The less harmful cigarette

PREVENTIVE

MEDICINE

9, 287-296

(1980)

The Less Harmful

Cigarette’

Risk assessment shows that the adverse effects of cigarette smoking on human health are clearly related to the total consumption of cigarettes. Such dose-response is evident from data on the incidence of lung and larynx cancer and is also supported by results from bioassays with Syrian golden hamsters and mice. The concept of a less harmful cigarette, therefore, involves primarily a reduction of the quantities of tar and nicotine in cigarette smoke. The identification of tumorigenic and toxic tobacco smoke constituents and the study of their formation during smoking has guided the development of products with 40-60% reduction of sales-weighted tar and nicotine levels in most western countries. These changes have been effected mainly through development of efficient filter tips, through selection of specific tobacco types, and modifications in tobacco blends. including the technology of reconstituted tobacco preparation. This presentation discusses details of the development of cigarettes with reduced levels of tar, nicotine, and carbon monoxide. It is emphasized that the risk for diseases associated with tobacco usage can be eliminated only by abstention from smoking, but that a risk reduction through product modification has been achieved and may be further- improved.

INTRODUCTION Reports of the adverse effects of cigarette smoking on human health by the Royal College of Physicians in 1962 (22) and by the Surgeon General of the U.S. Public Health Service in 1964 (29) led to increased efforts by private and public agencies to discourage cigarette smoking. More than 30 million people in the United States may have discontinued their smoking habits because of information campaigns, educational programs, and smoking cessation clinics, with the greatest success among college-educated men (21). However, we can take little comfort in this fact, for 54 million men, women, and teenagers in the United States were smoking cigarettes in 1978 (21) compared with an estimated 64 million in 1963 (29). It is unlikely that many of these will stop smoking soon. We believe that further refinement of a less harmful cigarette may effectively reduce the disease risks associated with cigarette smoking. Epidemiological data gathered during the last 10 years indicate that the modified cigarette has had some impact on reduction of risk among smokers for cancer and for coronary artery diseases. In the USA, Bross and Gibson (5), Wynder and associates (37) and Wynder and Stellman (39, 40), have shown, in retrospective studies, that the long-term smoker of filter cigarettes is at 10-30s lower risk for cancer of the larynx and lung than is the smoker of nonfilter cigarettes (Fig. 1). I Presented at the American Health FoundationiDeutsche Krebshilfe Conference on the Primary Prevention of Cancer: Assessment of Risk Factors and Future Directions, N.Y., N.Y., June 7-X. 1979. Supported by NlH contract NOl-CP-5666 and USDA grant 53-32U4-9-186. y To whom requests for reprints should be addressed. 287 009l-7435/80/020287-10$02.00/O Copyright Q 1980 by Academic Press, Inc. All rights of reproduction in any form reserved.

HOFFMANN,

a

NO OF CIGARETTES

SMOKE0

PER

DAY

TSO, AND

GORI

c

No DF CIGARETTES

LARYNX N LARYNX N 1

b

CANCER,

MALES

CANCER

SNOKED

PER

DA”

FEMALES

CASES CONTROLS

CASES CONTROLS

NO OF CGARETTES

SMOKED

PER

DAY

d

NO OF ClGARETTES

SMOKED

PER

DAY

FIG. 1. Age-adjusted relative risk of lung and larynx cancer for LTFS and NFS by quantity smoked. (a) Lung cancer, males: No. cases = 143 long-term filter cigarette smoker(s) (LTFS), 150 nonfilter cigarette smoker(s) (NFS): (b) larynx cancer, males: No. cases = 66 LTFS, 86 NFS: (c) lung cancer, females: No. cases = 50 LTFS, 13 NFS: (d) larynx cancer, females: No. cases = 20 LTFS, 17 NFS. See Ref. (40).

