Tobacco Documents Online

r 7Rr" : Cu`~7-F / N E-r,-c_rr 7?T;F-L: "THE LFSS HARAFUL CIGA.RE'r'TE". by D. Ho=fmann American Heal'th Foundat±ori T.C. Tso U.S. Dept: o= AgricultL_e : G.B. Gori National Cancer T_nstitute . ~ ~~ . ?or : resentz;:i on at,,Co^ "e_ ence crn the Pi-ar• Prevention o_ Cznce= r?ssessme:a of Risk ?zctors New Yoric, N.Y. c.^d?Ut•.Iz2 D_rectioS1s. . .7L'r^ .ee %-$. 1979

, G . FIRST DRAFT SECOND DRAFT THIRD DRAFT FOURTH' DRAFT May 23, 1979 June 1, 1979 June 5, 1979 June 6, 1919 IF FT DH~RAF~INAL June 14, 1979 THE LESS HARIMFUL CIGARETTE INTRODUCTION The reports on the adverse health effects of cigarette smoking by the Royal College of Physicians in 1962 (1) and ~ by the U.S. Surgeon General in 1964 (2) led to increased efforts by private and public agencies to discourage ciga- rette smoking. Over 30 million people in the USA may have dis-' continued their smoking habit because of information campaigns, educational programs and smoking cessation clinics, with the highest success achieved in college-educated males (3). How- ever, we can take little comfort in this fact, as 54 million men, women and teenagers are smoking cigarettes in the USA today (3) compared to an estimated 64 million in 1963 (2). Under current cultural, social, economic and political systems, it is unlikely that people will soon stop smoking. The only alternative in reducing the risk associ~ated with cigarette smoking appears to lie in the further improyeTlent of the •less harmful cigarette. The humanidata gathered during the last 10 years support the development of the less hazardous cigarette. In the USA, Bross and Gibson (4) and Wynder and associates (5-7) have shown, in retrospective studies, that the long term filter cigarette 4 smoker has a 10-308 lower risk for cancer of the larynx and lung than has the smoker of nonfilter cigarettes (Fig. 1& 2). Reports from the United Kingdom have demonstrated that cohorts of younger male and female cigarette smokers had asignificantly - 1 - ~QQ01~~.6J5

lower risk for lung cancer than older cohorts (8). These facts appear to reflect a greater number of junior smokers who have stopped smoking and that there are a greater manber of filter cigarette smokers (8). Recently, tiamrond et al reported in a prospective study that risks for coronary artery disease and lung cancer were significantly reduced for smokers of low "tar"-low nicotine cigarettes, compared to smokers of high "tar"-high nicotine cigarettes (9). These data reconfirm the increased disease 1 risks for smokers of all types of cigarettes, including low "tar" cigarettes, over those for nonsmokers, however, they also demonstrate that the risks for the consumer of low 'tar"-low nicotine cigarettes are of lesser magnitude than those for the "heavy " smoker. Additional data indicate that smokers of low "tar"-low nicotine cigarettes are more likely to eventually give up smoking than are smokers of other types of cigarettes (10). Auerbach et aZ have recently observed ' that progressive neoplastic changes in the bronchial epithelium of smokers, who had died within the years of 1970:to 1977 and who had:primarily smoked filter cigarettes, were less common than those in smokers of plain cigarettes who had died during the 1950's (25). - 2 -

In cancer of the oral cavity and esophagus, risk reductions have so far not been observed for long term smokers of filter cigarettes. This is likely so because these types of cancers are also related to other kinds of tobacco usage, as well as to alcohol consumption (6,12). Since cigarette smoking is of lesser influence for cancer of the pancreas, kidney and bladder, and since other factors play a significant role in the etiology of these cancers, the diminished smoke exposure of smokers of filter cigarettes may not be detectable (12,34,35). Furthermore; little is known about the reduction of organ specific carcinogens in the smoke of filter cigarettes (12,36,37). r - 3 -

