than a yack a day. Cigar and pipe smokers and tobacco chewers were small in 1-um.ber, they say. In a tabulation of the percentage of incidence of conditions associated with increased severity of arteriosclerosis, "it may be seen that there is no striking difference in the incidence of hypertension, diabetes, obesity, gallstones, or cortical hyperplasia of adrenals in n:)n-smokers and in the various categories of smokers," the authors say. "Lt is clear that cigarette smoking does not tend to promote development oE disorders that may contribute to the development of arteriosclerosis.. CONFIDENTIAL: 0230920 MINNE`'~OTA TOBACCO LITIGATION ~1MN

8. "A si,able minority of heavy smokers of cigarettes seem to develop scleroti.c changes inn their aortas at a faster rate than non-smokers and tend to hav.- slightly higher blood cholesterol levels. The incidence of myocardial iTfarction is only very slightly higher in heavy smokers of cigarettes t1r.an in non-smokers, and there is no consistent rise in the incidence oT' such lesions with degree of cigarette smoking. The incidence of otlrLer types of lesions related to arteriosclerosis is not affected by smo':ing habits. "The i'indings do not preclude the possibility that heart attacks due to myocard-i_.l infarction ma.y be more severe clinically, and more often fatal during th=:ir acute phase, in heavy smokers of cigarettes than in non-smokers." H:lsewhere the authors say, "The relation between cigarette smoking and heart attacks could be an indirect or even a fortuitous one. Heavy smokers m-oy have other habits or characteristics that make them vulnerable to m?rocardial infarets." 5. OTHER SYSTEMIC CONDITIONS POTTER, John F. M.D., Associate Editor, GP (Published at Kansas City, Mo.) "Cancer of the -_arynx." (Family Physician, Volume 3, pages 46-48, November 196<?) Two et;iologic agents of significance have been established in laryngeal carLcer, the author says. "This disease is seen most commonly among people who are heavy smokers and among those who have had a heavy con:;umption of alcohol." Cancer of the larynx is seen more commonly -t.<< men than in women in a ratio of about 1:10, and is seen in the l'ifth decade of life in both sexes, he says. SCHNEIDER, Mart_n, M.D., Professor of Radiology, University of Texas Medical Centor, Galveston "Epidermoid caroinomas of the oral cavity: A review." (American Journal of the Medic-Ll Sciences, Volume 244, pages 628-645, November 1962) Among the traumatic agents most frequently indicted in oral cancer etiology are chewing tobacco and sundry Asian mixtures, reversed cigar smoking aud pipe smoking, the latter suggesting "the likelihood of a chemical e;iology from the concentrated hydrocarbons carried by the tobacco smo?se," the author says. CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION TIMN 0230921

9. W-i-LSON, Edwin B., Ph.D., LL.D., Consultant, Office of Naval Researc:h, Boston, Mass. "NDte on the epidemiology of peptic ulcer." (Proceedings of the National Academy of Sciences, Volume 18, pages 1924-1927, November 1962) The author examined the tabulations on peptic ulcers provided by Hammond & Horn (J.A.M.A., March 15, 1958:1295), in part as follows: (T~Lble 1) Caise of death Number of deaths _ Smokin Observed Expected Ratio Gastric ulcer None 0 -- 1.00 Cigarette 46 0 Inf. Other 5 0 Inf. Duc iena.l ulcer None 8 -- 1.00 Cigarette 54 25 2.16 Other 11 12 0.92 "It is noted that those who never smoked never died of gastric ulc-:r," the author says. "This gave a zero under 'Expected' to go into the den' >minator of the expected deaths and accounts for the entry 1Inf.t (for infinity) in the ratio column. It is difficult to believe that with a mI_Lch larger sample one would continue to find that non-smokers never diet. of gastric ulcer, though the rate might be very small. The 46 cig?-rette smokers who died of gastric ulcer constitute enough to be really siTr.ificant statistically; but the 5 'other' smokers are too few to be si~+ificant and so the infinite ratio is not. "Turning to duodenal ulcer, we find 8 deaths among non-smokers, which is significa.ntly greater than 0 as found for gastric in the same popl?Lation. The figure of 54 for cigarette smokers is undoubtedly si&m-.Lfica.ntly greater than the 25 expected; indeed, of all the 14 different diseases or disease groups tabulated by Hammond & Horn in their Table 1, the laortality ratio of 2.16 for cigarette smokers for duodenal ulcer is the greatest except only that of non-malignant pulmonary diseases (for which it is 2.85).... Based on death statistics, the different sex ratio, the <Lifferent age distribution, a.nd the different reaction to smoking make the c:pidemiology of gastric and duodenal ulcer different," the author concludes. CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION TIM-S 0230922

10. 6. AMERICAN MEDICAL ASSOCIATION CLINICAL SESSION Following are excerpts from papers presented at the Clinical Session of the American Medical Association held at Los Angeles, California, November 25-27, 1962. BRESLOW, Lester, M.D., Chief, Division of Preventive Medicine Services, California State Department of Public Health, Berkeley "Environmental carcinogenesis." "Far ?'rom being a rare phenomenon, initiation of cancer by environmental a,-;ents may be the most common pattern of origin of cancer," the author said: "Probably the greatest stimulus to this idea has been the demonstratic)n by epidemiological research and other investigations that cigarette :imoking is responsible for the phenomenal increase in lung cancer. Already the leading site of fatal cancer in U.S. men, the lung is becomin~; a frequent site for female cancer as well -- due to cigarette smokirtg." HAAGEN-SMIT, A. J., M.D., California Institute of Technology, Pasadena "What is Los Angeles smog?" "Ther=~ is general agreement that at present the emissions from motor vehicles .:onstitute the largest smog source," the author said. KOTIN, Paul, M.)., Carcinogenesis Studies Branch, National Cancer Institute, Bethesda, Md. "Polluted urban air and related environmental factors in the pa.thogenesis of pulmonary cancer." "The real, and at least until recently, progressive increase of lung cancer appears almost certainly to be associated with the contamina- tion of our respiratory environment with carcinogenic agents and other environmental substances which serve to facilitate the action of these agents," the author said. "The specific epidemiological pattern of lung cancer incidence probably reflects the total of the combined effects of these exogenous environmental agents as modified by endogenous host factors. "The major emphasis of this presentation will be devoted to exogenous factcrs including polluted urban atmosphere, cigarette smoke, and viral infections. It must be emphasized that evidence for an exclusive environmental rource or factor acting in the pathogenesis of lung cancer is lacking. Tr.erefore, a discussion of air pollution and lung cancer, independent of its relation to other environmental factors, is unrealistic.... "Sinc,e the chemistry of polluted urban air and cigarette smoke are remarkably similar, it should be emphasized that much of what is being presente,_'. as pertinent to the former will also be applicable to the latter." CONFIDENTIAL: 1`.ZINNESOTA TOBACCO LITIGATION TIMN 0230923