Reports from the United Kingdom have demonstrated that cohorts of younger males and females had a significantly lower risk for lung cancer than older cohorts (31). This appears to reflect the greater number of young smokers who have stopped smoking and the greater proportion who now smoke filter instead of nonfilter cigarettes (31). In a recent prospective study, Hammond et al. reported that risks for coronary artery disease and lung cancer were significantly reduced

CONFERENCE:

PRIMARY

PREVENTION

OF CANCER

289

for smokers of low-tar, low-nicotine cigarettes, compared to smokers of high-tar, high-nicotine cigarettes (13). Auerbach et al. have recently observed that the incidence of progressive neoplastic changes in the bronchial epithelium of smokers was lower in those who died between 1970 and 1977 (and who had primarily smoked filter cigarettes), than in smokers of nonfilter cigarettes who had died during the 1950s(2). These data confirm the increased disease 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 smoker of low-tar, lownicotine cigarettes are of lesser magnitude than those for the “heavy” smoker of high-tar, high-nicotine cigarettes. 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 (28). No differences in the risks of cancers of the oral cavity and esophagus have been observed so far for long-term smokers of filter and nonfilter cigarettes, most likely because these types of cancers are also related to other patterns of tobacco use and to alcohol consumption (30, 39). Because cigarette smoking has less influence on cancer of the pancreas, kidney, and bladder, and because other factors play significant roles in the etiology of these cancers (30), any differences in risks for smokers of filter and nonfilter cigarettes may not be detectable (30, 33, 38). Furthermore, it is not known whether, or how far, organ-specific carcinogens are reduced in the smoke of filter cigarettes, as compared with nonfilter cigarettes (14, 17, 30). THE STATUS OF THE LESS HARMFUL

CIGARETTE

IN 1978/1979

Epidemiological studies have documented a dose -response relationship between the number of cigarettes smoked and the development of cancers of the lung, oral cavity, larynx, esophagus, pancreas, bladder, and kidney (7, 12, 29,30, 40). Bioassays have also demonstrated dose-response relationships for the amount of tar applied to the skin in mice and the incidence of skin tumors (4, 8). The development of tumors in the larynx of Syrian golden hamsters was also shown to be related to the daily dose of cigarette smoke over a period of 18 months (3, 8). Thus, the reduction of the tar content of cigarettes was an important step in reducing the hazards of cigarette smoking. In the United States, the salesweighted average amount of tar per cigarette fell from 39 mg in 1959 to 16 mg in 1977 (Fig. 2); nicotine levels fell from 2.5 mg in 1959 to 1.1 mg in 1977 (7) (Fig. 3). In Germany, sales-weighted average tar contents of cigarettes dropped from 25 mg in 1960 to 15 mg in 1975 and nicotine content fell from 1.45 to 0.65 mg (Fig. 4). Similar trends were reported for cigarettes sold in Switzerland and the United Kingdom (23, 32). Concurrent reductions also occurred for other smoke constituents, such as benzo[u]pyrene (17) (Fig. 5). Several developments have led to these reductions. One was the increased consumer acceptance of filter cigarettes: in 1956, 19% of American cigarettes and 19% of German cigarettes were filter-tipped; in 1977, filter-tipped brands amounted to 90% of the cigarettes sold in America and 89% of those sold in Germany. The other major changes were in the composition of the cigarette filler. The major modifications and their effects on smoke composition and on

290

HOFFMANN,

TSO,

AND

FILTER

GORI

C~GARE~-T~~

* IS

I,, ,,,,,,,,,,,,,,,,I 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 FIG. 2. Sales-weighted

average tar delivery of U.S. filter and nonfilter FTC, Federal Trade Commission. See Ref. (40).

cigarettes from 1959 to 1978.

tumorigenicity of the smoke in experimental settings are listed in Table 1 (IO, 11, 36). Furthermore, Wynder and Hoffmann have found indications that the tumorigenicity of the tar, measured by the incidence of tumors on the skin of mice, has been selectively reduced since 1954/1955(35) (Fig. 6). The most marked changes in the composition of commercial blended cigarettes of many western countries resulted from the use of tobaccos with less tar (from new cultivars and because of more careful selection), tobacco stems, reconsti-

/NON-FILTER

CIGARETTES

^

;I,,,,,,,,,,,,,I,,,,,1: 59 60 6, 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 FIG. 3. Sales-weighted

1978.

average nicotine deliveries

of U.S. filter and nontilter

cigarettes from 1959 to

CONFERENCE:

FIG. 4. Germany: Sales-weighted from 1961 to 1975. See Ref. (32).