THE STATUS OF THE LESS HARMFUL CIGARETTE IN 1978/79 '" Epidemiological studies have documented a dose response between number of cigarettes smoked and risk to develop cancer of the lung, oral cavity, larynx, esophagus, pancreas, bladder and kidney (2,7,11-13). Bioassays have also demonstrated dose responses between amount of "tar" applied to the skin in mice and development of tumors (14,15). The daily exposure to various quantities of cigarette smoke was also shown to be dose-related in respect to the development of tumors in the larynx of Syrian golden hamsters (15,16). Thus, the first approach toward the less hazardous cigarette was the reduction of "tar". In the USA we witnessed sales weighted average "tar" reductions from about 39 mg per cigarette in 1957 to 16 mg in 1977; nicotine reduction ranged from about 2.55 mg to 1.1 mg (7,Fig.3). For the average German cigarette in 1960 and 1975, these values were 25 mg and 15 mg for "tar" and 1.45 mg and 0.65 mg for nicotine, respectively (Fig.4). Similar trends in the reduction of "tar" and nicotine were reported for Switzer- land and the UK (17,18). Concurrent reductions also occurred for other smoke constituents, such as benzo(a)pyrene (17,Fig. : Several developments have led to these Feducti©ns. One was the increasing consumer acceptance of filter cigarettes (1956 USA 19%, Germany 19%; 1977 90% and 89%, respectively). The other major change occurred in the composition of the cigarette filler. The major modifications and their effects on smoke -4 -

composition and on tumorigenicity of the smoke in the e:<perimental setting are listed in Table 1 (19-22). Furthermore, we have indications that the tumorigenicity of the "tar" measured on mouse skin, has even been selectively reduced (22;Fig.5). The most marked changes in the make up of the commercial blended cigarette of many Western countries were brought about by breeding and use of new tobacco cultivars, by increased selection of low "tar" tobaccos, by the use of tobacco stems, reconstituted tobacco sheets, and expanded tobacco lamina and stems, as well as by the utilization of tobacco leaves with better combustibility. The reduction of "tar" and nicotine during the last two decades has been paralleled by a significant reduction in CO concentration in the smoke of commercial cigarettes (17). However, studies from Germany, the UK and the USA have non-perforated demonstrated that conventional/filter cigarettes can deliver snoke witlz sanewhat higher CO concentration than that of plain cigarettes (8,17,23), !wen'thaugh-cigarettes with perforatad.-£ilter tips, deliver significantly less CO than other types of cigarettes (Table 2). The perforated filter cigarettes, which work basically on an air dilution principle, appeared on the ~ market only in recent years. It is expected that in 1979 Q close to 25% of all cigarettes sold'on the US market ~' will have perforated filter tips. Russel has shown on rJ ~ CA _ 5 _ cc

smokers that the beneficial effects of these low CO, "tar", and nicotine cigarettes is only partially negated by more intensive smoking (24). Until recently, behavior scientists have assumed that the lowest acceptable nicotine level would be around 1.0 mg per cigarette (26). However, due to modifications, including enrichment of smoke flavor, consumers today accept products with 0.8 mg nicotine and less. The use of tobacco blends that are high in flavor components and/or the addition of extracts of flavor_rich tobaccos to certain blends, require thorough evaluation of the biological activities of smoke from such products. Continued assays on toxicity and tumorilgenicity must assure that the reduction of toxic and tumorigenic effects in the smoke of the low "tar"- low nicotine cigarette is not offset by the introduction of unknown factors It has been calculated from data published in large scale prospective studies (11) that a smoker of approximately 2 cigarettes per day of the "average" type of cigarette marketed before 1960 apparentl: faced no detectable risk of increased mortality when compared to the nonsmoker (20). Table 3 lists the delivery of smoke components of the "average" types of cigarette manufactured prior to 1960 the current "average" brands, as well as smoke delivery of a vs. 1978/79 low "tar" cigarette. These differences could be inter- preted to represent a true reduction in risk, if recent changes in smoke flavor components have no bearing on the biological activities of cigarette smoke. - 6 -