PRIMARY

average

PREVENTION

deliveries

of total

291

OF CANCER

condensate

and nicotine

per cigarette

tuted tobacco sheets, expanded tobacco lamina and stems, and tobacco leaves with better combustibility. The reduction of tar and nicotine during the last 20 years has been paralleled by a significant reduction in the concentration of carbon monoxide (CO) in commercial cigarette smoke (32). However, studies from Germany, the United Kingdom, and the United States have demonstrated that conventional, nonperforated filter cigarettes may deliver smoke with somewhat higher CO concentrations than do some nonfilter cigarettes (16, 3 1, 32), even though cigarettes with perforated filter tips deliver significantly less CO than other types of cigarettes (Table 2). The perforated filter cigarettes, which work basically on an air dilution principle, have appeared on the market only in recent years. It is expected that in 1979 close to 25% of all cigarettes sold on the U.S. market will have perforated filter tips. Sutton et al. have shown that the beneficial effects of these low-CO, low-tar, and low-nicotine cigarettes are only partially negated by more intensive smoking (24). Until recently, behavioral scientists have assumed that the lowest acceptable nicotine level would be about 1.0 mg per cigarette (9). However, because of

Yeorr of purchore

FIG. 5. USA: Decreasing cigarette (Hoffmann, 1952-

concentration 1975).

of benzo[rr

Jpyrene

in the condensate

of a leading

nonfilter

292

HOFFMANN,

TSO, AND TABLE

RELATIVE

GORI

1

EFFECTIVENESS OF TECHNIQUES USED COMMERCIALLY IN THE UNITED STATES REDUCING THE BIOLOGICAL ACTIVITY OF CIGARETTE SMOKE (1979-1980)”

Smoke constituents Methods Agriculture Tobacco type (bright-burley) New cultivars Nitrate fertilization Processing cut Use of stems RTS-nonpaper process’ RTS-paper process Expanded tobacco Expanded stems Production Paper porosity Cellulose acetate filters” Charcoal filters” Perforated filters

FOR

Biological activity”

Tar

Nicotine

BaP

Carcinogenicity

+ + +

+ + +

+ + +

4

+ +

k +

-c +

t+

+ ++ + +

+ + ++ ++

+ + + +

+

+

+

+ + ++

+ + ++

+ + t+

Tumor promotion

? 1

C?

++ ++ t? tt

+ + +

” Reductions: ++, >50%; +, significant; 2, insignificant; -t?, questionable; ?, unknown. BaP, benzo[a]pyrene; RTS, reconstituted tobacco sheets. h Comparison of gram to gram tar in mouse skin tests and/or hamster smoke inhalations. ’ Some RTS produce high levels of CO,. ” Reductions of tar, nicotine, and BaP (and other nonvolatiles), and volatile N-nitrosamines are, in general, somewhat greater with cellulose acetate filters than with charcoal filters.

-

0

1959161

195ll58

992 confidence

4 COndeflStit

I

I

1

I

1954155

1962163

lwlh5

limit 4

Ba P

6. Decline of tumorigenicity on mouse skin due to smoke condensate, as tested during period 1954- 1965, compared with responses to a 0.005% benzo[a]pyrene solution (numbers in entheses are no. of mice per group). FIG.

the par-

CONFERENCE:

PRIMARY

PREVENTION TABLE

CARBON

MONOXIDE

293

OF CANCER

2

IN SMOKE

OF CIGARETTES

Carbon monoxide (mg/cigarette) Reference USA (90% of av 197711978 sales)” UK (1975)b Germany (1975) Germany (1978)

(15) (31) (32) (1)

Nonfilter

Regular filter

Perforated filter

11.6-17.0 (N = 8) 9-16 (N = 9) 16-21 (N = 7) 14.5- 19.9 (N = 16)

14.4-20.0 (N = 23) 13-18 (N = 10) 15.5-22.5 (N = 17) 8.6- 18.5 (N = 15)

2.8-12.8 (N = 9) 2.2- 13.8 (N = 9)

(’ Average values for nonfilter cigarettes, 14.9 mg; for regular filter cigarettes, 17.1 mg; for perforated filter cigarettes, 8.9 mg. ’ Average values for nonfilter cigarettes, 12.5 mg; for filter cigarettes, 16.1 mg. N = number of brands tested.

modifications that maintain acceptable smoke flavor, increasing numbers of consumers today will accept products with 0.8 mg or less nicotine. Using tobacco blends that are high in flavor components or contain added extracts of flavor-rich tobaccos requires thorough evaluation of the biological activities of smoke from such products. New cigarettes must be assayed for toxicity and tumorigenicity so that the reduction of toxic and tumorigenic effects in the smoke of low-tar, low-nicotine cigarettes is not offset by the introduction of unknown factors. From data published in large-scale prospective studies (12), Gori calculated that a smoker of approximately two cigarettes per day of the “average” type of cigarette marketed before 1960, was apparently at no detectable greater risk of morTABLE 3 CHANGES

IN SMOKE

COMPOSITION

OF CIGARETTES

MANUFACTURED

IN THE UNITED

STATES

Average delivery per cigarette Smoke constituent TPM Nicotine (mg) CO (w) NO, (/a) HCN (/-cd Acrolein (wg) Phenol (pg) Benzo[a]pyrene (ng) ” See Ref. b See Ref. c See Ref. d See Ref.

(15). (10). (18). (34).

Before 1960 436 3.0b 23* 27W 41ob 1306 lO(r 35d

197811979” 16 1.1 17 280 200 80 60 18

197811979” (Low-tar cigarette) 8 0.6 8.9 100 130 50 20 10

294

HOFFMANN,

TSO, AND GORI

TABLE 4 RECENT

Method Homogenized leaf curing Denicotinizing of tobacco Close planting of tobacco Removal of protein

MODIFICATIONS

TOWARD

THE LESS HARMFUL

CIGARETTE

Result of modification Less toxic smoke Reduction of smoke alkaloids and other pyridyl derivatives Reduction of toxicity and tumorigenicity of smoke Reduction in smoke of NO,, HCN, N-nitrosamines, amines, quinolines, and other tumorigenic agents

Reference

(6, 27) (19, 20) (41)

(25, 26)

tality than a nonsmoker (10). Table 3 lists the delivery of smoke components of the average types of cigarette manufactured before 1960 vs the current average brands, as well as smoke delivery of a 1978/1979low-tar cigarette. These differences could be interpreted to represent a true reduction in risk, if recent changes in smoke flavor components have no bearing on the biological activities of cigarette smoke. FUTURE DEVELOPMENTS

New methods for reducing the risk of smoking cigarettes continue to be examined in laboratory studies (Table 4). Although we realize that there will never be a totally safe cigarette, we hope that future developments can 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. Note udded in proof: Recent analytical studies have shown that certain cigarette filters, notably those made of cellulose acetate have the capacity for selective removal of nonvolatile N-nitrosamines, one group of organ-specific carcinogens. (Hoffmann, D., Adams, J. D. and Piade, J. J. (1980) On the Selective Filtration of Tobacco-Specific Nitrosamines from Smoke by Cigarette Filters. Submitted for publication).