FUTURE DEVELOPMENTS New concepts towards further improvements with respect to a less harmful smoking product continue to be tested in laboratory studies (Table 4). Although we realize that there will never be a totally "safe" cigarette, it is anticipated that future developments will further reduce the risks associated with smoking and that such developments will lead to products acceptable to the majority of those who choose to continue to smoke.

REFERENCES I. The Royal College of Physicians, Lond'on, "Smoking and Health" Pitman Publ. Co., London, 1962, 70 pp. 2. U.S. Public Health Service, "Smoking and Health", Report of the Advisory Committee to the Surgeon General of the U.S. Public Health Service. PHS Publ. No. 1103, 1964, 387 pp. 3. National Commission on Smoking and Public Policy. "A National Dilemma; Cigarette Smoking or the Health of Ameri- cans." American Cancer Society, New York, 1978, 151 pp. 4. Bross, I.D.J. and Gibson, R., Risks of Lung Cancer in Smokers Who Switch to Filter Cigarettes. Am. J. Public Health 58: 1396-1403, 1968. 5. Wynder, E.L. Mabuchi, K. and Beattie, E.J., The Epidemiology of Lung Cancer. Recent Trends. J. Am. Med. Assoc. 213: 2221-2228, 1970. 6. Wynder, E.L. and Stellman, S.D., Comparative Epidemiology of Tobacco Related Cancers. Cancer Res. 37: 4608-4622, 1977. 7. Wynder, E.L. and Stellman, S.D., The Impact of Long TernL Filter Cigarette Usage on Lung and Larynx Cancer Risk: A Case Control Study. J. Natl. Cancer Inst. 62: 471-477, 1979. 8. Wald, N.J., Mortality from Lung Cancer and Coronary Heart Disease in Relation to Changes in Smoking Habit. Lancet 1: 136-138, 1976.

9. Hammond, E.C., Garfinkel, L., and Seidman, H'.. 0. Some recent Findings Concerning Cigarette Smoking. In "Origins of Human Cancer." H.H. Hiatt, J.D. Watson and J.A. Winsten (eds), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. 1977, Book A, pp•101-112'. U.S. Public Health Service: "Modification of Smoking 11. Behavior in "Smoking and Health". U.S. Public Health Service, Chapter 19, 1979. Haenszel,W., Editor, "Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases" Natl. Cancer Inst. Monogr. 19, 1966, 465 p. 12. U.S. Public Health Service: "Smoking and Health" A Report to ~ the Surgeon General. Chapter 5"Cancer"' U.S.Govt. Printing Office 1979: 284-109/6619. 13. Doll, R. and Peto, R., Cigarette Smoking and Bronchial Carcino- 14. ma; Dose and Time Relationship Among Regular Smokers and Lifelong Nonsmokers. J. Epidemiol.Comm.Health 22: 303-313,1978. Bock, F.G., Dose Response: Experimental Carcinogenesis. 15. Natl.Cancer Inst. Monogr. 28: 57-63, 1968. Dontenwill, W.P., Tumorigenic Effect of Chronic Cigarette Smoke Inhalation on Syrian Golden Hamsters. In "Experimental Lung Cancer." E. Karbe and J.F. Park, eds. New York, 1974, 331-359. Springer Verlag,