REFERENCES 1. Adlkofer, F. Carbon monoxide in the smoke of commercial cigarettes sold in 1978 in the Federal Republic of Germany. Unpublished data. 2. Auerbach, O., Hammond, E. C., and Garlinkel, L. Changes of bronchial epithelium in relation to cigarette smoking, 1955-60 13s.1970-77. Neub Engl. J. Med. 300, 381-386 (1979). 3. Bernfeld, P., Homburger, F., and Russfield, A. B. Strain differences in the response of inbred Syrian hamsters to cigarette smoke inhalation. J. Nar. C~ncrr Inst. 53, 1141- 1151 (1974). 4. Bock, F. G. Dose response: Experimental carcinogenesis. Nat. Cunc,c~rInst. Monogr. 28, 57-63 (1968). 5. Bross, I. D. J., and Gibson, R. Risks of lung cancer in smokers who switch to filter cigarettes. Amer. J. Pub. Heulth 58, 1396- 1403 (1968). 6. DeJong, D. W., Lam, J., Lowe, R., Yoder, E., and Tso, T. C. Homogenized leaf curing. II. Bright tobacco. Beifr. Tabakforsch. 8, 93-101 (1975). 7. Doll, R., and Peto, R. Cigarette smoking and bronchial carcinoma: Dose and time relationship among regular smokers and lifelong nonsmokers. J. Epidemic>/. Commrrn. Heulfh 22, 303-313 (1978). 8. Dontenwill, W. P. Tumorigenic effects of chronic cigarette smoke inhalation on Syrian golden hamsters, in “Experimental Lung Cancer” (E. Karbe and J. F. Park, Eds.), pp. 331-359. Springer-Verlag, New York, 1974.

CONFERENCE:

PRIMARY

PREVENTION

OF CANCER

295

9. Garrik, M. E., Cullen J. W., Gritz, E. R.. Vogt, 1‘. M., and West, L. J. Research on smoking behavior. Ntrt. Insf. Drug Ahsr Res. Monogr. 17, (1977). 10. Gori, G. B. Low risk cigarettes: A prescription. Science 194, 1243- 1246 (1976). Il. Gori, G. B. “Toward Less Hazardous Cigarettes,” Report No. 1, DHEW Pub]. No. (NIH) 76-905; Report No. 2, DHEW Publ. No. (NIH) 76-1111: Report No. 3, DHEW Publ. No. (NIH) 77-1280; Report No. 4, in press. 12. Haenszel, W., Ed. Epidemiological approaches to the study of cancer and other chronic diseases. Not. Crrnc,rr- Inst. Monogr. 19 (1966). 13. Hammond, E. C., Garfinkel, L., and Seidman, H. Some recent findings concerning cigarette smoking, in “Origins of Human Cancer” (H. H. Hiatt, J. D. Watson, and J. A. Winsten, Eds.). Book A, pp. 101~ 112. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1977. 14. Hecht, S. S., Chen, C. B., and Hoffmann, D. Tobacco-specific nitrosamines: Occurrence, formation, carcinogenicity, and metabolism. Ac~c~oro~t.cC/tern. Rcs. 12, 92-98 (1979). 15. Hoffmann, D., Adams, J. D., and Wynder, E. L. Unpublished data. 16. Hoffmann, D., Hecht, S. S., Schmeltz, I., LaVoie, E. and Wynder, E. L. Recent studies in tobacco carcinogenesis: Chemistry, bioassay, and bioassay monitoring. NCI-Smoking and Health Program Contractors Meeting. Savannah, GA, March 11 - 14, 1979, in press. 17. Hoffmann, D., Schmeltz, I., Hecht, S. S., and Wynder, E. L. Tobacco carcinogenesis, iti “Polycyclic Hydrocarbons and Cancer” (H. V. Gelboin and P. 0. T’so. Eds.), pp. 85-117. Academic Press, New York, 1978. 18. Hoffmann, D., and Wynder, E. L. Die quantitative Bestimmung von Phenolen in Tabakrauch. Bcitr. Ttrhr/~.fimc~li. 1, 101 - 106 (1961). 19. Jones. S. 0.. Ashburn, J. G.. Stewart, G. M., and Moser. G. P. “Denicotinizing Process.” U.S. Pat. 3 612 066, Oct. 12, 1971. 20. Moser, G. P. “A Process for Removing Nicotine From Tobacco.” U.S. Pat. 3 151 118, Sept. 29, 1964. 21. National Commission on Smoking and Public Policy. “A National Dilemma: Cigarette Smoking or the Health of Americans,” American Cancer Society, New York, 1978. 22. Royal College of Physicians. “Smoking and Health.” Pitman, London, 1962. 23. Russell, M. A. H. Smoking problems: An overview. Ntrt. /nst. f)rrr~l Ahrr.vr He.,. Mono,qr. 17, 13-33 (1977). 24. Sutton, S. R., Feyerabend, C., Cole, P. V., and Russell, M. A. H. Adjustment of smokers to dilution of tobacco smoke by ventilated cigarette holders. C/ill. P/lcrrrricrc,o/. The,. 24, 395-405 (1978). 25. Tso, T. C. Tobacco as potential food source and smoke material. &itr. 7trhrr~,fi,~sch. 9, 63-66 (1977). 26. Tso. T. C., and Gori, G. B. A novel approach in tobacco production as food source and smoke material-Year 1976 and Year 2000, in “Proceedings of the Sixth International Tobacco Science Congress.” pp. 81-86. Tokyo. Japan, Nov. 1976. 27. Tso. T. C., Lowe, R., and DeJong, D. W. Homogenized leaf curing. 1. Theoretical basis and some preliminary results. Beirr. T~rhrr~fiwsc~/r. 8, 44-51 ( 1975). 28. U.S. Public Health Service. Modification of smoking behavior, irk “Smoking and Health.” Chapt. 19. U.S. Public Health Service, 1979. 29. 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. 30. U.S. Public Health Service. Cancer, in “Smoking and Health: A Report to the Surgeon General.” U.S. Government Printing Office: 284-109/6619, 1979. 31. Wald, N. J. Mortality from lung cancer and coronary heart disease in relation to changes in smoking habit. Ltr?rcrt 1, 136- 138 (1976). 32. Weber, K. H. Recent changes in tobacco products and their acceptance by the consumer, in “Proceedings of the Sixth International Tobacco Scientific Congress,” pp. 47-63. Tokyo, Japan, Nov., 1976. 33. Wynder, E. L., and Goldsmith, R. The epidemiology of bladder cancer: A second look. C‘tr,ic,cr 40, l246- 1268 (1977). 34. Wynder, E. L., and Hoffmann, D. Some practical aspects of the smoking and cancer problem, Nrlr. Eng/. J. Med. 262, 540-543 ( 1960).

296

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TSO, AND

GORI

35. Wynder, E. L., and Hoffmann, D. Tobacco and health: A societal challenge. New Engl. J. Med. 300, 894-903 (1979). 36. Wynder, E. L., Hoffmann, D., and Gori, G. B. Smoking and health. I. Modifying the risk for the smoker. In “Proceedings of the Third World Conference on Smoking and Health.” DHEW Pub]. No. (NlH) 76-1221, 1976. 37. Wynder, E. L., Mabuchi, K., and Beattie, E. J. The epidemiology of lung cancer: Recent trends. JAMA 213, 2221-2228 (1970). 38. Wynder, E. L., Mabuchi, K., Maruchi, N., and Fortner, J. G. Epidemiology of cancer of the pancreas. J. Nut. Cuncer Inst. 50, 645-667 (1973). 39. Wynder, E. L., and Stellman, S. D. Comparative epidemiology of tobacco related cancers. Cancer Res. 37, 4608-4622 (1977). 40. Wynder, E. L., and Stellman, S. D. The impact of long-term filter cigarette usage on lung and larynx cancer risk: A case control study. J. Nut. Cancer Inst. 62, 471-477 (1979). 41. 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, (E. L. Wynder, D. Hoffmann, and G. B. Gori, Eds.). DHEW Pub]. No. (NIH) 76-1221: 57-65, 1976.