16. Bernfeld, P., Homburger, F. and Russfieldy A.B., Strain Differences in the Response of Inbred Syrian Hamsters to Cigarette Smoke Inhalation. J. Natl. Cancer Inst. 53: 1141-1151, 1974. 17. Weber, K.H., Recent Changes in Tobacco Products and Their Acceptance by the Consumer. Proc. 6. Internatl. Tobacco Sci. Congress. Nov., 1976, Tokyo, Japan 47-63. 18. Russel, M.A.H., Smoking Problems: An Overview. Natl. Inst. Drug Abuse Monogr. 17: 13-33, 1977. 19. Wynder, E.L., Hoffmann, D. and Gori, G.B., Smoking and Health I. Modifying the Risk for the Smoker. Proc. 3 World Conf. Smoking and Health. DHEW Publ. No(NIH) 76-1221,1976, 564 pp. 20. Gori, G.B., Low Risk Cigarettes: A Prescription. Science 194: 1243-1246, 1976. 21. Gori, G.B. Toward Less Hazardous Cigarette, Report No. 1, DHEW Publ. No{NIH)76-905; Report No. 2 DHEW Publ. No(NIH76-1111; Report No. 3 DHEW Publ. No(NIH)77-1280, Report No. 4- in print. 22. Wynder, E.L. and Hoffmann, D., Tobacco and Health : P, Societal Challenge, New Engl. J. Med. 300: 854-903, 1979. 23. Hoffmann, D., Hecht, S.S., Schmeltz, I., and LaVoie, E., and Wynder, E.L., Recent Studies in Tobacco Carcinogenesis: Chemistry, Bioassay and Bioassay Monitoring. In print.

24. Sutton, S.R., Feyerabend, C., Cole, P.V. and Russel, M.A.H., Adjustment of Smokers to Dilution of Tobacco Smoke by Ventilated Cigarette Holders. Clin. Pharm. Therap. 24: 395-405, 1978. 25. Auerbach, 0., Hammond, E.C. and Garfinkel, L., Changes of BronchialEpithelium in Relation to Cigarette Smoking 1955-1960 va. 1970-77. New Engl. J. Med. 300: 381-386, 1979. 26. Garrik, M.E., Cullen, J.W., Gritz, E.R., Vogt, T.M. and West,'L.J., "Research on Smoking Behavior." Natl. Inst. Drug Abuse Res. Monogr. 17, 1977, 3'83 p. 27. Tso, T.C., Lowe, R. and DeJong, D.W., Homogenized Leaf Curing. I. Theoretical Basis and Some Preliminary Results. Beitr. Tabakforsch. 8: 44-51, 1975. 28. DeJong, D.W., Lam, J., Lowe, R., Yoder, E. and Tso, T.C., Homogenized Leaf Curing. II. Bright Tobacco. Beitr. Tabakforsch 8: 93-101, 1975. 29. Moser, G.P., "A Process for Removing Nicotine From Tobacco" U.S. Pat. 3 151 118, Sept. 29, 1964. 30. Jones, S.O., Ashburn, J.G., Stewart, G.M. and Moser, G.P. "Denicotinizing Process" U.S. Pat. 3 612 066, Oct. 12, 1971. 331. Zilkey, B.F. and Walker, E.K., Whole Plant Flue-cured Tobacco and Tobacco Sheet Smoke and Smoke Condensate Characteristics. In "Smoking and Health" Vol. 1, "Modifying the Risk for the Smoker", E.L. Wynder, D. Hoffmann, and G.B. Gori, eds. DHEW Pubi. No(NIH)76-1221: 57-65, 1976.

32. Tso, T.C. and Gori, G.B., A Novel Approach in Tobacco Production as Food Source and Smoke Material - Year 1976 and Year 2000. Proc. 6. Intern. Tobacco Sci. Congress. 33. Nov., 1976, Tokyo, Japan 81-86. Tso, T.C., Tobacco as Potential Food Source and Smoke Material. Beitr. Tabakforsch. 9: 63-66, 1977. 34. Wynder, E.L., and Goldsmith, R. The Epidemiology of Bladder Cancer. A Second Look. Cancer 40~: 1246-1268, 1977. 35. Wynder, E.L., Mabuchi, K., Maruchi, N. and Fortner, J.G. Epidemiology of Cancer of the Pancreas. J. Natl. Cancer Inst. 50: 645-667, 1973. 36. Hoffmann, D., Schmeltz, I., Hecht, S.S. and Wynder, E.L. Tobacco Carcinogenesis. In: "Polycyclic Hydrocarbons and ~ 4 Cancer", H.V. Gelboin and P.O. T"so, eds., Academic Press, d Vol. 1, 85-117, 1978. 0 37 Hecht Chen C and Hoffmann D S S B Tobacco-S cifi . . , . , . ., , ., pe c r~ ~ ,. Nitrosamines: Occurrence, Formation, Carcinogenicity, and ~ ~ Metabolism. Accounts Chem. Res. 12: 92-98, 1979. ~ 38. Hoffmann, D. and Wynder, E.L. Die quantitative Bestimmung von Phenolen im Tabakrauch. Beitr. Tabakforsch. 1: 101-106, 1961. 39. Wynder, E.L. and Hoffmann, D. Some Practical Aspects of the Smoking and Cancer Problem. New Engl. J. Med. 262: 540-543, 1960. , 40. Hoffmann, D., Adams, J.D. and Wynder, E.L. UnpubZished data.

TABLE 1 RANGE OF CARBON MONOXIDE IN SMOKE OF CIGARETTESI COUNTRY CIGARETTES4 Nonfilter Regular Filter Perforated Filter mg/cig mg/cig mg/cig USA2 (23) 11.6-17.0 [8] 14.4-20.0 ['23] 2.8-12.8 [9l UK3 (8) 9-16 [9l 13-18 [1'0l -- Germany (17) .16-21 (7] 15.5-22.5 [17] -- 1975 1 Brackets - numbers of commercial cigarettes tested. Parenthesis - reference number. 2 Covers more than 90% of the US market in 1977/78: average values (mg); nonfilter 14.9; regular filter 17.08; perforated filter 8.93. 3Average values (mg): nonfilter 12.5; filter 16.1.

TABLE 2 THE LESS HARMFUL CIGARETTE 1979-1980 REDUCTIONS OF BIOLOGICAL ACTIVITY OF CIGARETTE SMOKEI SELECTIVE REDUCTION OF AETyODS SMOKE CONSTITUENTS BIOLOGICAL ACTIVIiPY2 "Tar" Nicotine BaP Carcinogenicity Tumor Promotion. REMARKS I. Agricultural Aspects robacco Type 3 (Bright - Burley) + + + + + Yew'Cultivars + + + ? Fertilization + + + + 7 (nitrate) II. Tobacco Processing -ut + + + +? ? Jse of Stems + + + ++ ++ 2econstituted robacco Sheets (RTS)4 + + + ++ + Some RTS gi hi h CO 2TS-Paper Process ++ + + ++ g + =-xpanded Tobacco + ++ + +7 + Expanded Stems + ++ + ++ ? III.Cigarette Production Paper Porosity + + + + ? =ellulose Filters Acetate + + + + + :harcoal Filters5 + + + + T Perforated Filters ++ ++ ++ + ? LNethodology known to be applied to comnercial U.S. cigarettes. Reductions: ++ >50%; + significant; + insignificant; +7 questionable; ? unknown. r Comparison of gram to gram "tar" on mouse skin tests andror hamster smoke inhalations. Replacing Bright with Burley Tobaccos. }Data given for RTS related to those not made by the paper process. 'Reductions of "tar", nicotine and BaP (and other nonvolatiles) and volatile N-nitrosamines are, in general, greater with cellulose acetate filters than with charcoal, filters.

TABLE 3 CHANGES IN SMOKE COMPOSITION OF U.S. CIGARETTES SMOKE AVERAGE DELIVERY PER CIGARETTE CONSTITUENT • BEFORE 19601 1978/794 1978f794 (LOW'nTAR" CIGARET" TPi+t 43 16 NICOTINE (MG) 3.0 1.1 0.6 CO (MG) 23 17 8.9 N0x ( uG) ' 270' 280 100 HCN (uG) 410 200 130 ACROLEIN (uG) 130 80 50 PHENOL (uG) 1002 60 20 BENZO(A)PYRENE (NG) 353 18 10 I 1Gori, 1976 (20); 2Hoffmann and Wynder, 1960 (38); 3Wynder and Hoffmann (39); 4Hoffmann et aZ, 1979 (40). .

1 TABLE 4 RECENT MODIFICATIONS TOWARD THE LESS HARMFUL CIGARETTE METHOD RESULT OF MODIFICATION REFERENCE Homogenized Leaf Curing Less Toxic Smoke 27,28 Denicotinizing of Tobacco Reduction of Smoke Alkaloids and other Pyridyl Derivatives 29,30 Close Planting of Tobacco Smoke Reduced in Toxicity and Tumorigenicity 31 Removal of_ Protein NOxF Reduction in Smoke of/HCN, N-Nitrosamines, Amines, Quinolines and Other Tumorigenic Agents 32,33 049~ 40LY0 i0 0 00

Figure 1. Age-adjusted relative risk of lung and larynx cancer for LTFS and N~FS by quantity smoked. Fraction=No.cases/No. controls, LTFS= long term filter cigarette smoker(s), NFS= nonfilter ciga- rette smoker(s), F= filter cigarettes, NF=nonfil- ter cigarettes. AY Lung cancer, males: No. cases= 143 LTFS, 150 NFS; B) Larynx cancer, mal~es: No. cases=66 LTFS, 86 NFS, C) Lung cancer, females: No. cases=50 LTFS, 13' NFS, D) Larynx cancer, fe- males: No. cases=20 LTFS, 17 NFS. Wynder and Stellman(7). LDAY.. GINCDI (bIET.[SG mE L)..MALCs MQ.OI. GGaRETTES SuOaED KR.OAT LPC ~CDl.(10.CRIICTT(L I). tD1X:LS b OI ClG+RElTE3SwOrtCO ([R DAT IUR.w. C.hC(R, w."f MD.: o.. Gfi.tnr(S SRDnED KR, Wt LaR.Mt CuCU1.. F(.ALES

Figure 2. Sales weighted average tar delivery of U.S. filter and nonfilter cigarettes, 1957-78..: FTC=Federal Trade Commission. Wynder and Stellman (7). SALES WEIGHTED AVERAGE TAR DELIVERIES ( FRONI' 1959 TO PRESENTI 35 30 ® s E 20 Q ~ u .- ~ 1 10 © 59 60 61 62 63 64 65 66 67 68 69 70 71' . 72 7374 75 76 77 78 -V ,

Figure 3. Germany - Sales weighted average deliveries of total condensate and nicotine per cigarette - 1961-1975. Weber 1976 (17) 1960 1965 1970, 1975 © Moist condensate * Dry condensate 0 Nicotine

. Figure 4. USA - Decreasing concentration of benzo(a)pyrene in the condensate of a leading non-filter cigarette. t //V 1955 1960 1965 1970 1975 Years of purchase m ki 46

,C Figure 5. Decline of tumorigenicity on mouse skin due to smoke condensate,as teste&during the period~1954-19G5,compared with responses to a 0.005% benzo(a)pyrene solution (numbers in parenthesis are number of mice per group). a 100 T T ~ i. ~ 140) Q T 120) Q 1201 {1 ~ 8J i 190) Q i ~ ~ d t20l p JL 1 i E 60 o. c b2461 ~ A 40 d a t E 0 ' 1200) a 1200) 0 246) j 1501 1 ~ r.. `` 0 I - 1 I I J 1954/55 1957/58 1959161 1962/63 1964165 99% confidence I'imit_ Condensate BP on